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1. Prognostic gene expression signature for high-grade serous ovarian cancer.

Author: Millstein, J, Budden, T, Goode, EL, Anglesio, MS, Talhouk, A, Intermaggio, MP, Leong, HS, Chen, S, Elatre, W, Gilks, B, Nazeran, T, Volchek, M, Bentley, RC, Wang, C, Chiu, DS, Kommoss, S, Leung, SCY, Senz, J, Lum, A, Chow, V, Sudderuddin, H, Mackenzie, R, George, J, AOCS Group, Fereday, S, Hendley, J, Traficante, N, Steed, H, Koziak, JM, Köbel, M, McNeish, IA, Goranova, T, Ennis, D, Macintyre, G, Silva De Silva, D, Ramón Y Cajal, T, García-Donas, J, Hernando Polo, S, Rodriguez, GC, Cushing-Haugen, KL, Harris, HR, Greene, CS, Zelaya, RA, Behrens, S, Fortner, RT, Sinn, P, Herpel, E, Lester, J, Lubiński, J, Oszurek, O, Tołoczko, A, Cybulski, C, Menkiszak, J, Pearce, CL, Pike, MC, Tseng, C, Alsop, J, Rhenius, V, Song, H, Jimenez-Linan, M, Piskorz, AM, Gentry-Maharaj, A, Karpinskyj, C, Widschwendter, M, Singh, N, Kennedy, CJ, Sharma, R, Harnett, PR, Gao, B, Johnatty, SE, Sayer, R, Boros, J, Winham, SJ, Keeney, GL, Kaufmann, SH, Larson, MC, Luk, H, Hernandez, BY, Thompson, PJ, Wilkens, LR, Carney, ME, Trabert, B, Lissowska, J, Brinton, L, Sherman, ME, Bodelon, C, Hinsley, S, Lewsley, LA, Glasspool, R, Banerjee, SN, Stronach, EA, Haluska, P, Ray-Coquard, I, Mahner, S, Winterhoff, B, Slamon, D, Levine, DA, Kelemen, LE, Benitez, J, and Chang-Claude, J
Subjects: AOCS Group, Humans, Cystadenocarcinoma, Serous, Ovarian Neoplasms, Prognosis, Proportional Hazards Models, Survival Analysis, Female, Transcriptome, formalin-fixed paraffin-embedded, gene expression, high-grade serous ovarian cancer, overall survival, prognosis, Rare Diseases, Genetic Testing, Cancer, Ovarian Cancer, Genetics, 4.4 Population screening, 4.2 Evaluation of markers and technologies, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract: BackgroundMedian overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC.Patients and methodsExpression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies.ResultsExpression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years.ConclusionThe OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.
Published: 2020

2. Bilateral Oophorectomy and All-Cause Mortality in Women With BRCA1 and BRCA2 Sequence Variations

Author: Kotsopoulos, J, Gronwald, J, Huzarski, T, Møller, P, Pal, T, Mccuaig, J, Singer, C, Karlan, B, Aeilts, A, Eng, C, Eisen, A, Bordeleau, L, Foulkes, W, Tung, N, Couch, F, Fruscio, R, Neuhausen, S, Zakalik, D, Cybulski, C, Metcalfe, K, Olopade, O, Sun, P, Lubinski, J, Narod, S, Kotsopoulos, Joanne, Gronwald, Jacek, Huzarski, Tomasz, Møller, Pål, Pal, Tuya, McCuaig, Jeanna M, Singer, Christian F, Karlan, Beth Y, Aeilts, Amber, Eng, Charis, Eisen, Andrea, Bordeleau, Louise, Foulkes, William D, Tung, Nadine, Couch, Fergus J, Fruscio, Robert, Neuhausen, Susan L, Zakalik, Dana, Cybulski, Cezary, Metcalfe, Kelly, Olopade, Olufunmilayo I, Sun, Ping, Lubinski, Jan, Narod, Steven A, Kotsopoulos, J, Gronwald, J, Huzarski, T, Møller, P, Pal, T, Mccuaig, J, Singer, C, Karlan, B, Aeilts, A, Eng, C, Eisen, A, Bordeleau, L, Foulkes, W, Tung, N, Couch, F, Fruscio, R, Neuhausen, S, Zakalik, D, Cybulski, C, Metcalfe, K, Olopade, O, Sun, P, Lubinski, J, Narod, S, Kotsopoulos, Joanne, Gronwald, Jacek, Huzarski, Tomasz, Møller, Pål, Pal, Tuya, McCuaig, Jeanna M, Singer, Christian F, Karlan, Beth Y, Aeilts, Amber, Eng, Charis, Eisen, Andrea, Bordeleau, Louise, Foulkes, William D, Tung, Nadine, Couch, Fergus J, Fruscio, Robert, Neuhausen, Susan L, Zakalik, Dana, Cybulski, Cezary, Metcalfe, Kelly, Olopade, Olufunmilayo I, Sun, Ping, Lubinski, Jan, and Narod, Steven A
Abstract: IMPORTANCE Preventive bilateral salpingo-oophorectomy is offered to women at high risk of ovarian cancer who carry a pathogenic variant in BRCA1 or BRCA2; however, the association of oophorectomy with all-cause mortality has not been clearly defined. OBJECTIVE To evaluate the association between bilateral oophorectomy and all-cause mortality among women with a BRCA1 or BRCA2 sequence variation. DESIGN, SETTING, AND PARTICIPANTS In this international, longitudinal cohort study ofwomen with BRCA sequence variations, information on bilateral oophorectomy was obtained via biennial questionnaire. Participants were women with a BRCA1 or BRCA2 sequence variation, no prior history of cancer, and at least 1 follow-up questionnaire completed. Women were followed up from age 35 to 75 years for incident cancers and deaths. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs for all-cause mortality associated with a bilateral oophorectomy (time dependent). Data analysis was performed from January 1 to June 1, 2023. EXPOSURES Self-reported bilateral oophorectomy (with or without salpingectomy). MAIN OUTCOMES AND MEASURES All-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality. RESULTS There were 4332 women (mean age, 42.6 years) enrolled in the cohort, of whom 2932 (67.8%) chose to undergo a preventive oophorectomy at a mean (range) age of 45.4 (23.0-77.0) years. After a mean follow-up of 9.0 years, 851 women had developed cancer and 228 had died; 57 died of ovarian or fallopian tube cancer, 58 died of breast cancer, 16 died of peritoneal cancer, and 97 died of other causes. The age-adjusted HR for all-cause mortality associated with oophorectomy was 0.32 (95% CI, 0.24-0.42; P < .001). The age-adjusted HR was 0.28 (95% CI, 0.20-0.38; P < .001) and 0.43 (95% CI, 0.22-0.90; P = .03) for women with BRCA1 and BRCA2 sequence variations, respectively. For women with BRCA1 sequence variations, the estima
Published: 2024

3. MRI Surveillance and Breast Cancer Mortality in Women With BRCA1 and BRCA2 Sequence Variations

Author: Lubinski, J, Kotsopoulos, J, Moller, P, Pal, T, Eisen, A, Peck, L, Karlan, B, Aeilts, A, Eng, C, Bordeleau, L, Foulkes, W, Tung, N, Couch, F, Fruscio, R, Ramon Y Cajal, T, Singer, C, Neuhausen, S, Zakalik, D, Cybulski, C, Gronwald, J, Huzarski, T, Stempa, K, Dungan, J, Cullinane, C, Olopade, O, Metcalfe, K, Sun, P, Narod, S, Lubinski, Jan, Kotsopoulos, Joanne, Moller, Pal, Pal, Tuya, Eisen, Andrea, Peck, Larissa, Karlan, Beth Y, Aeilts, Amber, Eng, Charis, Bordeleau, Louise, Foulkes, William D, Tung, Nadine, Couch, Fergus J, Fruscio, Robert, Ramon Y Cajal, Teresa, Singer, Christian F, Neuhausen, Susan L, Zakalik, Dana, Cybulski, Cezary, Gronwald, Jacek, Huzarski, Tomasz, Stempa, Klaudia, Dungan, Jeffrey, Cullinane, Carey, Olopade, Olufunmilayo I, Metcalfe, Kelly, Sun, Ping, Narod, Steven A, Lubinski, J, Kotsopoulos, J, Moller, P, Pal, T, Eisen, A, Peck, L, Karlan, B, Aeilts, A, Eng, C, Bordeleau, L, Foulkes, W, Tung, N, Couch, F, Fruscio, R, Ramon Y Cajal, T, Singer, C, Neuhausen, S, Zakalik, D, Cybulski, C, Gronwald, J, Huzarski, T, Stempa, K, Dungan, J, Cullinane, C, Olopade, O, Metcalfe, K, Sun, P, Narod, S, Lubinski, Jan, Kotsopoulos, Joanne, Moller, Pal, Pal, Tuya, Eisen, Andrea, Peck, Larissa, Karlan, Beth Y, Aeilts, Amber, Eng, Charis, Bordeleau, Louise, Foulkes, William D, Tung, Nadine, Couch, Fergus J, Fruscio, Robert, Ramon Y Cajal, Teresa, Singer, Christian F, Neuhausen, Susan L, Zakalik, Dana, Cybulski, Cezary, Gronwald, Jacek, Huzarski, Tomasz, Stempa, Klaudia, Dungan, Jeffrey, Cullinane, Carey, Olopade, Olufunmilayo I, Metcalfe, Kelly, Sun, Ping, and Narod, Steven A
Abstract: IMPORTANCE Magnetic resonance imaging (MRI) surveillance is offered to women with a pathogenic variant in the BRCA1 or BRCA2 gene who face a high lifetime risk of breast cancer. Surveillance with MRI is effective in downstaging breast cancers, but the association of MRI surveillance with mortality risk has not been well defined. OBJECTIVE To compare breast cancer mortality rates in women with a BRCA1 or BRCA2 sequence variation who entered an MRI surveillance program with those who did not. DESIGN, SETTING, AND PARTICIPANTS Women with a BRCA1 or BRCA2 sequence variation were identified from 59 participating centers in 11 countries. Participants completed a baseline questionnaire between 1995 and 2015 and a follow-up questionnaire every 2 years to document screening histories, incident cancers, and vital status. Women who had breast cancer, a screening MRI examination, or bilateral mastectomy prior to enrollment were excluded. Participants were followed up from age 30 years (or the date of the baseline questionnaire, whichever was later) until age 75 years, the last follow-up, or death from breast cancer. Data were analyzed from January 1 to July 31, 2023. EXPOSURES Entrance into an MRI surveillance program. MAIN OUTCOMES AND MEASURES Cox proportional hazards modelingwas used to estimate the hazard ratios (HRs) and 95% CIs for breast cancer mortality associated with MRI surveillance compared with no MRI surveillance using a time-dependent analysis. RESULTS A total of 2488 women (mean [range] age at study entry 41.2 [30-69] years), with a sequence variation in the BRCA1 (n = 2004) or BRCA2 (n = 484) genes were included in the analysis. Of these participants, 1756 (70.6%) had at least 1 screening MRI examination and 732 women (29.4%) did not. After a mean follow-up of 9.2 years, 344 women (13.8%) developed breast cancer and 35 women (1.4%) died of breast cancer. The age-adjusted HRs for breast cancer mortality associated with entering an MRI surveillance program were 0
Published: 2024

4. Prognostic gene expression signature for high-grade serous ovarian cancer

Author: Bowtell, D., Chenevix-Trench, G., Green, A., Webb, P., DeFazio, A., Gertig, D., Traficante, N., Fereday, S., Moore, S., Hung, J., Harrap, K., Sadkowsky, T., Pandeya, N., Malt, M., Mellon, A., Robertson, R., Vanden Bergh, T., Jones, M., Mackenzie, P., Maidens, J., Nattress, K., Chiew, Y.E., Stenlake, A., Sullivan, H., Alexander, B., Ashover, P., Brown, S., Corrish, T., Green, L., Jackman, L., Ferguson, K., Martin, K., Martyn, A., Ranieri, B., White, J., Jayde, V., Mamers, P., Bowes, L., Galletta, L., Giles, D., Hendley, J., Alsop, K., Schmidt, T., Shirley, H., Ball, C., Young, C., Viduka, S., Tran, Hoa, Bilic, Sanela, Glavinas, Lydia, Brooks, Julia, Stuart-Harris, R., Kirsten, F., Rutovitz, J., Clingan, P., Glasgow, A., Proietto, A., Braye, S., Otton, G., Shannon, J., Bonaventura, T., Stewart, J., Begbie, S., Friedlander, M., Bell, D., Baron-Hay, S., Ferrier,a, A., Gard, G., Nevell, D., Pavlakis, N., Valmadre, S., Young, B., Camaris, C., Crouch, R., Edwards, L., Hacker, N., Marsden, D., Robertson, G., Beale, P., Beith, J., Carter, J., Dalrymple, C., Houghton, R., Russell, P., Links, M., Grygiel, J., Hill, J., Brand, A., Byth, K., Jaworski, R., Harnett, P., Sharma, R., Wain, G., Ward, B., Papadimos, D., Crandon, A., Cummings, M., Horwood, K., Obermair, A., Perrin, L., Wyld, D., Nicklin, J., Davy, M., Oehler, M.K., Hall, C., Dodd, T., Healy, T., Pittman, K., Henderson, D., Miller, J., Pierdes, J., Blomfield, P., Challis, D., McIntosh, R., Parker, A., Brown, B., Rome, R., Allen, D., Grant, P., Hyde, S., Laurie, R., Robbie, M., Healy, D., Jobling, T., Manolitsas, T., McNealage, J., Rogers, P., Susil, B., Sumithran, E., Simpson, I., Phillips, K., Rischin, D., Fox, S., Johnson, D., Lade, S., Loughrey, M., O’Callaghan, N., Murray, W., Waring, P., Billson, V., Pyman, J., Neesham, D., Quinn, M., Underhill, C., Bell, R., Ng, L.F., Blum, R., Ganju, V., Hammond, I., Leung, Y., McCartney, A., Buck, M., Haviv, I., Purdie, D., Whiteman, D., Zeps, N., Millstein, J., Budden, T., Goode, E.L., Anglesio, M.S., Talhouk, A., Intermaggio, M.P., Leong, H.S., Chen, S., Elatre, W., Gilks, B., Nazeran, T., Volchek, M., Bentley, R.C., Wang, C., Chiu, D.S., Kommoss, S., Leung, S.C.Y., Senz, J., Lum, A., Chow, V., Sudderuddin, H., Mackenzie, R., George, J., Steed, H., Koziak, J.M., Köbel, M., McNeish, I.A., Goranova, T., Ennis, D., Macintyre, G., Silva De Silva, D., Ramón y Cajal, T., García-Donas, J., Hernando Polo, S., Rodriguez, G.C., Cushing-Haugen, K.L., Harris, H.R., Greene, C.S., Zelaya, R.A., Behrens, S., Fortner, R.T., Sinn, P., Herpel, E., Lester, J., Lubiński, J., Oszurek, O., Tołoczko, A., Cybulski, C., Menkiszak, J., Pearce, C.L., Pike, M.C., Tseng, C., Alsop, J., Rhenius, V., Song, H., Jimenez-Linan, M., Piskorz, A.M., Gentry-Maharaj, A., Karpinskyj, C., Widschwendter, M., Singh, N., Kennedy, C.J., Harnett, P.R., Gao, B., Johnatty, S.E., Sayer, R., Boros, J., Winham, S.J., Keeney, G.L., Kaufmann, S.H., Larson, M.C., Luk, H., Hernandez, B.Y., Thompson, P.J., Wilkens, L.R., Carney, M.E., Trabert, B., Lissowska, J., Brinton, L., Sherman, M.E., Bodelon, C., Hinsley, S., Lewsley, L.A., Glasspool, R., Banerjee, S.N., Stronach, E.A., Haluska, P., Ray-Coquard, I., Mahner, S., Winterhoff, B., Slamon, D., Levine, D.A., Kelemen, L.E., Benitez, J., Chang-Claude, J., Gronwald, J., Wu, A.H., Menon, U., Goodman, M.T., Schildkraut, J.M., Wentzensen, N., Brown, R., Berchuck, A., deFazio, A., Gayther, S.A., García, M.J., Henderson, M.J., Rossing, M.A., Beeghly-Fadiel, A., Fasching, P.A., Orsulic, S., Karlan, B.Y., Konecny, G.E., Huntsman, D.G., Bowtell, D.D., Brenton, J.D., Doherty, J.A., Pharoah, P.D.P., and Ramus, S.J.
Published: 2020
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5. Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

Author: Amankwah, EK, Lin, HY, Tyrer, JP, Lawrenson, K, Dennis, J, Chornokur, G, Aben, KKH, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chen, Z, Chen, YA, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, du Bois, A, Despierre, E, Dicks, E, Doherty, JA, Dörk, T, Dürst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, BT, Karlan, BY, Jim, H, Kellar, M, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lim, BK, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, Mcguire, V, Mclaughlin, JR, Mcneish, I, Menon, U, Milne, RL, Modugno, F, Moysich, KB, Ness, RB, Nevanlinna, H, Eilber, U, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, and Weber, RP
Subjects: Epidemiology, Public Health and Health Services, Genetics
Abstract: Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value
Published: 2015

6. Erratum: Correction to: Survival from breast cancer in women with a BRCA2 mutation by treatment (British journal of cancer (2021) 124 9 (1524-1532))

Author: Evans D. G., Evans, D, Phillips, K, Milne, R, Fruscio, R, Cybulski, C, Gronwald, J, Lubinski, J, Huzarski, T, Hyder, Z, Forde, C, Metcalfe, K, Senter, L, Weitzel, J, Tung, N, Zakalik, D, Ekholm, M, Sun, P, Narod, S, Evans D. G., Phillips K. -A., Milne R. L., Fruscio R., Cybulski C., Gronwald J., Lubinski J., Huzarski T., Hyder Z., Forde C., Metcalfe K., Senter L., Weitzel J., Tung N., Zakalik D., Ekholm M., Sun P., Narod S. A., Evans D. G., Evans, D, Phillips, K, Milne, R, Fruscio, R, Cybulski, C, Gronwald, J, Lubinski, J, Huzarski, T, Hyder, Z, Forde, C, Metcalfe, K, Senter, L, Weitzel, J, Tung, N, Zakalik, D, Ekholm, M, Sun, P, Narod, S, Evans D. G., Phillips K. -A., Milne R. L., Fruscio R., Cybulski C., Gronwald J., Lubinski J., Huzarski T., Hyder Z., Forde C., Metcalfe K., Senter L., Weitzel J., Tung N., Zakalik D., Ekholm M., Sun P., and Narod S. A.
Published: 2023

7. Contraceptive use and the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation

Author: Xia, Y, Gronwald, J, Karlan, B, Lubinski, J, Mccuaig, J, Brooks, J, Moller, P, Eisen, A, Sun, S, Senter, L, Bordeleau, L, Neuhausen, S, Singer, C, Tung, N, Foulkes, W, Sun, P, Narod, S, Kotsopoulos, J, Yerushalmi, R, Fruscio, R, Rastelli, A, Zovato, S, Hyder, Z, Huzarski, T, Cybulski, C, Sweet, K, Wood, M, Mckinnon, W, Elser, C, Pal, T, Wiesner, G, Friedman, E, Meschino, W, Snyder, C, Metcalfe, K, Poll, A, Gojska, N, Warner, E, Kim, R, Rosen, B, Demsky, R, Ainsworth, P, Panabaker, K, Steele, L, Saal, H, Serfas, K, Panchal, S, Cullinane, A, Reilly, R, Blum, J, Kwong, A, Rayson, D, Isaacs, C, Ramón y Cajal, T, Dungan, J, Cohen, S, Xia Y. Y., Gronwald J., Karlan B., Lubinski J., McCuaig J. M., Brooks J., Moller P., Eisen A., Sun S., Senter L., Bordeleau L., Neuhausen S. L., Singer C. F., Tung N., Foulkes W. D., Sun P., Narod S. A., Kotsopoulos J., Yerushalmi R., Fruscio R., Rastelli A., Zovato S, Hyder Z., Huzarski T., Cybulski C, Sweet K., Wood M., McKinnon W., Elser C., Pal T., Wiesner G., Friedman E., Meschino W., Snyder C., Metcalfe K., Poll A., Gojska N., Warner E., Kim R. H., Rosen B., Demsky R., Ainsworth P., Panabaker K., Steele L., Saal H., Serfas K., Panchal S., Cullinane A., Reilly R. E., Blum J. L., Kwong A., Cybulski C., Rayson D., Isaacs C., Ramón y Cajal T., Dungan J., Cohen S., Xia, Y, Gronwald, J, Karlan, B, Lubinski, J, Mccuaig, J, Brooks, J, Moller, P, Eisen, A, Sun, S, Senter, L, Bordeleau, L, Neuhausen, S, Singer, C, Tung, N, Foulkes, W, Sun, P, Narod, S, Kotsopoulos, J, Yerushalmi, R, Fruscio, R, Rastelli, A, Zovato, S, Hyder, Z, Huzarski, T, Cybulski, C, Sweet, K, Wood, M, Mckinnon, W, Elser, C, Pal, T, Wiesner, G, Friedman, E, Meschino, W, Snyder, C, Metcalfe, K, Poll, A, Gojska, N, Warner, E, Kim, R, Rosen, B, Demsky, R, Ainsworth, P, Panabaker, K, Steele, L, Saal, H, Serfas, K, Panchal, S, Cullinane, A, Reilly, R, Blum, J, Kwong, A, Rayson, D, Isaacs, C, Ramón y Cajal, T, Dungan, J, Cohen, S, Xia Y. Y., Gronwald J., Karlan B., Lubinski J., McCuaig J. M., Brooks J., Moller P., Eisen A., Sun S., Senter L., Bordeleau L., Neuhausen S. L., Singer C. F., Tung N., Foulkes W. D., Sun P., Narod S. A., Kotsopoulos J., Yerushalmi R., Fruscio R., Rastelli A., Zovato S, Hyder Z., Huzarski T., Cybulski C, Sweet K., Wood M., McKinnon W., Elser C., Pal T., Wiesner G., Friedman E., Meschino W., Snyder C., Metcalfe K., Poll A., Gojska N., Warner E., Kim R. H., Rosen B., Demsky R., Ainsworth P., Panabaker K., Steele L., Saal H., Serfas K., Panchal S., Cullinane A., Reilly R. E., Blum J. L., Kwong A., Cybulski C., Rayson D., Isaacs C., Ramón y Cajal T., Dungan J., and Cohen S.
Abstract: Background BRCA1 and BRCA2 (BRCA) mutation carriers face a high lifetime risk of developing ovarian cancer. Oral contraceptives are protective in this population; however, the impact of other types of contraception (e.g. intrauterine devices, implants, injections) is unknown. We undertook a matched case-control study to evaluate the relationship between type of contraception and risk of ovarian cancer among women with BRCA mutations. Methods A total of 1733 matched pairs were included in this analysis. Women were matched according to year of birth, date of study entry, country of residence, BRCA mutation type and history of breast cancer. Detailed information on hormonal, reproductive and lifestyle exposures were collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with each contraceptive exposure. Results Ever use of any contraceptive was significantly associated with reduced risk of ovarian cancer (OR = 0.62; 95% CI 0.52–0.75; P < 0.0001), which was driven by significant inverse associations with oral contraceptives (OR = 0.66; 95% CI 0.54–0.79; P < 0.0001) and contraceptive implants (OR = 0.30; 95% CI 0.12–0.73; P = 0.008). We observed a similar effect with use of injections (OR = 0.37; 95% CI 0.10–1.38; P = 0.14), but this did not achieve significance. No significant associations were observed between patterns of intrauterine device use and risk of ovarian cancer. Conclusions These findings support a protective effect of oral contraceptives and implants on risk of ovarian cancer among women with BRCA mutations. The possible protective effect of injections requires further evaluation.
Published: 2022

8. CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

Author: Kang, E-Y, Weir, A, Meagher, NS, Farrington, K, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Bolithon, A, Popovic, G, Leung, B, Tang, K, Lambie, N, Millstein, J, Alsop, J, Anglesio, MS, Ataseven, B, Barlow, E, Beckmann, MW, Berger, J, Bisinotto, C, Boesmueller, H, Boros, J, Brand, AH, Brooks-Wilson, A, Brucker, SY, Carney, ME, Casablanca, Y, Cazorla-Jimenez, A, Cohen, PA, Conrads, TP, Cook, LS, Coulson, P, Courtney-Brooks, M, Cramer, DW, Crowe, P, Cunningham, JM, Cybulski, C, Darcy, KM, El-Bahrawy, MA, Elishaev, E, Erber, R, Farrell, R, Fereday, S, Fischer, A, Garcia, MJ, Gayther, SA, Gentry-Maharaj, A, Gilks, CB, Grube, M, Harnett, PR, Harrington, SP, Harter, P, Hartmann, A, Hecht, JL, Heikaus, S, Hein, A, Heitz, F, Hendley, J, Hernandez, BY, Hernando Polo, S, Heublein, S, Hirasawa, A, Hogdall, E, Hogdall, CK, Horlings, HM, Huntsman, DG, Huzarski, T, Jewell, A, Jimenez-Linan, M, Jones, ME, Kaufmann, SH, Kennedy, CJ, Khabele, D, Kommoss, FKF, Kruitwagen, RFPM, Lambrechts, D, Le, ND, Lener, M, Lester, J, Leung, Y, Linder, A, Loverix, L, Lubinski, J, Madan, R, Maxwell, GL, Modugno, F, Neuhausen, SL, Olawaiye, A, Olbrecht, S, Orsulic, S, Palacios, J, Pearce, CL, Pike, MC, Quinn, CM, Mohan, GR, Rodriguez-Antona, C, Ruebner, M, Ryan, A, Salfinger, SG, Sasamoto, N, Schildkraut, JM, Schoemaker, MJ, Shah, M, Sharma, R, Shvetsov, YB, Singh, N, Sonke, GS, Steele, L, Stewart, CJR, Sundfeldt, K, Swerdlow, AJ, Talhouk, A, Tan, A, Taylor, SE, Terry, KL, Toloczko, A, Traficante, N, Van de Vijver, KK, van der Aa, MA, Van Gorp, T, Van Nieuwenhuysen, E, Van-Wagensveld, L, Vergote, I, Vierkant, RA, Wang, C, Wilkens, LR, Winham, SJ, Wu, AH, Benitez, J, Berchuck, A, Candido Dos Reis, FJ, DeFazio, A, Fasching, PA, Goode, EL, Goodman, MT, Gronwald, J, Karlan, BY, Kommoss, S, Menon, U, Sinn, H-P, Staebler, A, Brenton, JD, Bowtell, DD, Pharoah, PDP, Ramus, SJ, Kobel, M, Kang, E-Y, Weir, A, Meagher, NS, Farrington, K, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Bolithon, A, Popovic, G, Leung, B, Tang, K, Lambie, N, Millstein, J, Alsop, J, Anglesio, MS, Ataseven, B, Barlow, E, Beckmann, MW, Berger, J, Bisinotto, C, Boesmueller, H, Boros, J, Brand, AH, Brooks-Wilson, A, Brucker, SY, Carney, ME, Casablanca, Y, Cazorla-Jimenez, A, Cohen, PA, Conrads, TP, Cook, LS, Coulson, P, Courtney-Brooks, M, Cramer, DW, Crowe, P, Cunningham, JM, Cybulski, C, Darcy, KM, El-Bahrawy, MA, Elishaev, E, Erber, R, Farrell, R, Fereday, S, Fischer, A, Garcia, MJ, Gayther, SA, Gentry-Maharaj, A, Gilks, CB, Grube, M, Harnett, PR, Harrington, SP, Harter, P, Hartmann, A, Hecht, JL, Heikaus, S, Hein, A, Heitz, F, Hendley, J, Hernandez, BY, Hernando Polo, S, Heublein, S, Hirasawa, A, Hogdall, E, Hogdall, CK, Horlings, HM, Huntsman, DG, Huzarski, T, Jewell, A, Jimenez-Linan, M, Jones, ME, Kaufmann, SH, Kennedy, CJ, Khabele, D, Kommoss, FKF, Kruitwagen, RFPM, Lambrechts, D, Le, ND, Lener, M, Lester, J, Leung, Y, Linder, A, Loverix, L, Lubinski, J, Madan, R, Maxwell, GL, Modugno, F, Neuhausen, SL, Olawaiye, A, Olbrecht, S, Orsulic, S, Palacios, J, Pearce, CL, Pike, MC, Quinn, CM, Mohan, GR, Rodriguez-Antona, C, Ruebner, M, Ryan, A, Salfinger, SG, Sasamoto, N, Schildkraut, JM, Schoemaker, MJ, Shah, M, Sharma, R, Shvetsov, YB, Singh, N, Sonke, GS, Steele, L, Stewart, CJR, Sundfeldt, K, Swerdlow, AJ, Talhouk, A, Tan, A, Taylor, SE, Terry, KL, Toloczko, A, Traficante, N, Van de Vijver, KK, van der Aa, MA, Van Gorp, T, Van Nieuwenhuysen, E, Van-Wagensveld, L, Vergote, I, Vierkant, RA, Wang, C, Wilkens, LR, Winham, SJ, Wu, AH, Benitez, J, Berchuck, A, Candido Dos Reis, FJ, DeFazio, A, Fasching, PA, Goode, EL, Goodman, MT, Gronwald, J, Karlan, BY, Kommoss, S, Menon, U, Sinn, H-P, Staebler, A, Brenton, JD, Bowtell, DD, Pharoah, PDP, Ramus, SJ, and Kobel, M
Abstract: BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.
Published: 2023

9. Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study

Author: Weir, A, Kang, E-Y, Meagher, NS, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Gentry-Maharaj, A, Ryan, A, Singh, N, Widschwendter, M, Alsop, J, Anglesio, MS, Beckmann, MW, Berger, J, Bisinotto, C, Boros, J, Brand, AH, Brenton, JD, Brooks-Wilson, A, Carney, ME, Cunningham, JM, Cushing-Haugen, KL, Cybulski, C, Elishaev, E, Erber, R, Fereday, S, Fischer, A, Paz-Ares, L, Gayarre, J, Gilks, BC, Grube, M, Harnett, PR, Harris, HR, Hartmann, A, Hein, A, Hendley, J, Hernandez, BY, Heublein, S, Huang, Y, Huzarski, T, Jakubowska, A, Jimenez-Linan, M, Kennedy, CJ, Kommoss, FKF, Koziak, JM, Kraemer, B, Le, ND, Lesnock, J, Lester, J, Lubinski, J, Menkiszak, J, Ney, B, Olawaiye, A, Orsulic, S, Osorio, A, Robles-Diaz, L, Ruebner, M, Shah, M, Sharma, R, Shvetsov, YB, Steed, H, Talhouk, A, Taylor, SE, Traficante, N, Vierkant, RA, Wang, C, Wilkens, LR, Winham, SJ, Benitez, J, Berchuck, A, Bowtell, DD, Candido dos Reis, FJ, Cook, LS, DeFazio, A, Doherty, JA, Fasching, PA, Garcia, MJ, Goode, EL, Goodman, MT, Gronwald, J, Huntsman, DG, Karlan, BY, Kommoss, S, Modugno, F, Schildkraut, JM, Sinn, H-P, Staebler, A, Kelemen, LE, Ford, CE, Menon, U, Pharoah, PDP, Koebel, M, Ramus, SJ, Bowtell, D, Brand, A, Harnett, P, Weir, A, Kang, E-Y, Meagher, NS, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Gentry-Maharaj, A, Ryan, A, Singh, N, Widschwendter, M, Alsop, J, Anglesio, MS, Beckmann, MW, Berger, J, Bisinotto, C, Boros, J, Brand, AH, Brenton, JD, Brooks-Wilson, A, Carney, ME, Cunningham, JM, Cushing-Haugen, KL, Cybulski, C, Elishaev, E, Erber, R, Fereday, S, Fischer, A, Paz-Ares, L, Gayarre, J, Gilks, BC, Grube, M, Harnett, PR, Harris, HR, Hartmann, A, Hein, A, Hendley, J, Hernandez, BY, Heublein, S, Huang, Y, Huzarski, T, Jakubowska, A, Jimenez-Linan, M, Kennedy, CJ, Kommoss, FKF, Koziak, JM, Kraemer, B, Le, ND, Lesnock, J, Lester, J, Lubinski, J, Menkiszak, J, Ney, B, Olawaiye, A, Orsulic, S, Osorio, A, Robles-Diaz, L, Ruebner, M, Shah, M, Sharma, R, Shvetsov, YB, Steed, H, Talhouk, A, Taylor, SE, Traficante, N, Vierkant, RA, Wang, C, Wilkens, LR, Winham, SJ, Benitez, J, Berchuck, A, Bowtell, DD, Candido dos Reis, FJ, Cook, LS, DeFazio, A, Doherty, JA, Fasching, PA, Garcia, MJ, Goode, EL, Goodman, MT, Gronwald, J, Huntsman, DG, Karlan, BY, Kommoss, S, Modugno, F, Schildkraut, JM, Sinn, H-P, Staebler, A, Kelemen, LE, Ford, CE, Menon, U, Pharoah, PDP, Koebel, M, Ramus, SJ, Bowtell, D, Brand, A, and Harnett, P
Abstract: BACKGROUND: Recently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC. METHODS: Two prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis. RESULTS: Consistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p < 0.0001). GMNN protein expression was not significantly associated with overall HSGC patient survival. However, HGSCs with >35% GMNN expression showed a trend for better outcomes, though this was not significant. CONCLUSION: We provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.
Published: 2023

10. p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study

Author: Kobel, M, Kang, E-Y, Weir, A, Rambau, PF, Lee, C-H, Nelson, GS, Ghatage, P, Meagher, NS, Riggan, MJ, Alsop, J, Anglesio, MS, Beckmann, MW, Bisinotto, C, Boisen, M, Boros, J, Brand, AH, Brooks-Wilson, A, Carney, ME, Coulson, P, Courtney-Brooks, M, Cushing-Haugen, KL, Cybulski, C, Deen, S, El-Bahrawy, MA, Elishaev, E, Erber, R, Fereday, S, Fischer, A, Gayther, SA, Barquin-Garcia, A, Gentry-Maharaj, A, Gilks, CB, Gronwald, H, Grube, M, Harnett, PR, Harris, HR, Hartkopf, AD, Hartmann, A, Hein, A, Hendley, J, Hernandez, BY, Huang, Y, Jakubowska, A, Jimenez-Linan, M, Jones, ME, Kennedy, CJ, Kluz, T, Koziak, JM, Lesnock, J, Lester, J, Lubinski, J, Longacre, TA, Lycke, M, Mateoiu, C, McCauley, BM, McGuire, V, Ney, B, Olawaiye, A, Orsulic, S, Osorio, A, Paz-Ares, L, Ramon Y Cajal, T, Rothstein, JH, Ruebner, M, Schoemaker, MJ, Shah, M, Sharma, R, Sherman, ME, Shvetsov, YB, Singh, N, Steed, H, Storr, SJ, Talhouk, A, Traficante, N, Wang, C, Whittemore, AS, Widschwendter, M, Wilkens, LR, Winham, SJ, Benitez, J, Berchuck, A, Bowtell, DD, Candido dos Reis, FJ, Campbell, I, Cook, LS, DeFazio, A, Doherty, JA, Fasching, PA, Fortner, RT, Garcia, MJ, Goodman, MT, Goode, EL, Gronwald, J, Huntsman, DG, Karlan, BY, Kelemen, LE, Kommoss, S, Le, ND, Martin, SG, Menon, U, Modugno, F, Pharoah, PDP, Schildkraut, JM, Sieh, W, Staebler, A, Sundfeldt, K, Swerdlow, AJ, Ramus, SJ, Brenton, JD, Kobel, M, Kang, E-Y, Weir, A, Rambau, PF, Lee, C-H, Nelson, GS, Ghatage, P, Meagher, NS, Riggan, MJ, Alsop, J, Anglesio, MS, Beckmann, MW, Bisinotto, C, Boisen, M, Boros, J, Brand, AH, Brooks-Wilson, A, Carney, ME, Coulson, P, Courtney-Brooks, M, Cushing-Haugen, KL, Cybulski, C, Deen, S, El-Bahrawy, MA, Elishaev, E, Erber, R, Fereday, S, Fischer, A, Gayther, SA, Barquin-Garcia, A, Gentry-Maharaj, A, Gilks, CB, Gronwald, H, Grube, M, Harnett, PR, Harris, HR, Hartkopf, AD, Hartmann, A, Hein, A, Hendley, J, Hernandez, BY, Huang, Y, Jakubowska, A, Jimenez-Linan, M, Jones, ME, Kennedy, CJ, Kluz, T, Koziak, JM, Lesnock, J, Lester, J, Lubinski, J, Longacre, TA, Lycke, M, Mateoiu, C, McCauley, BM, McGuire, V, Ney, B, Olawaiye, A, Orsulic, S, Osorio, A, Paz-Ares, L, Ramon Y Cajal, T, Rothstein, JH, Ruebner, M, Schoemaker, MJ, Shah, M, Sharma, R, Sherman, ME, Shvetsov, YB, Singh, N, Steed, H, Storr, SJ, Talhouk, A, Traficante, N, Wang, C, Whittemore, AS, Widschwendter, M, Wilkens, LR, Winham, SJ, Benitez, J, Berchuck, A, Bowtell, DD, Candido dos Reis, FJ, Campbell, I, Cook, LS, DeFazio, A, Doherty, JA, Fasching, PA, Fortner, RT, Garcia, MJ, Goodman, MT, Goode, EL, Gronwald, J, Huntsman, DG, Karlan, BY, Kelemen, LE, Kommoss, S, Le, ND, Martin, SG, Menon, U, Modugno, F, Pharoah, PDP, Schildkraut, JM, Sieh, W, Staebler, A, Sundfeldt, K, Swerdlow, AJ, Ramus, SJ, and Brenton, JD
Abstract: Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.
Published: 2023

11. Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.

Author: Wang, A, Shen, J, Rodriguez, AA, Saunders, EJ, Chen, F, Janivara, R, Darst, BF, Sheng, X, Xu, Y, Chou, AJ, Benlloch, S, Dadaev, T, Brook, MN, Plym, A, Sahimi, A, Hoffman, TJ, Takahashi, A, Matsuda, K, Momozawa, Y, Fujita, M, Laisk, T, Figuerêdo, J, Muir, K, Ito, S, Liu, X, Biobank Japan Project, Uchio, Y, Kubo, M, Kamatani, Y, Lophatananon, A, Wan, P, Andrews, C, Lori, A, Choudhury, PP, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokolorczyk, D, Lubinski, J, Rentsch, CT, Cho, K, Mcmahon, BH, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Røder, A, Stroomberg, HV, Batra, J, Chambers, S, Horvath, L, Clements, JA, Tilly, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordstrom, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, S, Cook, MB, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-É, Stanford, JL, Ostrander, EA, Koutros, S, Beane Freeman, LE, Stampfer, M, Wolk, A, Håkansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sørensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, Lu, Y-J, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gómez-Caamaño, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandão, A, Watya, S, Lubwama, A, Bensen, JT, Butler, EN, Mohler, JL, Taylor, JA, Kogevinas, M, Dierssen-Sotos, T, Castaño-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Pilie, P, Yu, Y, Bohlender, RJ, Gu, J, Strom, SS, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Brenner, H, Chen, X, Holleczek, B, Schöttker, B, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, CM, Rybicki, BA, Gamulin, M, Lessel, D, Kulis, T, Usmani, N, Abraham, A, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, J, Petrovics, G, Casey, G, Wang, Y, Tettey, Y, Lachance, J, Tang, W, Biritwum, RB, Adjei, AA, Tay, E, Truelove, A, Niwa, S, Yamoah, K, Govindasami, K, Chokkalingam, AP, Keaton, JM, Hellwege, JN, Clark, PE, Jalloh, M, Gueye, SM, Niang, L, Ogunbiyi, O, Shittu, O, Amodu, O, Adebiyi, AO, Aisuodionoe-Shadrach, OI, Ajibola, HO, Jamda, MA, Oluwole, OP, Nwegbu, M, Adusei, B, Mante, S, Darkwa-Abrahams, A, Diop, H, Gundell, SM, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Kachuri, L, Varma, R, McKean-Cowdin, R, Torres, M, Preuss, MH, Loos, RJF, Zawistowski, M, Zöllner, S, Lu, Z, Van Den Eeden, SK, Easton, DF, Ambs, S, Edwards, TL, Mägi, R, Rebbeck, TR, Fritsche, L, Chanock, SJ, Berndt, SI, Wiklund, F, Nakagawa, H, Witte, JS, Gaziano, JM, Justice, AC, Mancuso, N, Terao, C, Eeles, RA, Kote-Jarai, Z, Madduri, RK, Conti, DV, Haiman, CA, Wang, A, Shen, J, Rodriguez, AA, Saunders, EJ, Chen, F, Janivara, R, Darst, BF, Sheng, X, Xu, Y, Chou, AJ, Benlloch, S, Dadaev, T, Brook, MN, Plym, A, Sahimi, A, Hoffman, TJ, Takahashi, A, Matsuda, K, Momozawa, Y, Fujita, M, Laisk, T, Figuerêdo, J, Muir, K, Ito, S, Liu, X, Biobank Japan Project, Uchio, Y, Kubo, M, Kamatani, Y, Lophatananon, A, Wan, P, Andrews, C, Lori, A, Choudhury, PP, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokolorczyk, D, Lubinski, J, Rentsch, CT, Cho, K, Mcmahon, BH, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Røder, A, Stroomberg, HV, Batra, J, Chambers, S, Horvath, L, Clements, JA, Tilly, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordstrom, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, S, Cook, MB, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-É, Stanford, JL, Ostrander, EA, Koutros, S, Beane Freeman, LE, Stampfer, M, Wolk, A, Håkansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sørensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, Lu, Y-J, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gómez-Caamaño, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandão, A, Watya, S, Lubwama, A, Bensen, JT, Butler, EN, Mohler, JL, Taylor, JA, Kogevinas, M, Dierssen-Sotos, T, Castaño-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Pilie, P, Yu, Y, Bohlender, RJ, Gu, J, Strom, SS, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Brenner, H, Chen, X, Holleczek, B, Schöttker, B, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, CM, Rybicki, BA, Gamulin, M, Lessel, D, Kulis, T, Usmani, N, Abraham, A, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, J, Petrovics, G, Casey, G, Wang, Y, Tettey, Y, Lachance, J, Tang, W, Biritwum, RB, Adjei, AA, Tay, E, Truelove, A, Niwa, S, Yamoah, K, Govindasami, K, Chokkalingam, AP, Keaton, JM, Hellwege, JN, Clark, PE, Jalloh, M, Gueye, SM, Niang, L, Ogunbiyi, O, Shittu, O, Amodu, O, Adebiyi, AO, Aisuodionoe-Shadrach, OI, Ajibola, HO, Jamda, MA, Oluwole, OP, Nwegbu, M, Adusei, B, Mante, S, Darkwa-Abrahams, A, Diop, H, Gundell, SM, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Kachuri, L, Varma, R, McKean-Cowdin, R, Torres, M, Preuss, MH, Loos, RJF, Zawistowski, M, Zöllner, S, Lu, Z, Van Den Eeden, SK, Easton, DF, Ambs, S, Edwards, TL, Mägi, R, Rebbeck, TR, Fritsche, L, Chanock, SJ, Berndt, SI, Wiklund, F, Nakagawa, H, Witte, JS, Gaziano, JM, Justice, AC, Mancuso, N, Terao, C, Eeles, RA, Kote-Jarai, Z, Madduri, RK, Conti, DV, and Haiman, CA
Abstract: The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
Published: 2023

12. 41P HLA genotypes modify the age-related penetrance of BRCA1 pathogenic variants in breast cancer patients

Author: Kuligina, E.S., Romanko, A.A., Martianov, A.S., Gorgul, J.A., Kashyap, A., Cybulski, C., Lubinski, J., Trofimov, D.S., Jankevic, T., and Imyanitov, E.
Published: 2023
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13. Breast cancer risk after age 60 among BRCA1 and BRCA2 mutation carriers

Author: Stjepanovic, N, Lubinski, J, Moller, P, Randall Armel, S, Foulkes, W, Tung, N, Neuhausen, S, Kotsopoulos, J, Sun, P, Sun, S, Eisen, A, Narod, S, Senter, L, Couch, C, Fruscio, R, Weitzel, J, Olopade, O, Singer, C, Pal, T, Huzarski, T, Cybulski, C, Sweet, K, Zakalik, D, Wood, M, Mckinnon, W, Elser, C, Wiesner, G, Friedman, E, Meschino, W, Snyder, C, Metcalfe, K, Poll, A, Warner, E, Kim, R, Demsky, R, Ainsworth, P, Steele, L, Saal, H, Serfas, K, Panchal, S, Cullinane, C, Reilly, R, Blum, J, Kwong, A, Rayson, D, Cajal, T, Dungan, J, Yerushalmi, R, Ginsburg, O, Schraeder, I, Cohen, S, Lemirelemire, E, Zovato, S, Rastelli, A, Gronwald, J, Mccuaig, J, Karlan, B, Bordeleau, L, Stjepanovic N., Lubinski J., Moller P., Randall Armel S., Foulkes W. D., Tung N., Neuhausen S. L., Kotsopoulos J., Sun P., Sun S., Eisen A., Narod S. A., Senter L., Couch C. E. F., Fruscio R., Weitzel J. N., Olopade O., Singer C. F., Pal T., Huzarski T., Cybulski C., Sweet K., Zakalik D., Wood M., McKinnon W., Elser C., Wiesner G., Friedman E., Meschino W., Snyder C., Metcalfe K., Poll A., Warner E., Kim R., Demsky R., Ainsworth P., Steele L., Saal H., Serfas K., Panchal S., Cullinane C. A., Reilly R. E., Blum J. L., Kwong A., Rayson D., Cajal T. R., Dungan J., Yerushalmi R., Ginsburg O., Schraeder I., Cohen S., LemireLemire E., Zovato S., Rastelli A., Gronwald J., McCuaig J., Karlan B., Bordeleau L., Stjepanovic, N, Lubinski, J, Moller, P, Randall Armel, S, Foulkes, W, Tung, N, Neuhausen, S, Kotsopoulos, J, Sun, P, Sun, S, Eisen, A, Narod, S, Senter, L, Couch, C, Fruscio, R, Weitzel, J, Olopade, O, Singer, C, Pal, T, Huzarski, T, Cybulski, C, Sweet, K, Zakalik, D, Wood, M, Mckinnon, W, Elser, C, Wiesner, G, Friedman, E, Meschino, W, Snyder, C, Metcalfe, K, Poll, A, Warner, E, Kim, R, Demsky, R, Ainsworth, P, Steele, L, Saal, H, Serfas, K, Panchal, S, Cullinane, C, Reilly, R, Blum, J, Kwong, A, Rayson, D, Cajal, T, Dungan, J, Yerushalmi, R, Ginsburg, O, Schraeder, I, Cohen, S, Lemirelemire, E, Zovato, S, Rastelli, A, Gronwald, J, Mccuaig, J, Karlan, B, Bordeleau, L, Stjepanovic N., Lubinski J., Moller P., Randall Armel S., Foulkes W. D., Tung N., Neuhausen S. L., Kotsopoulos J., Sun P., Sun S., Eisen A., Narod S. A., Senter L., Couch C. E. F., Fruscio R., Weitzel J. N., Olopade O., Singer C. F., Pal T., Huzarski T., Cybulski C., Sweet K., Zakalik D., Wood M., McKinnon W., Elser C., Wiesner G., Friedman E., Meschino W., Snyder C., Metcalfe K., Poll A., Warner E., Kim R., Demsky R., Ainsworth P., Steele L., Saal H., Serfas K., Panchal S., Cullinane C. A., Reilly R. E., Blum J. L., Kwong A., Rayson D., Cajal T. R., Dungan J., Yerushalmi R., Ginsburg O., Schraeder I., Cohen S., LemireLemire E., Zovato S., Rastelli A., Gronwald J., McCuaig J., Karlan B., and Bordeleau L.
Abstract: Purpose: It is not known whether the risk of breast cancer among BRCA1 and BRCA2 mutation carriers after age 60 is high enough to justify intensive screening or prophylactic surgery. Thus, we conducted a prospective analysis of breast cancer risk in BRCA1 and BRCA2 mutation carriers from age 60 until age 80. Methods: Subjects had no history of cancer and both breasts intact at age 60 (n = 699). Women were followed until a breast cancer diagnosis, prophylactic bilateral mastectomy or death. We calculated the annual cancer rate and cumulative incidence of breast cancer (invasive and in situ) from age 60 to age 80. We assessed the associations between hormone replacement therapy, family history of breast cancer and bilateral oophorectomy and breast cancer risk. Results: Over a mean follow-up of 7.9 years, 61 invasive and 20 in situ breast cancers were diagnosed in the cohort. The mean annual rate of invasive breast cancer was 1.8% for BRCA1 mutation carriers and 1.7% for BRCA2 mutation carriers. The cumulative risk of invasive breast cancer from age 60 to 80 was 20.1% for women with a BRCA1 mutation and was 17.3% for women with a BRCA2 mutation. Hormone replacement therapy, family history and oophorectomy were not associated with breast cancer risk. Conclusions: Findings from this large prospective study indicate that the risk of developing breast cancer remains high after age 60 in both BRCA1 and BRCA2 mutation carriers. These findings warrant further evaluation of the role of breast cancer screening in older mutation carriers.
Published: 2021

14. Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score

Author: Minh-Phuong, H-L, Karunamuni, R, Fan, CC, Asona, L, Thompson, WK, Martinez, ME, Eeles, RA, Kote-Jarai, Z, Muir, KR, Lophatananon, A, Schleutker, J, Pashayan, N, Batra, J, Groenberg, H, Neal, DE, Nordestgaard, BG, Tangen, CM, MacInnis, RJ, Wolk, A, Albanes, D, Haiman, CA, Travis, RC, Blot, WJ, Stanford, JL, Mucci, LA, West, CML, Nielsen, SF, Kibel, AS, Cussenot, O, Berndt, S, Koutros, S, Sorensen, KD, Cybulski, C, Grindedal, EM, Menegaux, F, Park, JY, Ingles, SA, Maier, C, Hamilton, RJ, Rosenstein, BS, Lu, Y-J, Watya, S, Vega, A, Kogevinas, M, Wiklund, F, Penney, KL, Huff, CD, Teixeira, MR, Multigner, L, Leach, RJ, Brenner, H, John, EM, Kaneva, R, Logothetis, CJ, Neuhausen, SL, De Ruyck, K, Ost, P, Razack, A, Newcomb, LF, Fowke, JH, Gamulin, M, Abraham, A, Claessens, F, Castelao, JE, Townsend, PA, Crawford, DC, Petrovics, G, van Schaik, RHN, Parent, M-E, Hu, JJ, Zheng, W, Mills, IG, Andreassen, OA, Dale, AM, Seibert, TM, Minh-Phuong, H-L, Karunamuni, R, Fan, CC, Asona, L, Thompson, WK, Martinez, ME, Eeles, RA, Kote-Jarai, Z, Muir, KR, Lophatananon, A, Schleutker, J, Pashayan, N, Batra, J, Groenberg, H, Neal, DE, Nordestgaard, BG, Tangen, CM, MacInnis, RJ, Wolk, A, Albanes, D, Haiman, CA, Travis, RC, Blot, WJ, Stanford, JL, Mucci, LA, West, CML, Nielsen, SF, Kibel, AS, Cussenot, O, Berndt, S, Koutros, S, Sorensen, KD, Cybulski, C, Grindedal, EM, Menegaux, F, Park, JY, Ingles, SA, Maier, C, Hamilton, RJ, Rosenstein, BS, Lu, Y-J, Watya, S, Vega, A, Kogevinas, M, Wiklund, F, Penney, KL, Huff, CD, Teixeira, MR, Multigner, L, Leach, RJ, Brenner, H, John, EM, Kaneva, R, Logothetis, CJ, Neuhausen, SL, De Ruyck, K, Ost, P, Razack, A, Newcomb, LF, Fowke, JH, Gamulin, M, Abraham, A, Claessens, F, Castelao, JE, Townsend, PA, Crawford, DC, Petrovics, G, van Schaik, RHN, Parent, M-E, Hu, JJ, Zheng, W, Mills, IG, Andreassen, OA, Dale, AM, and Seibert, TM
Abstract: BACKGROUND: Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets. METHODS: In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured. RESULTS: The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively. CONCLUSIONS: We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry d
Published: 2022

15. Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

Author: Meagher, NS, Gorringe, KL, Wakefield, M, Bolithon, A, Pang, CNI, Chiu, DS, Anglesio, MS, Mallitt, K-A, Doherty, JA, Harris, HR, Schildkraut, JM, Berchuck, A, Cushing-Haugen, KL, Chezar, K, Chou, A, Tan, A, Alsop, J, Barlow, E, Beckmann, MW, Boros, J, Bowtell, DDL, Brand, AH, Brenton, JD, Campbell, I, Cheasley, D, Cohen, J, Cybulski, C, Elishaev, E, Erber, R, Farrell, R, Fischer, A, Fu, Z, Gilks, B, Gill, AJ, Gourley, C, Grube, M, Harnett, PR, Hartmann, A, Hettiaratchi, A, Hogdall, CK, Huzarski, T, Jakubowska, A, Jimenez-Linan, M, Kennedy, CJ, Kim, B-G, Kim, J-W, Kim, J-H, Klett, K, Koziak, JM, Lai, T, Laslavic, A, Lester, J, Leung, Y, Li, N, Liauw, W, Lim, BWX, Linder, A, Lubinski, J, Mahale, S, Mateoiu, C, McInerny, S, Menkiszak, J, Minoo, P, Mittelstadt, S, Morris, D, Orsulic, S, Park, S-Y, Pearce, CL, Pearson, J, Pike, MC, Quinn, CM, Mohan, GR, Rao, J, Riggan, MJ, Ruebner, M, Salfinger, S, Scott, CL, Shah, M, Steed, H, Stewart, CJR, Subramanian, D, Sung, S, Tang, K, Timpson, P, Ward, RL, Wiedenhoefer, R, Thorne, H, Cohen, PA, Crowe, P, Fasching, PA, Gronwald, J, Hawkins, NJ, Hogdall, E, Huntsman, DG, James, PA, Karlan, BY, Kelemen, LE, Kommoss, S, Konecny, GE, Modugno, F, Park, SK, Staebler, A, Sundfeldt, K, Wu, AH, Talhouk, A, Pharoah, PDP, Anderson, L, DeFazio, A, Kobel, M, Friedlander, ML, Ramus, SJ, Meagher, NS, Gorringe, KL, Wakefield, M, Bolithon, A, Pang, CNI, Chiu, DS, Anglesio, MS, Mallitt, K-A, Doherty, JA, Harris, HR, Schildkraut, JM, Berchuck, A, Cushing-Haugen, KL, Chezar, K, Chou, A, Tan, A, Alsop, J, Barlow, E, Beckmann, MW, Boros, J, Bowtell, DDL, Brand, AH, Brenton, JD, Campbell, I, Cheasley, D, Cohen, J, Cybulski, C, Elishaev, E, Erber, R, Farrell, R, Fischer, A, Fu, Z, Gilks, B, Gill, AJ, Gourley, C, Grube, M, Harnett, PR, Hartmann, A, Hettiaratchi, A, Hogdall, CK, Huzarski, T, Jakubowska, A, Jimenez-Linan, M, Kennedy, CJ, Kim, B-G, Kim, J-W, Kim, J-H, Klett, K, Koziak, JM, Lai, T, Laslavic, A, Lester, J, Leung, Y, Li, N, Liauw, W, Lim, BWX, Linder, A, Lubinski, J, Mahale, S, Mateoiu, C, McInerny, S, Menkiszak, J, Minoo, P, Mittelstadt, S, Morris, D, Orsulic, S, Park, S-Y, Pearce, CL, Pearson, J, Pike, MC, Quinn, CM, Mohan, GR, Rao, J, Riggan, MJ, Ruebner, M, Salfinger, S, Scott, CL, Shah, M, Steed, H, Stewart, CJR, Subramanian, D, Sung, S, Tang, K, Timpson, P, Ward, RL, Wiedenhoefer, R, Thorne, H, Cohen, PA, Crowe, P, Fasching, PA, Gronwald, J, Hawkins, NJ, Hogdall, E, Huntsman, DG, James, PA, Karlan, BY, Kelemen, LE, Kommoss, S, Konecny, GE, Modugno, F, Park, SK, Staebler, A, Sundfeldt, K, Wu, AH, Talhouk, A, Pharoah, PDP, Anderson, L, DeFazio, A, Kobel, M, Friedlander, ML, and Ramus, SJ
Abstract: PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.
Published: 2022

16. Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8(+) TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas

Author: Heinze, K, Nazeran, TM, Lee, S, Kramer, P, Cairns, ES, Chiu, DS, Leung, SCY, Kang, EY, Meagher, NS, Kennedy, CJ, Boros, J, Kommoss, F, Vollert, H-W, Heitze, F, du Bois, A, Harter, P, Grube, M, Kraemer, B, Staebler, A, Kommoss, FKF, Heublein, S, Sinn, H-P, Singh, N, Laslavic, A, Elishaev, E, Olawaiye, A, Moysich, K, Modugno, F, Sharma, R, Brand, AH, Harnett, PR, DeFazio, A, Fortner, RT, Lubinski, J, Lener, M, Toloczko-Grabarek, A, Cybulski, C, Gronwald, H, Gronwald, J, Coulson, P, El-Bahrawy, MA, Jones, ME, Schoemaker, MJ, Swerdlow, AJ, Gorringe, KL, Campbell, I, Cook, L, Gayther, SA, Carney, ME, Shvetsov, YB, Hernandez, BY, Wilkens, LR, Goodman, MT, Mateoiu, C, Linder, A, Sundfeldt, K, Kelemen, LE, Gentry-Maharaj, A, Widschwendter, M, Menon, U, Bolton, KL, Alsop, J, Shah, M, Jimenez-Linan, M, Pharoah, PDP, Brenton, JD, Cushing-Haugen, KL, Harris, HR, Doherty, JA, Gilks, B, Ghatage, P, Huntsman, DG, Nelson, GS, Tinker, A, Lee, C-H, Goode, EL, Nelson, BH, Ramus, SJ, Kommoss, S, Talhouk, A, Kobel, M, Anglesio, MS, Heinze, K, Nazeran, TM, Lee, S, Kramer, P, Cairns, ES, Chiu, DS, Leung, SCY, Kang, EY, Meagher, NS, Kennedy, CJ, Boros, J, Kommoss, F, Vollert, H-W, Heitze, F, du Bois, A, Harter, P, Grube, M, Kraemer, B, Staebler, A, Kommoss, FKF, Heublein, S, Sinn, H-P, Singh, N, Laslavic, A, Elishaev, E, Olawaiye, A, Moysich, K, Modugno, F, Sharma, R, Brand, AH, Harnett, PR, DeFazio, A, Fortner, RT, Lubinski, J, Lener, M, Toloczko-Grabarek, A, Cybulski, C, Gronwald, H, Gronwald, J, Coulson, P, El-Bahrawy, MA, Jones, ME, Schoemaker, MJ, Swerdlow, AJ, Gorringe, KL, Campbell, I, Cook, L, Gayther, SA, Carney, ME, Shvetsov, YB, Hernandez, BY, Wilkens, LR, Goodman, MT, Mateoiu, C, Linder, A, Sundfeldt, K, Kelemen, LE, Gentry-Maharaj, A, Widschwendter, M, Menon, U, Bolton, KL, Alsop, J, Shah, M, Jimenez-Linan, M, Pharoah, PDP, Brenton, JD, Cushing-Haugen, KL, Harris, HR, Doherty, JA, Gilks, B, Ghatage, P, Huntsman, DG, Nelson, GS, Tinker, A, Lee, C-H, Goode, EL, Nelson, BH, Ramus, SJ, Kommoss, S, Talhouk, A, Kobel, M, and Anglesio, MS
Published: 2022

17. The impact of an expanded genetic testing program and selective oophorectomy on the incidence of ovarian cancer in West Pomerania

Author: Menkiszak, J., Sopik, V., Chudecka‐Głaz, A., Domagała, W., Urasińska, E., Symonowicz, H., Majdanik, E., Waloszczyk, P., Sycz, K., Świniarska, M., Huzarski, T., Cybulski, C., Debniak, T., Oszurek, O., Lubinski, J., Narod, S.A., and Gronwald, J.
Published: 2017
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18. 21P Analysis of germline variants in the immune response-related genes in BRCA1 mutation carriers: Possible modifying effect on age-dependent BRCA1 penetrance

Author: Kuligina, E.S., primary, Romanko, A.A., additional, Suspitsin, E.N., additional, Tumakova, A.V., additional, Martianov, A.S., additional, Bizin, I.V., additional, Gorgul, J., additional, Yanus, G.A., additional, Kashyap, A., additional, Cybulski, C., additional, Jakubowska, A., additional, Lubiński, J., additional, and Imyanitov, E.N., additional
Published: 2021
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19. Meeting abstracts from the Annual Conference on Hereditary Cancers 2016

Author: Cybulski, C. and KluÅºniak, W.
Subjects: Poles (European people) -- Genetic aspects -- Health aspects, Cancer -- Genetic aspects -- Risk factors -- Research, Gene mutation -- Research, Health
Abstract: Author(s): C. Cybulski[sup.1] , W. KluÅºniak[sup.1] , T. Huzarski[sup.1] , D. WokoÅorczyk[sup.1] , A. Kashyap[sup.1] , A. Jakubowska[sup.1] , M. Szwiec[sup.2] , T. Byrski[sup.1] , T. DÄbniak[sup.1] , B. Górski[sup.1] [...]
Published: 2017
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20. Mutations predisposing to breast cancer in 12 candidate genes in breast cancer patients from Poland

Author: Cybulski, C., Lubiński, J., Wokołorczyk, D., Kuźniak, W., Kashyap, A., Sopik, V., Huzarski, T., Gronwald, J., Byrski, T., Szwiec, M., Jakubowska, A., Górski, B., Dębniak, T., Narod, S. A, and Akbari, M. R
Published: 2015
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21. BRCA1 and BRCA2 mutations and the risk for colorectal cancer

Author: Sopik, V., Phelan, C., Cybulski, C., and Narod, S. A.
Published: 2015
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22. Recurrent mutations of BRCA1 and BRCA2 in Poland: an update

Author: Szwiec, M., Jakubowska, A., Górski, B., Huzarski, T., Tomiczek-Szwiec, J., Gronwald, J., Dębniak, T., Byrski, T., Kluźniak, W., Wokołorczyk, D., Birkenfeld, B., Akbari, M. R., Narod, S. A., Lubiński, J., and Cybulski, C.
Published: 2015
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23. Polygenic hazard score is associated with prostate cancer in multi-ethnic populations

Author: Huynh-Le, M.-P. (Minh-Phuong), Fan, C.C. (Chun Chieh), Karunamuni, R. (Roshan), Thompson, W.K. (Wesley K.), Martinez, M.E. (Maria Elena), Eeles, R. (Rosalind), Kote-Jarai, Z., Muir, K. (Kenneth), Schleutker, J. (Johanna), Pashayan, N. (Nora), Batra, J. (Jyotsna), Grönberg, H. (Henrik), Neal, D.E. (David E.), Donovan, J.L. (Jenny L.), Hamdy, F.C. (Freddie C.), Martin, R.M. (Richard M.), Nielsen, S.F. (Sune F.), Nordestgaard, B.G. (Børge), Wiklund, F. (Fredrik), Tangen, C.M. (Catherine M.), Giles, G.G. (Graham G.), Wolk, K. (Kerstin), Albanes, D. (Demetrius), Travis, S.P.L. (Simon), Blot, W.J. (William), Zheng, W. (Wei), Sanderson, M. (Maureen), Stanford, J.L. (Janet L.), Mucci, L.A. (Lorelei A.), West, C.M.L. (Catharine M. L.), Kibel, A. (Adam), Cussenot, O. (Olivier), Berndt, S.I. (Sonja), Koutros, S. (Stella), Sørensen, K.D. (Karina Dalsgaard), Cybulski, C. (Cezary), Grindedal, E.M. (Eli Marie), Menegaux, F. (Florence), Khaw, K.-T. (Kay-Tee), Park, J.Y. (Jong Y.), Ingles, S.A. (Sue), Maier, C. (Christiane), Hamilton, R.J. (Robert J.), Thibodeau, S.N. (Stephen), Rosenstein, B.S. (Barry S.), Lu, Y.-J. (Yong-Jie), Watya, S. (Stephen), Vega, A. (Ana), Kogevinas, M. (Manolis), Penney, K.L. (Kathryn L.), Huff, C. (Chad), Teixeira, M.R. (Manuel R.), Multigner, L. (Luc), Leach, R.J. (Robin J.), Cannon-Albright, L.A. (Lisa), Brenner, H. (Hermann), John, E.M. (Esther), Kaneva, R. (Radka), Logothetis, N.K. (Nikos), Floris, O.A.M., De Ruyck, K. (Kim), Pandha, H. (Hardev), Razack, A. (Azad), Newcomb, L.F. (Lisa F.), Fowke, J.H. (Jay H.), Gamulin, M. (Marija), Usmani, N. (Nawaid), Claessens, F. (Frank), Gago-Dominguez, M. (Manuela), Townsend, P.A. (Paul A.), Bush, W.S. (William S.), Roobol-Bouts, M.J. (Monique), Parent, M.-É. (Marie-Élise), Hu, J.J. (Jennifer J.), Mills, I.G. (Ian G.), Andreassen, O.A. (Ole), Dale, A.M. (Anders), Seibert, T.M. (Tyler M.), Huynh-Le, M.-P. (Minh-Phuong), Fan, C.C. (Chun Chieh), Karunamuni, R. (Roshan), Thompson, W.K. (Wesley K.), Martinez, M.E. (Maria Elena), Eeles, R. (Rosalind), Kote-Jarai, Z., Muir, K. (Kenneth), Schleutker, J. (Johanna), Pashayan, N. (Nora), Batra, J. (Jyotsna), Grönberg, H. (Henrik), Neal, D.E. (David E.), Donovan, J.L. (Jenny L.), Hamdy, F.C. (Freddie C.), Martin, R.M. (Richard M.), Nielsen, S.F. (Sune F.), Nordestgaard, B.G. (Børge), Wiklund, F. (Fredrik), Tangen, C.M. (Catherine M.), Giles, G.G. (Graham G.), Wolk, K. (Kerstin), Albanes, D. (Demetrius), Travis, S.P.L. (Simon), Blot, W.J. (William), Zheng, W. (Wei), Sanderson, M. (Maureen), Stanford, J.L. (Janet L.), Mucci, L.A. (Lorelei A.), West, C.M.L. (Catharine M. L.), Kibel, A. (Adam), Cussenot, O. (Olivier), Berndt, S.I. (Sonja), Koutros, S. (Stella), Sørensen, K.D. (Karina Dalsgaard), Cybulski, C. (Cezary), Grindedal, E.M. (Eli Marie), Menegaux, F. (Florence), Khaw, K.-T. (Kay-Tee), Park, J.Y. (Jong Y.), Ingles, S.A. (Sue), Maier, C. (Christiane), Hamilton, R.J. (Robert J.), Thibodeau, S.N. (Stephen), Rosenstein, B.S. (Barry S.), Lu, Y.-J. (Yong-Jie), Watya, S. (Stephen), Vega, A. (Ana), Kogevinas, M. (Manolis), Penney, K.L. (Kathryn L.), Huff, C. (Chad), Teixeira, M.R. (Manuel R.), Multigner, L. (Luc), Leach, R.J. (Robin J.), Cannon-Albright, L.A. (Lisa), Brenner, H. (Hermann), John, E.M. (Esther), Kaneva, R. (Radka), Logothetis, N.K. (Nikos), Floris, O.A.M., De Ruyck, K. (Kim), Pandha, H. (Hardev), Razack, A. (Azad), Newcomb, L.F. (Lisa F.), Fowke, J.H. (Jay H.), Gamulin, M. (Marija), Usmani, N. (Nawaid), Claessens, F. (Frank), Gago-Dominguez, M. (Manuela), Townsend, P.A. (Paul A.), Bush, W.S. (William S.), Roobol-Bouts, M.J. (Monique), Parent, M.-É. (Marie-Élise), Hu, J.J. (Jennifer J.), Mills, I.G. (Ian G.), Andreassen, O.A. (Ole), Dale, A.M. (Anders), and Seibert, T.M. (Tyler M.)
Abstract: Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10−180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men f
Published: 2021
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24. Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.

Author: Huynh-Le M.-P., Fan C.C., Karunamuni R., Thompson W.K., Martinez M.E., Eeles R.A., Kote-Jarai Z., Muir K., Schleutker J., Pashayan N., Batra J., Gronberg H., Neal D.E., Donovan J.L., Hamdy F.C., Martin R.M., Nielsen S.F., Nordestgaard B.G., Wiklund F., Tangen C.M., Giles G.G., Wolk A., Albanes D., Travis R.C., Blot W.J., Zheng W., Sanderson M., Stanford J.L., Mucci L.A., West C.M.L., Kibel A.S., Cussenot O., Berndt S.I., Koutros S., Sorensen K.D., Cybulski C., Grindedal E.M., Menegaux F., Khaw K.-T., Park J.Y., Ingles S.A., Maier C., Hamilton R.J., Thibodeau S.N., Rosenstein B.S., Lu Y.-J., Watya S., Vega A., Kogevinas M., Penney K.L., Huff C., Teixeira M.R., Multigner L., Leach R.J., Cannon-Albright L., Brenner H., John E.M., Kaneva R., Logothetis C.J., Neuhausen S.L., De Ruyck K., Pandha H., Razack A., Newcomb L.F., Fowke J.H., Gamulin M., Usmani N., Claessens F., Gago-Dominguez M., Townsend P.A., Bush W.S., Roobol M.J., Parent M.-E., Hu J.J., Mills I.G., Andreassen O.A., Dale A.M., Seibert T.M., Huynh-Le M.-P., Fan C.C., Karunamuni R., Thompson W.K., Martinez M.E., Eeles R.A., Kote-Jarai Z., Muir K., Schleutker J., Pashayan N., Batra J., Gronberg H., Neal D.E., Donovan J.L., Hamdy F.C., Martin R.M., Nielsen S.F., Nordestgaard B.G., Wiklund F., Tangen C.M., Giles G.G., Wolk A., Albanes D., Travis R.C., Blot W.J., Zheng W., Sanderson M., Stanford J.L., Mucci L.A., West C.M.L., Kibel A.S., Cussenot O., Berndt S.I., Koutros S., Sorensen K.D., Cybulski C., Grindedal E.M., Menegaux F., Khaw K.-T., Park J.Y., Ingles S.A., Maier C., Hamilton R.J., Thibodeau S.N., Rosenstein B.S., Lu Y.-J., Watya S., Vega A., Kogevinas M., Penney K.L., Huff C., Teixeira M.R., Multigner L., Leach R.J., Cannon-Albright L., Brenner H., John E.M., Kaneva R., Logothetis C.J., Neuhausen S.L., De Ruyck K., Pandha H., Razack A., Newcomb L.F., Fowke J.H., Gamulin M., Usmani N., Claessens F., Gago-Dominguez M., Townsend P.A., Bush W.S., Roobol M.J., Parent M.-E., Hu J.J., Mills I.G., Andreassen O.A., Dale A.M., and Seibert T.M.
Abstract: Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score >= 7, stage T3-T4, PSA >= 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10-180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.Copyright © 2021, The Author(s).
Published: 2021

25. Survival from breast cancer in women with a BRCA2 mutation by treatment.

Author: Evans D.G., Phillips K.-A., Milne R.L., Fruscio R., Cybulski C., Gronwald J., Lubinski J., Huzarski T., Hyder Z., Forde C., Metcalfe K., Senter L., Weitzel J., Tung N., Zakalik D., Ekholm M., Sun P., Narod S.A., Evans D.G., Phillips K.-A., Milne R.L., Fruscio R., Cybulski C., Gronwald J., Lubinski J., Huzarski T., Hyder Z., Forde C., Metcalfe K., Senter L., Weitzel J., Tung N., Zakalik D., Ekholm M., Sun P., and Narod S.A.
Abstract: BACKGROUND: The impact of various breast-cancer treatments on patients with a BRCA2 mutation has not been studied. We sought to estimate the impact of bilateral oophorectomy and other treatments on breast cancer-specific survival among patients with a germline BRCA2 mutation. METHOD(S): We identified 664 women with stage I-III breast cancer and a BRCA2 mutation by combining five different datasets (retrospective and prospective). Subjects were followed for 7.2 years from diagnosis to death from breast cancer. Tumour characteristics and cancer treatments were patient-reported and derived from medical records. Predictors of survival were determined using Cox proportional hazard models, adjusted for other treatments and for prognostic features. RESULT(S): The 10-year breast-cancer survival for ER-positive patients was 78.9% and for ER-negative patients was 82.3% (adjusted HR=1.23 (95% CI, 0.62-2.45, p=0.55)). The 10-year breast-cancer survival for women who had a bilateral oophorectomy was 89.1% and for women who did not have an oophorectomy was 59.0% (adjusted HR=0.45; 95% CI, 0.28-0.72, p=0.001). The adjusted hazard ratio for chemotherapy was 0.83 (95% CI, 0.65-1.53: p=0.56). CONCLUSION(S): For women with breast cancer and a germline BRCA2 mutation, positive ER status does not predict superior survival. Oophorectomy is associated with a reduced risk of death from breast cancer and should be considered in the treatment plan.
Published: 2021

26. Publisher Correction: Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction (Nature Genetics, (2021), 53, 1, (65-75), 10.1038/s41588-020-00748-0).

Author: Lessel D., Townsend P.A., Aukim-Hastie C., Bush W.S., Aldrich M.C., Crawford D.C., Srivastava S., Cullen J.C., Petrovics G., Casey G., Roobol M.J., Jenster G., van Schaik R.H.N., Hu J.J., Sanderson M., Varma R., McKean-Cowdin R., Torres M., Mancuso N., Berndt S.I., Van Den Eeden S.K., Easton D.F., Chanock S.J., Cook M.B., Wiklund F., Nakagawa H., Witte J.S., Eeles R.A., Kote-Jarai Z., Haiman C.A., Conti D.V., Darst B.F., Moss L.C., Saunders E.J., Sheng X., Chou A., Schumacher F.R., Olama A.A.A., Benlloch S., Dadaev T., Brook M.N., Sahimi A., Hoffmann T.J., Takahashi A., Matsuda K., Momozawa Y., Fujita M., Muir K., Lophatananon A., Wan P., Le Marchand L., Wilkens L.R., Stevens V.L., Gapstur S.M., Carter B.D., Schleutker J., Tammela T.L.J., Sipeky C., Auvinen A., Giles G.G., Southey M.C., MacInnis R.J., Cybulski C., Wokolorczyk D., Lubinski J., Neal D.E., Donovan J.L., Hamdy F.C., Martin R.M., Nordestgaard B.G., Nielsen S.F., Weischer M., Bojesen S.E., Roder M.A., Iversen P., Batra J., Chambers S., Moya L., Horvath L., Clements J.A., Tilley W., Risbridger G.P., Gronberg H., Aly M., Szulkin R., Eklund M., Nordstrom T., Pashayan N., Dunning A.M., Ghoussaini M., Travis R.C., Key T.J., Riboli E., Park J.Y., Sellers T.A., Lin H.-Y., Albanes D., Weinstein S.J., Mucci L.A., Giovannucci E., Lindstrom S., Kraft P., Hunter D.J., Penney K.L., Turman C., Tangen C.M., Goodman P.J., Thompson I.M., Hamilton R.J., Fleshner N.E., Finelli A., Parent M.-E., Stanford J.L., Ostrander E.A., Geybels M.S., Koutros S., Freeman L.E.B., Stampfer M., Wolk A., Hakansson N., Andriole G.L., Hoover R.N., Machiela M.J., Sorensen K.D., Borre M., Blot W.J., Zheng W., Yeboah E.D., Mensah J.E., Lu Y.-J., Zhang H.-W., Feng N., Mao X., Wu Y., Zhao S.-C., Sun Z., Thibodeau S.N., McDonnell S.K., Schaid D.J., West C.M.L., Burnet N., Barnett G., Maier C., Schnoeller T., Luedeke M., Kibel A.S., Drake B.F., Cussenot O., Cancel-Tassin G., Menegaux F., Truong T., Koudou Y.A., John E.M., Grindedal E.M., Maehle L., Khaw K.-T., Ingles S.A., Stern M.C., Vega A., Gomez-Caamano A., Fachal L., Rosenstein B.S., Kerns S.L., Ostrer H., Teixeira M.R., Paulo P., Brandao A., Watya S., Lubwama A., Bensen J.T., Fontham E.T.H., Mohler J., Taylor J.A., Kogevinas M., Llorca J., Castano-Vinyals G., Cannon-Albright L., Teerlink C.C., Huff C.D., Strom S.S., Multigner L., Blanchet P., Brureau L., Kaneva R., Slavov C., Mitev V., Leach R.J., Weaver B., Brenner H., Cuk K., Holleczek B., Saum K.-U., Klein E.A., Hsing A.W., Kittles R.A., Murphy A.B., Logothetis C.J., Kim J., Neuhausen S.L., Steele L., Ding Y.C., Isaacs W.B., Nemesure B., Hennis A.J.M., Carpten J., Pandha H., Michael A., De Ruyck K., De Meerleer G., Ost P., Xu J., Razack A., Lim J., Teo S.-H., Newcomb L.F., Lin D.W., Fowke J.H., Neslund-Dudas C., Rybicki B.A., Gamulin M., Kulis T., Usmani N., Singhal S., Parliament M., Claessens F., Joniau S., Van den Broeck T., Gago-Dominguez M., Castelao J.E., Martinez M.E., Larkin S., Lessel D., Townsend P.A., Aukim-Hastie C., Bush W.S., Aldrich M.C., Crawford D.C., Srivastava S., Cullen J.C., Petrovics G., Casey G., Roobol M.J., Jenster G., van Schaik R.H.N., Hu J.J., Sanderson M., Varma R., McKean-Cowdin R., Torres M., Mancuso N., Berndt S.I., Van Den Eeden S.K., Easton D.F., Chanock S.J., Cook M.B., Wiklund F., Nakagawa H., Witte J.S., Eeles R.A., Kote-Jarai Z., Haiman C.A., Conti D.V., Darst B.F., Moss L.C., Saunders E.J., Sheng X., Chou A., Schumacher F.R., Olama A.A.A., Benlloch S., Dadaev T., Brook M.N., Sahimi A., Hoffmann T.J., Takahashi A., Matsuda K., Momozawa Y., Fujita M., Muir K., Lophatananon A., Wan P., Le Marchand L., Wilkens L.R., Stevens V.L., Gapstur S.M., Carter B.D., Schleutker J., Tammela T.L.J., Sipeky C., Auvinen A., Giles G.G., Southey M.C., MacInnis R.J., Cybulski C., Wokolorczyk D., Lubinski J., Neal D.E., Donovan J.L., Hamdy F.C., Martin R.M., Nordestgaard B.G., Nielsen S.F., Weischer M., Bojesen S.E., Roder M.A., Iversen P., Batra J., Chambers S., Moya L., Horvath L., Clements J.A., Tilley W., Risbridger G.P., Gronberg H., Aly M., Szulkin R., Eklund M., Nordstrom T., Pashayan N., Dunning A.M., Ghoussaini M., Travis R.C., Key T.J., Riboli E., Park J.Y., Sellers T.A., Lin H.-Y., Albanes D., Weinstein S.J., Mucci L.A., Giovannucci E., Lindstrom S., Kraft P., Hunter D.J., Penney K.L., Turman C., Tangen C.M., Goodman P.J., Thompson I.M., Hamilton R.J., Fleshner N.E., Finelli A., Parent M.-E., Stanford J.L., Ostrander E.A., Geybels M.S., Koutros S., Freeman L.E.B., Stampfer M., Wolk A., Hakansson N., Andriole G.L., Hoover R.N., Machiela M.J., Sorensen K.D., Borre M., Blot W.J., Zheng W., Yeboah E.D., Mensah J.E., Lu Y.-J., Zhang H.-W., Feng N., Mao X., Wu Y., Zhao S.-C., Sun Z., Thibodeau S.N., McDonnell S.K., Schaid D.J., West C.M.L., Burnet N., Barnett G., Maier C., Schnoeller T., Luedeke M., Kibel A.S., Drake B.F., Cussenot O., Cancel-Tassin G., Menegaux F., Truong T., Koudou Y.A., John E.M., Grindedal E.M., Maehle L., Khaw K.-T., Ingles S.A., Stern M.C., Vega A., Gomez-Caamano A., Fachal L., Rosenstein B.S., Kerns S.L., Ostrer H., Teixeira M.R., Paulo P., Brandao A., Watya S., Lubwama A., Bensen J.T., Fontham E.T.H., Mohler J., Taylor J.A., Kogevinas M., Llorca J., Castano-Vinyals G., Cannon-Albright L., Teerlink C.C., Huff C.D., Strom S.S., Multigner L., Blanchet P., Brureau L., Kaneva R., Slavov C., Mitev V., Leach R.J., Weaver B., Brenner H., Cuk K., Holleczek B., Saum K.-U., Klein E.A., Hsing A.W., Kittles R.A., Murphy A.B., Logothetis C.J., Kim J., Neuhausen S.L., Steele L., Ding Y.C., Isaacs W.B., Nemesure B., Hennis A.J.M., Carpten J., Pandha H., Michael A., De Ruyck K., De Meerleer G., Ost P., Xu J., Razack A., Lim J., Teo S.-H., Newcomb L.F., Lin D.W., Fowke J.H., Neslund-Dudas C., Rybicki B.A., Gamulin M., Kulis T., Usmani N., Singhal S., Parliament M., Claessens F., Joniau S., Van den Broeck T., Gago-Dominguez M., Castelao J.E., Martinez M.E., and Larkin S.
Abstract: In the version of this article originally published, the names of the equally contributing authors and jointly supervising authors were switched. The correct affiliations are: "These authors contributed equally: David V. Conti, Burcu F. Darst. These authors jointly supervised this work: David V. Conti, Rosalind A. Eeles, Zsofia Kote-Jarai, Christopher A. Haiman." The error has been corrected in the HTML and PDF versions of the article.Copyright © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
Published: 2021

27. KLK3 SNP-SNP interactions for prediction of prostate cancer aggressiveness.

Author: Pandha H., Berglund A.E., Chen A., French-Kwawu J., Harris D., Pow-Sang J., Yamoah K., Cleveland J.L., Awasthi S., Rounbehler R.J., Gerke T., Dhillon J., Eeles R., Teixeira M.R., Cannon-Albright L., Brenner H., Kaneva R., Fang Z., Srinivasan S., Clements J., Batra J., Park J.Y., Lin H.-Y., Huang P.-Y., Cheng C.-H., Tung H.-Y., Kote-Jarai Z., Muir K., Schleutker J., Pashayan N., Neal D.E., Nielsen S.F., Nordestgaard B.G., Gronberg H., Wiklund F., Giles G.G., Haiman C.A., Travis R.C., Stanford J.L., Kibel A.S., Cybulski C., Khaw K.-T., Maier C., Thibodeau S.N., Pandha H., Berglund A.E., Chen A., French-Kwawu J., Harris D., Pow-Sang J., Yamoah K., Cleveland J.L., Awasthi S., Rounbehler R.J., Gerke T., Dhillon J., Eeles R., Teixeira M.R., Cannon-Albright L., Brenner H., Kaneva R., Fang Z., Srinivasan S., Clements J., Batra J., Park J.Y., Lin H.-Y., Huang P.-Y., Cheng C.-H., Tung H.-Y., Kote-Jarai Z., Muir K., Schleutker J., Pashayan N., Neal D.E., Nielsen S.F., Nordestgaard B.G., Gronberg H., Wiklund F., Giles G.G., Haiman C.A., Travis R.C., Stanford J.L., Kibel A.S., Cybulski C., Khaw K.-T., Maier C., and Thibodeau S.N.
Abstract: Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP-SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P<3.5x10-9) and 3145 (P<1x10-5) SNP-SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3. The 3 most common gene-gene interactions were KLK3-COL4A1:COL4A2, KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP-SNP interactions were supported by gene expression and protein-protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness.
Published: 2021

28. The CHEK2 variant C.349A>G is associated with prostate cancer risk and carriers share a common ancestor.

Author: Neuhausen S.L., Brandao A., Paulo P., Maia S., Pinheiro M., Peixoto A., Cardoso M., Silva M.P., Santos C., Eeles R.A., John E.M., Kaneva R., Logothetis C.J., De Ruyck K., Razack A., Newcomb L.F., Lessel D., Usmani N., Claessens F., Gago-Dominguez M., Townsend P.A., Roobol M.J., Teixeira M.R., Kote-Jarai Z., Muir K., Schleutker J., Wang Y., Pashayan N., Batra J., Gronberg H., Neal D.E., Nordestgaard B.G., Tangen C.M., Southey M.C., Wolk A., Albanes D., Haiman C.A., Travis R.C., Stanford J.L., Mucci L.A., West C.M.L., Nielsen S.F., Kibel A.S., Cussenot O., Berndt S.I., Koutros S., Sorensen K.D., Cybulski C., Grindedal E.M., Park J.Y., Ingles S.A., Maier C., Hamilton R.J., Rosenstein B.S., Vega A., Kogevinas M., Wiklund F., Penney K.L., Brenner H., Neuhausen S.L., Brandao A., Paulo P., Maia S., Pinheiro M., Peixoto A., Cardoso M., Silva M.P., Santos C., Eeles R.A., John E.M., Kaneva R., Logothetis C.J., De Ruyck K., Razack A., Newcomb L.F., Lessel D., Usmani N., Claessens F., Gago-Dominguez M., Townsend P.A., Roobol M.J., Teixeira M.R., Kote-Jarai Z., Muir K., Schleutker J., Wang Y., Pashayan N., Batra J., Gronberg H., Neal D.E., Nordestgaard B.G., Tangen C.M., Southey M.C., Wolk A., Albanes D., Haiman C.A., Travis R.C., Stanford J.L., Mucci L.A., West C.M.L., Nielsen S.F., Kibel A.S., Cussenot O., Berndt S.I., Koutros S., Sorensen K.D., Cybulski C., Grindedal E.M., Park J.Y., Ingles S.A., Maier C., Hamilton R.J., Rosenstein B.S., Vega A., Kogevinas M., Wiklund F., Penney K.L., and Brenner H.
Abstract: The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.Copyright © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Published: 2021

29. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Author: Thompson I.M., Muir K., Lophatananon A., Wan P., Stern M.C., Vega A., Gomez-Caamano A., Fachal L., Rosenstein B.S., Kerns S.L., Ostrer H., Teixeira M.R., Paulo P., Brandao A., Watya S., Lubwama A., Bensen J.T., Fontham E.T.H., Mohler J., Taylor J.A., Kogevinas M., Llorca J., Castano-Vinyals G., Cannon-Albright L., Teerlink C.C., Huff C.D., Strom S.S., Multigner L., Blanchet P., Brureau L., Kaneva R., Slavov C., Mitev V., Leach R.J., Weaver B., Brenner H., Cuk K., Holleczek B., Saum K.-U., Klein E.A., Hsing A.W., Kittles R.A., Murphy A.B., Logothetis C.J., Kim J., Neuhausen S.L., Steele L., Ding Y.C., Isaacs W.B., Nemesure B., Hennis A.J.M., Carpten J., Pandha H., Michael A., De Ruyck K., De Meerleer G., Ost P., Xu J., Razack A., Lim J., Teo S.-H., Newcomb L.F., Lin D.W., Fowke J.H., Neslund-Dudas C., Rybicki B.A., Gamulin M., Lessel D., Kulis T., Usmani N., Singhal S., Parliament M., Claessens F., Joniau S., Van den Broeck T., Gago-Dominguez M., Castelao J.E., Martinez M.E., Larkin S., Townsend P.A., Aukim-Hastie C., Bush W.S., Aldrich M.C., Crawford D.C., Srivastava S., Cullen J.C., Petrovics G., Casey G., Roobol M.J., Jenster G., van Schaik R.H.N., Hu J.J., Sanderson M., Varma R., McKean-Cowdin R., Torres M., Mancuso N., Berndt S.I., Van Den Eeden S.K., Easton D.F., Chanock S.J., Cook M.B., Wiklund F., Nakagawa H., Witte J.S., Eeles R.A., Kote-Jarai Z., Haiman C.A., Conti D.V., Darst B.F., Moss L.C., Saunders E.J., Sheng X., Chou A., Schumacher F.R., Olama A.A.A., Benlloch S., Dadaev T., Brook M.N., Sahimi A., Hoffmann T.J., Takahashi A., Matsuda K., Momozawa Y., Le Marchand L., Wilkens L.R., Stevens V.L., Gapstur S.M., Carter B.D., Schleutker J., Tammela T.L.J., Sipeky C., Auvinen A., Giles G.G., Southey M.C., MacInnis R.J., Cybulski C., Wokolorczyk D., Lubinski J., Neal D.E., Donovan J.L., Hamdy F.C., Martin R.M., Nordestgaard B.G., Nielsen S.F., Weischer M., Bojesen S.E., Roder M.A., Iversen P., Batra J., Chambers S., Moya L., Horvath L., Clements J.A., Tilley W., Risbridger G.P., Gronberg H., Aly M., Szulkin R., Eklund M., Nordstrom T., Pashayan N., Dunning A.M., Ghoussaini M., Travis R.C., Key T.J., Riboli E., Park J.Y., Sellers T.A., Lin H.-Y., Albanes D., Weinstein S.J., Mucci L.A., Giovannucci E., Lindstrom S., Kraft P., Hunter D.J., Penney K.L., Turman C., Tangen C.M., Goodman P.J., Fujita M., Hamilton R.J., Fleshner N.E., Finelli A., Parent M.-E., Stanford J.L., Ostrander E.A., Geybels M.S., Koutros S., Freeman L.E.B., Stampfer M., Wolk A., Hakansson N., Andriole G.L., Hoover R.N., Machiela M.J., Sorensen K.D., Borre M., Blot W.J., Zheng W., Yeboah E.D., Mensah J.E., Lu Y.-J., Zhang H.-W., Feng N., Mao X., Wu Y., Zhao S.-C., Sun Z., Thibodeau S.N., McDonnell S.K., Schaid D.J., West C.M.L., Burnet N., Barnett G., Maier C., Schnoeller T., Luedeke M., Kibel A.S., Drake B.F., Cussenot O., Cancel-Tassin G., Menegaux F., Truong T., Koudou Y.A., John E.M., Grindedal E.M., Maehle L., Khaw K.-T., Ingles S.A., Thompson I.M., Muir K., Lophatananon A., Wan P., Stern M.C., Vega A., Gomez-Caamano A., Fachal L., Rosenstein B.S., Kerns S.L., Ostrer H., Teixeira M.R., Paulo P., Brandao A., Watya S., Lubwama A., Bensen J.T., Fontham E.T.H., Mohler J., Taylor J.A., Kogevinas M., Llorca J., Castano-Vinyals G., Cannon-Albright L., Teerlink C.C., Huff C.D., Strom S.S., Multigner L., Blanchet P., Brureau L., Kaneva R., Slavov C., Mitev V., Leach R.J., Weaver B., Brenner H., Cuk K., Holleczek B., Saum K.-U., Klein E.A., Hsing A.W., Kittles R.A., Murphy A.B., Logothetis C.J., Kim J., Neuhausen S.L., Steele L., Ding Y.C., Isaacs W.B., Nemesure B., Hennis A.J.M., Carpten J., Pandha H., Michael A., De Ruyck K., De Meerleer G., Ost P., Xu J., Razack A., Lim J., Teo S.-H., Newcomb L.F., Lin D.W., Fowke J.H., Neslund-Dudas C., Rybicki B.A., Gamulin M., Lessel D., Kulis T., Usmani N., Singhal S., Parliament M., Claessens F., Joniau S., Van den Broeck T., Gago-Dominguez M., Castelao J.E., Martinez M.E., Larkin S., Townsend P.A., Aukim-Hastie C., Bush W.S., Aldrich M.C., Crawford D.C., Srivastava S., Cullen J.C., Petrovics G., Casey G., Roobol M.J., Jenster G., van Schaik R.H.N., Hu J.J., Sanderson M., Varma R., McKean-Cowdin R., Torres M., Mancuso N., Berndt S.I., Van Den Eeden S.K., Easton D.F., Chanock S.J., Cook M.B., Wiklund F., Nakagawa H., Witte J.S., Eeles R.A., Kote-Jarai Z., Haiman C.A., Conti D.V., Darst B.F., Moss L.C., Saunders E.J., Sheng X., Chou A., Schumacher F.R., Olama A.A.A., Benlloch S., Dadaev T., Brook M.N., Sahimi A., Hoffmann T.J., Takahashi A., Matsuda K., Momozawa Y., Le Marchand L., Wilkens L.R., Stevens V.L., Gapstur S.M., Carter B.D., Schleutker J., Tammela T.L.J., Sipeky C., Auvinen A., Giles G.G., Southey M.C., MacInnis R.J., Cybulski C., Wokolorczyk D., Lubinski J., Neal D.E., Donovan J.L., Hamdy F.C., Martin R.M., Nordestgaard B.G., Nielsen S.F., Weischer M., Bojesen S.E., Roder M.A., Iversen P., Batra J., Chambers S., Moya L., Horvath L., Clements J.A., Tilley W., Risbridger G.P., Gronberg H., Aly M., Szulkin R., Eklund M., Nordstrom T., Pashayan N., Dunning A.M., Ghoussaini M., Travis R.C., Key T.J., Riboli E., Park J.Y., Sellers T.A., Lin H.-Y., Albanes D., Weinstein S.J., Mucci L.A., Giovannucci E., Lindstrom S., Kraft P., Hunter D.J., Penney K.L., Turman C., Tangen C.M., Goodman P.J., Fujita M., Hamilton R.J., Fleshner N.E., Finelli A., Parent M.-E., Stanford J.L., Ostrander E.A., Geybels M.S., Koutros S., Freeman L.E.B., Stampfer M., Wolk A., Hakansson N., Andriole G.L., Hoover R.N., Machiela M.J., Sorensen K.D., Borre M., Blot W.J., Zheng W., Yeboah E.D., Mensah J.E., Lu Y.-J., Zhang H.-W., Feng N., Mao X., Wu Y., Zhao S.-C., Sun Z., Thibodeau S.N., McDonnell S.K., Schaid D.J., West C.M.L., Burnet N., Barnett G., Maier C., Schnoeller T., Luedeke M., Kibel A.S., Drake B.F., Cussenot O., Cancel-Tassin G., Menegaux F., Truong T., Koudou Y.A., John E.M., Grindedal E.M., Maehle L., Khaw K.-T., and Ingles S.A.
Abstract: Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.Copyright © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
Published: 2021

30. Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer

Author: Song, H, Dicks, EM, Tyrer, J, Intermaggio, M, Chenevix-Trench, G, Bowtell, DD, Traficante, N, Group, A, Brenton, J, Goranova, T, Hosking, K, Piskorz, A, Van Oudenhove, E, Doherty, J, Harris, HR, Rossing, MA, Duerst, M, Dork, T, Bogdanova, NV, Modugno, F, Moysich, K, Odunsi, K, Ness, R, Karlan, BY, Lester, J, Jensen, A, Krüger Kjaer, S, Høgdall, E, Campbell, IG, Lázaro, C, Pujara, MA, Cunningham, J, Vierkant, R, Winham, SJ, Hildebrandt, M, Huff, C, Li, D, Wu, X, Yu, Y, Permuth, JB, Levine, DA, Schildkraut, JM, Riggan, MJ, Berchuck, A, Webb, PM, Group, OS, Cybulski, C, Gronwald, J, Jakubowska, A, Lubinski, J, Alsop, J, Harrington, P, Chan, I, Menon, U, Pearce, CL, Wu, AH, De Fazio, A, Kennedy, CJ, Goode, E, Ramus, S, Gayther, S, Pharoah, P, Song, H, Dicks, EM, Tyrer, J, Intermaggio, M, Chenevix-Trench, G, Bowtell, DD, Traficante, N, Group, A, Brenton, J, Goranova, T, Hosking, K, Piskorz, A, Van Oudenhove, E, Doherty, J, Harris, HR, Rossing, MA, Duerst, M, Dork, T, Bogdanova, NV, Modugno, F, Moysich, K, Odunsi, K, Ness, R, Karlan, BY, Lester, J, Jensen, A, Krüger Kjaer, S, Høgdall, E, Campbell, IG, Lázaro, C, Pujara, MA, Cunningham, J, Vierkant, R, Winham, SJ, Hildebrandt, M, Huff, C, Li, D, Wu, X, Yu, Y, Permuth, JB, Levine, DA, Schildkraut, JM, Riggan, MJ, Berchuck, A, Webb, PM, Group, OS, Cybulski, C, Gronwald, J, Jakubowska, A, Lubinski, J, Alsop, J, Harrington, P, Chan, I, Menon, U, Pearce, CL, Wu, AH, De Fazio, A, Kennedy, CJ, Goode, E, Ramus, S, Gayther, S, and Pharoah, P
Abstract: Purpose The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. Methods We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. Results The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. Conclusions We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.
Published: 2021

31. Survival from breast cancer in women with a BRCA2 mutation by treatment

Author: Evans, DG, Phillips, K-A, Milne, RL, Fruscio, R, Cybulski, C, Gronwald, J, Lubinski, J, Huzarski, T, Hyder, Z, Forde, C, Metcalfe, K, Senter, L, Weitzel, J, Tung, N, Zakalik, D, Ekholm, M, Sun, P, Narod, SA, Evans, DG, Phillips, K-A, Milne, RL, Fruscio, R, Cybulski, C, Gronwald, J, Lubinski, J, Huzarski, T, Hyder, Z, Forde, C, Metcalfe, K, Senter, L, Weitzel, J, Tung, N, Zakalik, D, Ekholm, M, Sun, P, and Narod, SA
Abstract: BACKGROUND: The impact of various breast-cancer treatments on patients with a BRCA2 mutation has not been studied. We sought to estimate the impact of bilateral oophorectomy and other treatments on breast cancer-specific survival among patients with a germline BRCA2 mutation. METHODS: We identified 664 women with stage I-III breast cancer and a BRCA2 mutation by combining five different datasets (retrospective and prospective). Subjects were followed for 7.2 years from diagnosis to death from breast cancer. Tumour characteristics and cancer treatments were patient-reported and derived from medical records. Predictors of survival were determined using Cox proportional hazard models, adjusted for other treatments and for prognostic features. RESULTS: The 10-year breast-cancer survival for ER-positive patients was 78.9% and for ER-negative patients was 82.3% (adjusted HR = 1.23 (95% CI, 0.62-2.45, p = 0.55)). The 10-year breast-cancer survival for women who had a bilateral oophorectomy was 89.1% and for women who did not have an oophorectomy was 59.0% (adjusted HR = 0.45; 95% CI, 0.28-0.72, p = 0.001). The adjusted hazard ratio for chemotherapy was 0.83 (95% CI, 0.65-1.53: p = 0.56). CONCLUSIONS: For women with breast cancer and a germline BRCA2 mutation, positive ER status does not predict superior survival. Oophorectomy is associated with a reduced risk of death from breast cancer and should be considered in the treatment plan.
Published: 2021

32. Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer

Author: Karunamuni, RA, Huynh-Le, M-P, Fan, CC, Thompson, W, Eeles, RA, Kote-Jarai, Z, Muir, K, Lophatananon, A, Schleutker, J, Pashayan, N, Batra, J, Groenberg, H, Walsh, EI, Turner, EL, Lane, A, Martin, RM, Neal, DE, Donovan, JL, Hamdy, FC, Nordestgaard, BG, Tangen, CM, MacInnis, RJ, Wolk, A, Albanes, D, Haiman, CA, Travis, RC, Stanford, JL, Mucci, LA, West, CML, Nielsen, SF, Kibel, AS, Wiklund, F, Cussenot, O, Berndt, SI, Koutros, S, Sorensen, KD, Cybulski, C, Grindedal, EM, Park, JY, Ingles, SA, Maier, C, Hamilton, RJ, Rosenstein, BS, Vega, A, Kogevinas, M, Penney, KL, Teixeira, MR, Brenner, H, John, EM, Kaneva, R, Logothetis, CJ, Neuhausen, SL, Razack, A, Newcomb, LF, Gamulin, M, Usmani, N, Claessens, F, Gago-Dominguez, M, Townsend, PA, Roobol, MJ, Zheng, W, Mills, IG, Andreassen, OA, Dale, AM, Seibert, TM, Karunamuni, RA, Huynh-Le, M-P, Fan, CC, Thompson, W, Eeles, RA, Kote-Jarai, Z, Muir, K, Lophatananon, A, Schleutker, J, Pashayan, N, Batra, J, Groenberg, H, Walsh, EI, Turner, EL, Lane, A, Martin, RM, Neal, DE, Donovan, JL, Hamdy, FC, Nordestgaard, BG, Tangen, CM, MacInnis, RJ, Wolk, A, Albanes, D, Haiman, CA, Travis, RC, Stanford, JL, Mucci, LA, West, CML, Nielsen, SF, Kibel, AS, Wiklund, F, Cussenot, O, Berndt, SI, Koutros, S, Sorensen, KD, Cybulski, C, Grindedal, EM, Park, JY, Ingles, SA, Maier, C, Hamilton, RJ, Rosenstein, BS, Vega, A, Kogevinas, M, Penney, KL, Teixeira, MR, Brenner, H, John, EM, Kaneva, R, Logothetis, CJ, Neuhausen, SL, Razack, A, Newcomb, LF, Gamulin, M, Usmani, N, Claessens, F, Gago-Dominguez, M, Townsend, PA, Roobol, MJ, Zheng, W, Mills, IG, Andreassen, OA, Dale, AM, and Seibert, TM
Abstract: BACKGROUND: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46). MATERIALS AND METHOD: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy. RESULTS: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer. CONCLUSIONS: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.
Published: 2021

33. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author: Conti, D, Darst, BF, Moss, LC, Saunders, EJ, Sheng, X, Chou, A, Schumacher, FR, Al Olama, AA, Benlloch, S, Dadaev, T, Brook, MN, Sahimi, A, Hoffmann, TJ, Takahashi, A, Matsuda, K, Momozawa, Y, Fujita, M, Muir, K, Lophatananon, A, Wan, P, Le Marchand, L, Wilkens, LR, Stevens, VL, Gapstur, SM, Carter, BD, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokolorczyk, D, Lubinski, J, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Roder, MA, Iversen, P, Batra, J, Chambers, S, Moya, L, Horvath, L, Clements, JA, Tilley, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordstrom, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, SJ, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-E, Stanford, JL, Ostrander, EA, Geybels, MS, Koutros, S, Freeman, LEB, Stampfer, M, Wolk, A, Hakansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sorensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, Lu, Y-J, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Burnet, N, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gomez-Caamano, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandao, A, Watya, S, Lubwama, A, Bensen, JT, Fontham, ETH, Mohler, J, Taylor, JA, Kogevinas, M, Llorca, J, Castano-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Strom, SS, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Weaver, B, Brenner, H, Cuk, K, Holleczek, B, Saum, K-U, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, C, Rybicki, BA, Gamulin, M, Lessel, D, Kulis, T, Usmani, N, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, JC, Petrovics, G, Casey, G, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Varma, R, McKean-Cowdin, R, Torres, M, Mancuso, N, Berndt, S, Van den Eeden, SK, Easton, DF, Chanock, SJ, Cook, MB, Wiklund, F, Nakagawa, H, Witte, JS, Eeles, RA, Kote-Jarai, Z, Haiman, CA, Conti, D, Darst, BF, Moss, LC, Saunders, EJ, Sheng, X, Chou, A, Schumacher, FR, Al Olama, AA, Benlloch, S, Dadaev, T, Brook, MN, Sahimi, A, Hoffmann, TJ, Takahashi, A, Matsuda, K, Momozawa, Y, Fujita, M, Muir, K, Lophatananon, A, Wan, P, Le Marchand, L, Wilkens, LR, Stevens, VL, Gapstur, SM, Carter, BD, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokolorczyk, D, Lubinski, J, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Roder, MA, Iversen, P, Batra, J, Chambers, S, Moya, L, Horvath, L, Clements, JA, Tilley, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordstrom, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, SJ, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-E, Stanford, JL, Ostrander, EA, Geybels, MS, Koutros, S, Freeman, LEB, Stampfer, M, Wolk, A, Hakansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sorensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, Lu, Y-J, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Burnet, N, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gomez-Caamano, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandao, A, Watya, S, Lubwama, A, Bensen, JT, Fontham, ETH, Mohler, J, Taylor, JA, Kogevinas, M, Llorca, J, Castano-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Strom, SS, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Weaver, B, Brenner, H, Cuk, K, Holleczek, B, Saum, K-U, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, C, Rybicki, BA, Gamulin, M, Lessel, D, Kulis, T, Usmani, N, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, JC, Petrovics, G, Casey, G, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Varma, R, McKean-Cowdin, R, Torres, M, Mancuso, N, Berndt, S, Van den Eeden, SK, Easton, DF, Chanock, SJ, Cook, MB, Wiklund, F, Nakagawa, H, Witte, JS, Eeles, RA, Kote-Jarai, Z, and Haiman, CA
Abstract: Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
Published: 2021

34. Polygenic hazard score is associated with prostate cancer in multi-ethnic populations

Author: Huynh-Le, M-P, Fan, CC, Karunamuni, R, Thompson, WK, Martinez, ME, Eeles, RA, Kote-Jarai, Z, Muir, K, Schleutker, J, Pashayan, N, Batra, J, Gronberg, H, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nielsen, SF, Nordestgaard, BG, Wiklund, F, Tangen, CM, Giles, GG, Wolk, A, Albanes, D, Travis, RC, Blot, WJ, Zheng, W, Sanderson, M, Stanford, JL, Mucci, LA, West, CML, Kibel, AS, Cussenot, O, Berndt, SI, Koutros, S, Sorensen, KD, Cybulski, C, Grindedal, EM, Menegaux, F, Khaw, K-T, Park, JY, Ingles, SA, Maier, C, Hamilton, RJ, Thibodeau, SN, Rosenstein, BS, Lu, Y-J, Watya, S, Vega, A, Kogevinas, M, Penney, KL, Huff, C, Teixeira, MR, Multigner, L, Leach, RJ, Cannon-Albright, L, Brenner, H, John, EM, Kaneva, R, Logothetis, CJ, Neuhausen, SL, De Ruyck, K, Pandha, H, Razack, A, Newcomb, LF, Fowke, JH, Gamulin, M, Usmani, N, Claessens, F, Gago-Dominguez, M, Townsend, PA, Bush, WS, Roobol, MJ, Parent, M-E, Hu, JJ, Mills, IG, Andreassen, OA, Dale, AM, Seibert, TM, Huynh-Le, M-P, Fan, CC, Karunamuni, R, Thompson, WK, Martinez, ME, Eeles, RA, Kote-Jarai, Z, Muir, K, Schleutker, J, Pashayan, N, Batra, J, Gronberg, H, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nielsen, SF, Nordestgaard, BG, Wiklund, F, Tangen, CM, Giles, GG, Wolk, A, Albanes, D, Travis, RC, Blot, WJ, Zheng, W, Sanderson, M, Stanford, JL, Mucci, LA, West, CML, Kibel, AS, Cussenot, O, Berndt, SI, Koutros, S, Sorensen, KD, Cybulski, C, Grindedal, EM, Menegaux, F, Khaw, K-T, Park, JY, Ingles, SA, Maier, C, Hamilton, RJ, Thibodeau, SN, Rosenstein, BS, Lu, Y-J, Watya, S, Vega, A, Kogevinas, M, Penney, KL, Huff, C, Teixeira, MR, Multigner, L, Leach, RJ, Cannon-Albright, L, Brenner, H, John, EM, Kaneva, R, Logothetis, CJ, Neuhausen, SL, De Ruyck, K, Pandha, H, Razack, A, Newcomb, LF, Fowke, JH, Gamulin, M, Usmani, N, Claessens, F, Gago-Dominguez, M, Townsend, PA, Bush, WS, Roobol, MJ, Parent, M-E, Hu, JJ, Mills, IG, Andreassen, OA, Dale, AM, and Seibert, TM
Abstract: Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10-180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.
Published: 2021

35. KLK3 SNP-SNP interactions for prediction of prostate cancer aggressiveness

Author: Lin, H-Y, Huang, P-Y, Cheng, C-H, Tung, H-Y, Fang, Z, Berglund, AE, Chen, A, French-Kwawu, J, Harris, D, Pow-Sang, J, Yamoah, K, Cleveland, JL, Awasthi, S, Rounbehler, RJ, Gerke, T, Dhillon, J, Eeles, R, Kote-Jarai, Z, Muir, K, Schleutker, J, Pashayan, N, Neal, DE, Nielsen, SF, Nordestgaard, BG, Gronberg, H, Wiklund, F, Giles, GG, Haiman, CA, Travis, RC, Stanford, JL, Kibel, AS, Cybulski, C, Khaw, K-T, Maier, C, Thibodeau, SN, Teixeira, MR, Cannon-Albright, L, Brenner, H, Kaneva, R, Pandha, H, Srinivasan, S, Clements, J, Batra, J, Park, JY, Lin, H-Y, Huang, P-Y, Cheng, C-H, Tung, H-Y, Fang, Z, Berglund, AE, Chen, A, French-Kwawu, J, Harris, D, Pow-Sang, J, Yamoah, K, Cleveland, JL, Awasthi, S, Rounbehler, RJ, Gerke, T, Dhillon, J, Eeles, R, Kote-Jarai, Z, Muir, K, Schleutker, J, Pashayan, N, Neal, DE, Nielsen, SF, Nordestgaard, BG, Gronberg, H, Wiklund, F, Giles, GG, Haiman, CA, Travis, RC, Stanford, JL, Kibel, AS, Cybulski, C, Khaw, K-T, Maier, C, Thibodeau, SN, Teixeira, MR, Cannon-Albright, L, Brenner, H, Kaneva, R, Pandha, H, Srinivasan, S, Clements, J, Batra, J, and Park, JY
Abstract: Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP-SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P < 3.5 × 10-9) and 3145 (P < 1 × 10-5) SNP-SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3. The 3 most common gene-gene interactions were KLK3-COL4A1:COL4A2, KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP-SNP interactions were supported by gene expression and protein-protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness.
Published: 2021

36. Survival from breast cancer in women with a BRCA2 mutation by treatment

Author: Evans, D, Phillips, K, Milne, R, Fruscio, R, Cybulski, C, Gronwald, J, Lubinski, J, Huzarski, T, Hyder, Z, Forde, C, Metcalfe, K, Senter, L, Weitzel, J, Tung, N, Zakalik, D, Ekholm, M, Sun, P, Narod, S, Evans, D Gareth, Phillips, Kelly-Anne, Milne, Roger L, Fruscio, Robert, Cybulski, Cezary, Gronwald, Jacek, Lubinski, Jan, Huzarski, Tomasz, Hyder, Zerin, Forde, Claire, Metcalfe, Kelly, Senter, Leigha, Weitzel, Jeffrey, Tung, Nadine, Zakalik, Dana, Ekholm, Maria, Sun, Ping, Narod, Steven A, Evans, D, Phillips, K, Milne, R, Fruscio, R, Cybulski, C, Gronwald, J, Lubinski, J, Huzarski, T, Hyder, Z, Forde, C, Metcalfe, K, Senter, L, Weitzel, J, Tung, N, Zakalik, D, Ekholm, M, Sun, P, Narod, S, Evans, D Gareth, Phillips, Kelly-Anne, Milne, Roger L, Fruscio, Robert, Cybulski, Cezary, Gronwald, Jacek, Lubinski, Jan, Huzarski, Tomasz, Hyder, Zerin, Forde, Claire, Metcalfe, Kelly, Senter, Leigha, Weitzel, Jeffrey, Tung, Nadine, Zakalik, Dana, Ekholm, Maria, Sun, Ping, and Narod, Steven A
Abstract: BACKGROUND: The impact of various breast-cancer treatments on patients with a BRCA2 mutation has not been studied. We sought to estimate the impact of bilateral oophorectomy and other treatments on breast cancer-specific survival among patients with a germline BRCA2 mutation.METHODS: We identified 664 women with stage I-III breast cancer and a BRCA2 mutation by combining five different datasets (retrospective and prospective). Subjects were followed for 7.2 years from diagnosis to death from breast cancer. Tumour characteristics and cancer treatments were patient-reported and derived from medical records. Predictors of survival were determined using Cox proportional hazard models, adjusted for other treatments and for prognostic features.RESULTS: The 10-year breast-cancer survival for ER-positive patients was 78.9% and for ER-negative patients was 82.3% (adjusted HR=1.23 (95% CI, 0.62-2.45, p=0.55)). The 10-year breast-cancer survival for women who had a bilateral oophorectomy was 89.1% and for women who did not have an oophorectomy was 59.0% (adjusted HR=0.45; 95% CI, 0.28-0.72, p=0.001). The adjusted hazard ratio for chemotherapy was 0.83 (95% CI, 0.65-1.53: p=0.56).CONCLUSIONS: For women with breast cancer and a germline BRCA2 mutation, positive ER status does not predict superior survival. Oophorectomy is associated with a reduced risk of death from breast cancer and should be considered in the treatment plan.
Published: 2021

37. Publisher Correction: Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author: Conti, DV, Darst, BF, Moss, LC, Saunders, EJ, Sheng, X, Chou, A, Schumacher, FR, Olama, AAA, Benlloch, S, Dadaev, T, Brook, MN, Sahimi, A, Hoffmann, TJ, Takahashi, A, Matsuda, K, Momozawa, Y, Fujita, M, Muir, K, Lophatananon, A, Wan, P, Le Marchand, L, Wilkens, LR, Stevens, VL, Gapstur, SM, Carter, BD, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokołorczyk, D, Lubiński, J, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Røder, MA, Iversen, P, Batra, J, Chambers, S, Moya, L, Horvath, L, Clements, JA, Tilley, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordström, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, SJ, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-É, Stanford, JL, Ostrander, EA, Geybels, MS, Koutros, S, Freeman, LEB, Stampfer, M, Wolk, A, Håkansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sørensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, Lu, Y-J, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Burnet, N, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gómez-Caamaño, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandão, A, Watya, S, Lubwama, A, Bensen, JT, Fontham, ETH, Mohler, J, Taylor, JA, Kogevinas, M, Llorca, J, Castaño-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Strom, SS, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Weaver, B, Brenner, H, Cuk, K, Holleczek, B, Saum, K-U, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, C, Rybicki, BA, Gamulin, M, Lessel, D, Kulis, T, Usmani, N, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, JC, Petrovics, G, Casey, G, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Varma, R, McKean-Cowdin, R, Torres, M, Mancuso, N, Berndt, SI, Van Den Eeden, SK, Easton, DF, Chanock, SJ, Cook, MB, Wiklund, F, Nakagawa, H, Witte, JS, Eeles, RA, Kote-Jarai, Z, Haiman, CA, Conti, DV, Darst, BF, Moss, LC, Saunders, EJ, Sheng, X, Chou, A, Schumacher, FR, Olama, AAA, Benlloch, S, Dadaev, T, Brook, MN, Sahimi, A, Hoffmann, TJ, Takahashi, A, Matsuda, K, Momozawa, Y, Fujita, M, Muir, K, Lophatananon, A, Wan, P, Le Marchand, L, Wilkens, LR, Stevens, VL, Gapstur, SM, Carter, BD, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokołorczyk, D, Lubiński, J, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Røder, MA, Iversen, P, Batra, J, Chambers, S, Moya, L, Horvath, L, Clements, JA, Tilley, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordström, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, SJ, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-É, Stanford, JL, Ostrander, EA, Geybels, MS, Koutros, S, Freeman, LEB, Stampfer, M, Wolk, A, Håkansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sørensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, Lu, Y-J, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Burnet, N, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gómez-Caamaño, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandão, A, Watya, S, Lubwama, A, Bensen, JT, Fontham, ETH, Mohler, J, Taylor, JA, Kogevinas, M, Llorca, J, Castaño-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Strom, SS, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Weaver, B, Brenner, H, Cuk, K, Holleczek, B, Saum, K-U, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, C, Rybicki, BA, Gamulin, M, Lessel, D, Kulis, T, Usmani, N, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, JC, Petrovics, G, Casey, G, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Varma, R, McKean-Cowdin, R, Torres, M, Mancuso, N, Berndt, SI, Van Den Eeden, SK, Easton, DF, Chanock, SJ, Cook, MB, Wiklund, F, Nakagawa, H, Witte, JS, Eeles, RA, Kote-Jarai, Z, and Haiman, CA
Abstract: In the version of this article originally published, the names of the equally contributing authors and jointly supervising authors were switched. The correct affiliations are: “These authors contributed equally: David V. Conti, Burcu F. Darst. These authors jointly supervised this work: David V. Conti, Rosalind A. Eeles, Zsofia Kote-Jarai, Christopher A. Haiman.” The error has been corrected in the HTML and PDF versions of the article.
Published: 2021

38. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Author: Conti, DV, Darst, BF, Moss, LC, Saunders, EJ, Sheng, X, Chou, A, Schumacher, FR, Olama, AAA, Benlloch, S, Dadaev, T, Brook, MN, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Sahimi, A, Burnet, N, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Hoffmann, TJ, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gómez-Caamaño, A, Takahashi, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandão, A, Watya, S, Lubwama, A, Bensen, JT, Matsuda, K, Fontham, ETH, Mohler, J, Taylor, JA, Kogevinas, M, Llorca, J, Castaño-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Strom, SS, Momozawa, Y, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Weaver, B, Brenner, H, Cuk, K, Fujita, M, Holleczek, B, Saum, K-U, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Muir, K, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Lophatananon, A, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, C, Rybicki, BA, Gamulin, M, Wan, P, Lessel, D, Kulis, T, Usmani, N, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Le Marchand, L, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, JC, Petrovics, G, Wilkens, LR, Casey, G, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Varma, R, McKean-Cowdin, R, Torres, M, Mancuso, N, Stevens, VL, Berndt, SI, Van Den Eeden, SK, Easton, DF, Chanock, SJ, Cook, MB, Wiklund, F, Nakagawa, H, Witte, JS, Eeles, RA, Kote-Jarai, Z, Gapstur, SM, Haiman, CA, Carter, BD, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokołorczyk, D, Lubiński, J, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Røder, MA, Iversen, P, Batra, J, Chambers, S, Moya, L, Horvath, L, Clements, JA, Tilley, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordström, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, SJ, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-É, Stanford, JL, Ostrander, EA, Geybels, MS, Koutros, S, Freeman, LEB, Stampfer, M, Wolk, A, Håkansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sørensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, Lu, Y-J, Conti, DV, Darst, BF, Moss, LC, Saunders, EJ, Sheng, X, Chou, A, Schumacher, FR, Olama, AAA, Benlloch, S, Dadaev, T, Brook, MN, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Sahimi, A, Burnet, N, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Hoffmann, TJ, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gómez-Caamaño, A, Takahashi, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandão, A, Watya, S, Lubwama, A, Bensen, JT, Matsuda, K, Fontham, ETH, Mohler, J, Taylor, JA, Kogevinas, M, Llorca, J, Castaño-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Strom, SS, Momozawa, Y, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Weaver, B, Brenner, H, Cuk, K, Fujita, M, Holleczek, B, Saum, K-U, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Muir, K, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Lophatananon, A, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, C, Rybicki, BA, Gamulin, M, Wan, P, Lessel, D, Kulis, T, Usmani, N, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Le Marchand, L, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, JC, Petrovics, G, Wilkens, LR, Casey, G, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Varma, R, McKean-Cowdin, R, Torres, M, Mancuso, N, Stevens, VL, Berndt, SI, Van Den Eeden, SK, Easton, DF, Chanock, SJ, Cook, MB, Wiklund, F, Nakagawa, H, Witte, JS, Eeles, RA, Kote-Jarai, Z, Gapstur, SM, Haiman, CA, Carter, BD, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokołorczyk, D, Lubiński, J, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Røder, MA, Iversen, P, Batra, J, Chambers, S, Moya, L, Horvath, L, Clements, JA, Tilley, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordström, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, SJ, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-É, Stanford, JL, Ostrander, EA, Geybels, MS, Koutros, S, Freeman, LEB, Stampfer, M, Wolk, A, Håkansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sørensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, and Lu, Y-J
Abstract: Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
Published: 2021

39. Polygenic hazard score is associated with prostate cancer in multi-ethnic populations

Author: Huynh-Le, MP, Fan, CC, Karunamuni, R, Thompson, WK, Martinez, M E, Eeles, RA, Kote-Jarai, Z, Muir, K, Schleutker, J, Pashayan, N, Batra, J, Grönberg, H, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nielsen, SF, Nordestgaard, BG, Wiklund, F, Tangen, C M, Giles, GG, Wolk, A, Albanes, D, Travis, RC, Blot, WJ, Zheng, W, Sanderson, M, Stanford, J L, Mucci, LA, West, CML, Kibel, AS, Cussenot, O, Berndt, SI, Koutros, S, Sørensen, KD, Cybulski, C, Grindedal, EM, Menegaux, F, Khaw, KTH, Park, JY, Ingles, SA, Maier, C, Hamilton, RJ, Thibodeau, SN, Rosenstein, B S, Lu, YJ, Watya, S, Vega, A, Kogevinas, M, Penney, KL, Huff, C, Teixeira, MR, Multigner, L, Leach, RJ, Cannon-Albright, L, Brenner, H, John, EM, Kaneva, R, Logothetis, CJ, Neuhausen, SL, De Ruyck, K, Pandha, H, Razack, A, Newcomb, LF, Fowke, JH, Gamulin, M, Usmani, N, Claessens, F, Gago-Dominguez, M, Townsend, PA, Bush, WS, Roobol - Bouts, Monique, Parent, MÉ, Hu, JJ, Mills, IG, Andreassen, OA, Dale, AM, Seibert, TM, Huynh-Le, MP, Fan, CC, Karunamuni, R, Thompson, WK, Martinez, M E, Eeles, RA, Kote-Jarai, Z, Muir, K, Schleutker, J, Pashayan, N, Batra, J, Grönberg, H, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nielsen, SF, Nordestgaard, BG, Wiklund, F, Tangen, C M, Giles, GG, Wolk, A, Albanes, D, Travis, RC, Blot, WJ, Zheng, W, Sanderson, M, Stanford, J L, Mucci, LA, West, CML, Kibel, AS, Cussenot, O, Berndt, SI, Koutros, S, Sørensen, KD, Cybulski, C, Grindedal, EM, Menegaux, F, Khaw, KTH, Park, JY, Ingles, SA, Maier, C, Hamilton, RJ, Thibodeau, SN, Rosenstein, B S, Lu, YJ, Watya, S, Vega, A, Kogevinas, M, Penney, KL, Huff, C, Teixeira, MR, Multigner, L, Leach, RJ, Cannon-Albright, L, Brenner, H, John, EM, Kaneva, R, Logothetis, CJ, Neuhausen, SL, De Ruyck, K, Pandha, H, Razack, A, Newcomb, LF, Fowke, JH, Gamulin, M, Usmani, N, Claessens, F, Gago-Dominguez, M, Townsend, PA, Bush, WS, Roobol - Bouts, Monique, Parent, MÉ, Hu, JJ, Mills, IG, Andreassen, OA, Dale, AM, and Seibert, TM
Abstract: Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10−180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.
Published: 2021

40. Impact of BRCA1 mutation on survival after early onset breast cancer

Author: Huzarski T, Byrski T, Gronwald J, Górski B, Domagała W, Cybulski C, Sun Ping, Oszurek O, Szwiec M, Gugała K, Stawicka M, Morawiec Z, Mierzwa T, Janiszewska H, Kilar E, Marczyk E, Kozak-Klonowska B, Siołek M, Surdyka D, Wiśniowski R, Posmyk M, Lubiński J, and Narod SA
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Genetics, QH426-470
Published: 2012
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41. Screening with Magnetic Resonance Imaging in women at low and intermediate risk of breast Cancer

Author: Huzarski T T, Górecka-Szyld B, Huzarska J J, Psut G, Wilk G, Sibilski R, Cybulski C, Kozak-Klonowska B, Siołek M, Kilar E, Czudowska D, Janiszewska H, Godlewski D, Mackiewicz A, Jarkiewicz-Tretyn J, Szabo-Moskal I, Gronwald J, Lubiński J, and Narod SA
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Genetics, QH426-470
Published: 2012
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42. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

Author: Fachal, L., Aschard, H., Beesley, J., Barnes, D.R., Allen, J., Kar, S., Pooley, K.A., Dennis, J., Michailidou, K., Turman, C., Soucy, P., Lemaçon, A., Lush, M., Tyrer, J.P., Ghoussaini, M., Marjaneh, M.M., Jiang, X., Agata, S., Aittomäki, K., Alonso, M.R., Andrulis, I.L., Anton-Culver, H., Antonenkova, N.N., Arason, A., Arndt, V., Aronson, K.J., Arun, B.K., Auber, B., Auer, P.L., Azzollini, J., Balmaña, J., Barkardottir, R.B., Barrowdale, D., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Białkowska, K., Blanco, A.M., Blomqvist, C., Blot, W., Bogdanova, N.V., Bojesen, S.E., Bolla, M.K., Bonanni, B., Borg, A., Bosse, K., Brauch, H., Brenner, H., Briceno, I., Brock, I.W., Brooks-Wilson, A., Brüning, T., Burwinkel, B., Buys, S.S., Cai, Q., Caldés, T., Caligo, M.A., Camp, N.J., Campbell, I., Canzian, F., Carroll, J.S., Carter, B.D., Castelao, J.E., Chiquette, J., Christiansen, H., Chung, W.K., Claes, K.B.M., Clarke, C.L., Mari, V., Berthet, P., Castera, L., Vaur, D., Lallaoui, H., Bignon, Y.-J., Uhrhammer, N., Bonadona, V., Lasset, C., Révillion, F., Vennin, P., Muller, D., Gomes, D.M., Ingster, O., Coupier, I., Pujol, P., Collonge-Rame, M.-A., Mortemousque, I., Bera, O., Rose, M., Baurand, A., Bertolone, G., Faivre, L., Dreyfus, H., Leroux, D., Venat-Bouvet, L., Bézieau, S., Delnatte, C., Chiesa, J., Gilbert-Dussardier, B., Gesta, P., Prieur, F.P., Bronner, M., Sokolowska, J., Coulet, F., Boutry-Kryza, N., Calender, A., Giraud, S., Leone, M., Fert-Ferrer, S., Stoppa-Lyonnet, D., Jiao, Y., Lesueur, F.L., Mebirouk, N., Barouk-Simonet, E., Bubien, V., Longy, M., Sevenet, N., Gladieff, L., Toulas, C., Reimineras, A., Sobol, H., Paillerets, B.B.-D., Cabaret, O., Caron, O., Guillaud-Bataille, M., Rouleau, E., Belotti, M., Buecher, B., Caputo, S., Colas, C., Pauw, A.D., Fourme, E., Gauthier-Villars, M., Golmard, L., Moncoutier, V., Saule, C., Donaldson, A., Murray, A., Brady, A., Brewer, C., Pottinger, C., Miller, C., Gallagher, D., Gregory, H., Cook, J., Eason, J., Adlard, J., Barwell, J., Ong, K.-R., Snape, K., Walker, L., Izatt, L., Side, L., Tischkowitz, M., Rogers, M.T., Porteous, M.E., Ahmed, M., Morrison, P.J., Brennan, P., Eeles, R., Davidson, R., Collée, M., Cornelissen, S., Couch, F.J., Cox, A., Cross, S.S., Cybulski, C., Czene, K., Daly, M.B., de la Hoya, M., Devilee, P., Diez, O., Ding, Y.C., Dite, G.S., Domchek, S.M., Dörk, T., dos-Santos-Silva, I., Droit, A., Dubois, S., Dumont, M., Duran, M., Durcan, L., Dwek, M., Eccles, D.M., Engel, C., Eriksson, M., Evans, D.G., Fasching, P.A., Fletcher, O., Floris, G., Flyger, H., Foretova, L., Foulkes, W.D., Friedman, E., Fritschi, L., Frost, D., Gabrielson, M., Gago-Dominguez, M., Gambino, G., Ganz, P.A., Gapstur, S.M., Garber, J., García-Sáenz, J.A., Gaudet, M.M., Georgoulias, V., Giles, G., Glendon, G., Godwin, A.K., Goldberg, M.S., Goldgar, D.E., González-Neira, A., Tibiletti, M.G., Greene, M.H., Grip, M., Gronwald, J., Grundy, A., Guénel, P., Hahnen, E., Haiman, C.A., Håkansson, N., Hall, P., Hamann, U., Harrington, P.A., Hartikainen, J.M., Hartman, M., He, W., Healey, C.S., Heemskerk-Gerritsen, B.A.M., Heyworth, J., Hillemanns, P., Hogervorst, F.B.L., Hollestelle, A., Hooning, M., Hopper, J., Howell, A., Huang, G., Hulick, P.J., Imyanitov, E.N., Sexton, A., Christian, A., Trainer, A., Spigelman, A., Fellows, A., Shelling, A., Fazio, A.D., Blackburn, A., Crook, A., Meiser, B., Patterson, B., Clarke, C., Saunders, C., Hunt, C., Scott, C., Amor, D., Marsh, D., Edkins, E., Salisbury, E., Haan, E., Neidermayr, E., Macrea, F., Farshid, G., Lindeman, G., Chenevix-Trench, G., Mann, G., Gill, G., Thorne, H., Hickie, I., Winship, I., Flanagan, J., Kollias, J., Visvader, J., Stone, J., Taylor, J., Burke, J., Saunus, J., Forbes, J., Kirk, J., French, J., Tucker, K., Wu, K., Phillips, K., Lipton, L., Andrews, L., Lobb, L., Kentwell, M., Spurdle, M., Cummings, M., Gleeson, M., Harris, M., Jenkins, M., Young, M.A., Delatycki, M., Wallis, M., Burgess, M., Price, M., Brown, M., Southey, M., Bogwitz, M., Field, M., Friedlander, M., Gattas, M., Saleh, M., Hayward, N., Pachter, N., Cohen, P., Duijf, P., James, P., Simpson, P., Fong, P., Butow, P., Williams, R., Kefford, R., Scott, R., Milne, R.L., Balleine, R., Dawson, S.–J., Lok, S., O’Connell, S., Greening, S., Nightingale, S., Edwards, S., Fox, S., McLachlan, S.-A., Lakhani, S., Antill, Y., Aalfs, C., Meijers-Heijboer, H., van Engelen, K., Gille, H., Boere, I., van Deurzen, C., Obdeijn, I.-M., van den Ouweland, A., Seynaeve, C., Siesling, S., Verloop, J., van Asperen, C.J., van Cronenburg, T., Blok, R., de Boer, M., Garcia, E.G., Adank, M., Hogervorst, F., Jenner, D., van Leeuwen, F., Rookus, M., Russell, N., Schmidt, M., van den Belt-Dusebout, S., Kets, C., Mensenkamp, A., de Bock, T., van der Hout, A., Mourits, M., Oosterwijk, J., Ausems, M., Koudijs, M., Baxter, R., Yip, D., Carpenter, J., Davis, A., Pathmanathan, N., Graham, D., Sachchithananthan, M., Isaacs, C., Iwasaki, M., Jager, A., Jakimovska, M., Jakubowska, A., James, P.A., Janavicius, R., Jankowitz, R.C., John, E.M., Johnson, N., Jones, M.E., Jukkola-Vuorinen, A., Jung, A., Kaaks, R., Kang, D., Kapoor, P.M., Karlan, B.Y., Keeman, R., Kerin, M.J., Khusnutdinova, E., Kiiski, J.I., Kitahara, C.M., Ko, Y.-D., Konstantopoulou, I., Kosma, V.-M., Koutros, S., Kubelka-Sabit, K., Kwong, A., Kyriacou, K., Laitman, Y., Lambrechts, D., Lee, E., Leslie, G., Lester, J., Lesueur, F., Lindblom, A., Lo, W.-Y., Long, J., Lophatananon, A., Loud, J.T., Lubiński, J., MacInnis, R.J., Maishman, T., Makalic, E., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M.E., Matsuo, K., Maurer, T., Mavroudis, D., Mayes, R., McGuffog, L., McLean, C., Meindl, A., Miller, A., Miller, N., Montagna, M., Moreno, F., Muir, K., Mulligan, A.M., Muñoz-Garzon, V.M., Muranen, T.A., Narod, S.A., Nassir, R., Nathanson, K.L., Neuhausen, S.L., Nevanlinna, H., Neven, P., Nielsen, F.C., Nikitina-Zake, L., Norman, A., Offit, K., Olah, E., Olopade, O.I., Olsson, H., Orr, N., Osorio, A., Pankratz, V.S., Papp, J., Park, S.K., Park-Simon, T.-W., Parsons, M.T., Paul, J., Pedersen, I.S., Peissel, B., Peshkin, B., Peterlongo, P., Peto, J., Plaseska-Karanfilska, D., Prajzendanc, K., Prentice, R., Presneau, N., Prokofyeva, D., Pujana, M.A., Pylkäs, K., Radice, P., Ramus, S.J., Rantala, J., Rau-Murthy, R., Rennert, G., Risch, H.A., Robson, M., Romero, A., Rossing, M., Saloustros, E., Sánchez-Herrero, E., Sandler, D.P., Santamariña, M., Sawyer, E.J., Scheuner, M.T., Schmidt, D.F., Schmutzler, R.K., Schneeweiss, A., Schoemaker, M.J., Schöttker, B., Schürmann, P., Scott, R.J., Senter, L., Seynaeve, C.M., Shah, M., Sharma, P., Shen, C.-Y., Shu, X.-O., Singer, C.F., Slavin, T.P., Smichkoska, S., Southey, M.C., Spinelli, J.J., Spurdle, A.B., Sutter, C., Swerdlow, A.J., Tamimi, R.M., Tan, Y.Y., Tapper, W.J., Taylor, J.A., Teixeira, M.R., Tengström, M., Teo, S.H., Terry, M.B., Teulé, A., Thomassen, M., Thull, D.L., Toland, A.E., Tollenaar, R.A.E.M., Tomlinson, I., Torres, D., Torres-Mejía, G., Troester, M.A., Truong, T., Tung, N., Tzardi, M., Ulmer, H.-U., Vachon, C.M., van der Kolk, L.E., van Rensburg, E.J., Vega, A., Viel, A., Vijai, J., Vogel, M.J., Wang, Q., Wappenschmidt, B., Weinberg, C.R., Weitzel, J.N., Wendt, C., Wildiers, H., Winqvist, R., Wolk, A., Wu, A.H., Yannoukakos, D., Zhang, Y., Zheng, W., Hunter, D., Pharoah, P.D.P., Chang-Claude, J., García-Closas, M., Schmidt, M.K., Kristensen, V.N., French, J.D., Edwards, S.L., Antoniou, A.C., Simard, J., Easton, D.F., Kraft, P., Dunning, A.M., Collaborators, GEMO Study, Collaborators, EMBRACE, Investigators, KConFab, Investigators, HEBON, Investigators, ABCTB, Fachal, Laura, Aschard, Hugues, Beesley, Jonathan, Barnes, Daniel R, Duijf, Pascal, Dunning, Alison M, GEMO Study Collaborators, EMBRACE Collaborators, KConFab Investigators, HEBON Investigators, ABCTB Investigators, MUMC+: MA Medische Oncologie (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), European Commission, Government of Canada, Canadian Institutes of Health Research, National Institutes of Health (US), Cancer Research UK, Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), QIMR Berghofer Medical Research Institute, University of Cambridge [UK] (CAM), NSCAD, University of Cyprus [Nicosia], Harvard T.H. Chan School of Public Health, This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement number 656144. Genotyping of the OncoArray was principally funded from three sources: the PERSPECTIVE project (funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie de la Science et de l’Innovation du Québec’ (through Genome Québec) and the Quebec Breast Cancer Foundation), the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (NIH grants U19 CA148065 and X01HG007492), and Cancer Research UK (C1287/A10118, C8197/A16565 and C1287/A16563). BCAC is funded by Cancer Research UK (C1287/A16563), by the European Community’s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 633784 (B-CAST) and 634935 (BRIDGES). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program, and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701). Combining of the GWAS data was supported in part by NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065 (DRIVE, part of the GAME-ON initiative). For a full description of funding and acknowledgments, see the Supplementary Note., We thank all of the individuals who took part in these studies, as well as all of the researchers, clinicians, technicians and administrative staff who enabled this work to be carried out, European Project: 656144,H2020,H2020-MSCA-IF-2014,RADIOGENFF(2016), European Project: 223175,EC:FP7:HEALTH,FP7-HEALTH-2007-B,COGS(2009), European Project: 633784,H2020,H2020-PHC-2014-two-stage,B-CAST(2015), European Project: 634935,H2020,H2020-PHC-2014-two-stage,BRIDGES(2015), Clinical Genetics, Medical Oncology, Pathology, Radiology & Nuclear Medicine, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Cyprus [Nicosia] (UCY), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Life Course Epidemiology (LCE), Targeted Gynaecologic Oncology (TARGON), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Aschard, Hugues [0000-0002-7554-6783], Barnes, Daniel R [0000-0002-3781-7570], Dennis, Joe [0000-0003-4591-1214], Michailidou, Kyriaki [0000-0001-7065-1237], Lemaçon, Audrey [0000-0002-1817-7029], Andrulis, Irene L [0000-0002-4226-6435], Arason, Adalgeir [0000-0003-0480-886X], Arndt, Volker [0000-0001-9320-8684], Auber, Bernd [0000-0003-1880-291X], Azzollini, Jacopo [0000-0002-9364-9778], Bojesen, Stig E [0000-0002-4061-4133], Bonanni, Bernardo [0000-0003-3589-2128], Brauch, Hiltrud [0000-0001-7531-2736], Campbell, Ian [0000-0002-7773-4155], Carroll, Jason S [0000-0003-3643-0080], Claes, Kathleen BM [0000-0003-0841-7372], Collée, J Margriet [0000-0002-9272-9346], Devilee, Peter [0000-0002-8023-2009], Dörk, Thilo [0000-0002-9458-0282], Dwek, Miriam [0000-0001-7184-2932], Fletcher, Olivia [0000-0001-9387-7116], Floris, Giuseppe [0000-0003-2391-5425], Foulkes, William D [0000-0001-7427-4651], García-Sáenz, José A [0000-0001-6880-0301], Greene, Mark H [0000-0003-1852-9239], Guénel, Pascal [0000-0002-8359-518X], Heemskerk-Gerritsen, Bernadette AM [0000-0002-9724-6693], Hollestelle, Antoinette [0000-0003-1166-1966], Hulick, Peter J [0000-0001-8397-4078], Jakimovska, Milena [0000-0002-1506-0669], Jakubowska, Anna [0000-0002-5650-0501], James, Paul A [0000-0002-4361-4657], Jones, Michael E [0000-0001-7479-3451], Kapoor, Pooja Middha [0000-0001-5503-8215], Keeman, Renske [0000-0002-5452-9933], Konstantopoulou, Irene [0000-0002-0470-0309], Leslie, Goska [0000-0001-5756-6222], Lesueur, Fabienne [0000-0001-7404-4549], Matsuo, Keitaro [0000-0003-1761-6314], McLean, Catriona [0000-0002-0302-5727], Miller, Austin [0000-0001-9739-8462], Muir, Kenneth [0000-0001-6429-988X], Muranen, Taru A [0000-0002-5895-1808], Nathanson, Katherine L [0000-0002-6740-0901], Nevanlinna, Heli [0000-0002-0916-2976], Olopade, Olufunmilayo I [0000-0002-9936-1599], Orr, Nick [0000-0003-2866-942X], Pankratz, V Shane [0000-0002-3742-040X], Parsons, Michael T [0000-0003-3242-8477], Paul, James [0000-0001-7367-5816], Peshkin, Beth [0000-0002-2997-4701], Peterlongo, Paolo [0000-0001-6951-6855], Peto, Julian [0000-0002-1685-8912], Plaseska-Karanfilska, Dijana [0000-0001-8877-2416], Pylkäs, Katri [0000-0002-2449-0521], Radice, Paolo [0000-0001-6298-4111], Rennert, Gad [0000-0002-8512-068X], Robson, Mark [0000-0002-3109-1692], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Scott, Christopher [0000-0003-1340-0647], Scott, Rodney J [0000-0001-7724-3404], Spurdle, Amanda B [0000-0003-1337-7897], Stone, Jennifer [0000-0001-5077-0124], Sutter, Christian [0000-0003-4051-5888], Tan, Yen Yen [0000-0003-1063-5352], Teixeira, Manuel R [0000-0002-4896-5982], Toland, Amanda E [0000-0002-0271-1792], Tomlinson, Ian [0000-0003-3037-1470], Viel, Alessandra [0000-0003-2804-0840], Vijai, Joseph [0000-0002-7933-151X], Wolk, Alicja [0000-0001-7387-6845], Yannoukakos, Drakoulis [0000-0001-7509-3510], Pharoah, Paul DP [0000-0001-8494-732X], Schmidt, Marjanka K [0000-0002-2228-429X], Milne, Roger L [0000-0001-5764-7268], Edwards, Stacey L [0000-0001-7428-4139], Simard, Jacques [0000-0001-6906-3390], Easton, Douglas F [0000-0003-2444-3247], Kraft, Peter [0000-0002-4472-8103], Dunning, Alison M [0000-0001-6651-7166], Apollo - University of Cambridge Repository, Academic Medical Center, ARD - Amsterdam Reproduction and Development, Human genetics, CCA - Cancer biology and immunology, Molecular cell biology and Immunology, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, University of Helsinki, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, Doctoral Programme in Clinical Research, Staff Services, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, and Department of Obstetrics and Gynecology
Subjects: CHROMATIN, Linkage disequilibrium, Genome-wide association study, Regulatory Sequences, Nucleic Acid, Genome-wide association studies, Linkage Disequilibrium, Basic medicine, 0302 clinical medicine, Breast cancer, MESH: Risk Factors, Risk Factors, COMPREHENSIVE MOLECULAR PORTRAITS, 11 Medical and Health Sciences, HEBON Investigators, Genetics & Heredity, 0303 health sciences, [STAT.AP]Statistics [stat]/Applications [stat.AP], PROTEIN FUNCTION, Tumor, breast tumor, MESH: Polymorphism, Single Nucleotide, 1184 Genetics, developmental biology, physiology, MESH: Genetic Predisposition to Disease, apoptosis, Chromosome Mapping, Single Nucleotide, 3. Good health, MESH: Linkage Disequilibrium, Female, MESH: Biomarkers, Tumor, Biomarkers, Tumor/genetics, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, SUSCEPTIBILITY LOCI, MESH: Bayes Theorem, Quantitative Trait Loci, ABCTB Investigators, INTEGRATIVE ANALYSIS, Breast Neoplasms, Computational biology, Biology, Quantitative trait locus, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, Article, ENHANCER, GEMO Study Collaborators, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, REVEALS, Genetics, Biomarkers, Tumor, MESH: Regulatory Sequences, Nucleic Acid, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, FUNCTIONAL VARIANTS, EMBRACE Collaborators, Gene, 030304 developmental biology, Genetic association, Bayes Theorem, Genome-Wide Association Study, MESH: Humans, Science & Technology, Nucleic Acid, gene mapping, 06 Biological Sciences, MESH: Quantitative Trait Loci, DNA binding site, ESTROGEN-RECEPTOR, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Clinical medicine, Expression quantitative trait loci, MESH: Genome-Wide Association Study, Human genome, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, KConFab Investigators, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Chromosome Mapping, Chromosome Mapping/methods, Regulatory Sequences, MESH: Female, Biomarkers, 030217 neurology & neurosurgery, MESH: Breast Neoplasms, Developmental Biology
Abstract: Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes., This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement number 656144. Genotyping of the OncoArray was principally funded from three sources: the PERSPECTIVE project (funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie de la Science et de l’Innovation du Québec’ (through Genome Québec) and the Quebec Breast Cancer Foundation); the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (NIH grants U19 CA148065 and X01HG007492); and Cancer Research UK (C1287/A10118, C8197/A16565 and C1287/A16563). BCAC is funded by Cancer Research UK (C1287/A16563), by the European Community’s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 633784 (B-CAST) and 634935 (BRIDGES). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program, and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701). Combining of the GWAS data was supported in part by NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065 (DRIVE; part of the GAME-ON initiative).
Published: 2020

43. Neoadjuvant chemotherapy with Cisplatin in BRCA1 mutation carriers – results of treatment

Author: Byrski T, Gronwald J, Huzarski T, Marczyk E, Blecharz P, Ashuryk O, Cybulski C, Zuziak D, Wiśniowski R, Godlewski D, Narod SA, and Lubiński J
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Genetics, QH426-470
Published: 2012
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44. Prospective observation of breast/ovarian cancer risk in BRCA1 carriers depending on serum selenium level optimized with diet

Author: Lubiński J, Huzarski T, Jakubowska A, Gronwald J, Jaworska K, Muszyńska M, Sukiennicki G, Durda K, Cybulski C, Dębniak T, Tołoczko A, Oszurek O, Serrano-Fernandez P, Scott R, and Narod S
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Genetics, QH426-470
Published: 2012
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45. Why choose the treatment with cisplatin for BRCA1 breast cancers patients?

Author: Byrski T, Huzarski T, Marczyk E, Blecharz P, Gronwald J, Ashuryk O, Cybulski C, Dębniak T, Zuziak D, Godlewski D, Kladny J, Lubinski J, and Narod SA
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Genetics, QH426-470
Published: 2012
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46. The CHEK2 variant C.349A>G is associated with prostate cancer risk and carriers share a common ancestor

Author: Brandão, A. (Andreia), Paulo, P. (Paula), Maia, S. (Sofia), Pinheiro, M. (Manuela), Peixoto, A. (Ana), Cardoso, M. (Marta), Silva, M.P. (Maria P.), Santos, C. (Catarina), Eeles, R. (Rosalind), Kote-Jarai, Z., Muir, K.R. (K.), Schleutker, J. (Johanna), Wang, Y. (Ying), Pashayan, N. (Nora), Batra, J. (Jyotsna), Grönberg, H. (Henrik), Neal, D. (David), Nordestgaard, B.G. (Børge), Tangen, C.M. (Catherine M.), Southey, M.C. (Melissa), Wolk, K. (Kerstin), Albanes, D. (Demetrius), Haiman, C.A. (Christopher), Travis, S.P.L. (Simon), Stanford, J.L. (Janet L.), Mucci, L.A. (Lorelei A.), West, C.M.L. (Catharine M. L.), Nielsen, S.F. (Sune F.), Kibel, A. (Adam), Cussenot, O. (Olivier), Berndt, S.I. (Sonja), Koutros, S. (Stella), Sørensen, K.D. (Karina Dalsgaard), Cybulski, C. (Cezary), Grindedal, E.M. (Eli Marie), Park, J.Y. (Jong Y.), Ingles, S.A. (Sue), Maier, C. (Christiane), Hamilton, R.J. (Robert J.), Rosenstein, B.S. (Barry S.), Vega, A. (Ana), Kogevinas, M. (Manolis), Wiklund, F. (Fredrik), Penney, K.L. (Kathryn L.), Brenner, H. (Hermann), John, E.M. (Esther), Kaneva, R. (Radka), Logothetis, N.K. (Nikos), Floris, O.A.M., De Ruyck, K. (Kim), Razack, A. (Azad), Newcomb, L.F. (Lisa F.), Lessel, D. (Davor), Usmani, N. (Nawaid), Claessens, F., Gago-Dominguez, M. (Manuela), Townsend, P.A. (Paul A.), Roobol-Bouts, M.J. (Monique), Teixeira, P.J., Brandão, A. (Andreia), Paulo, P. (Paula), Maia, S. (Sofia), Pinheiro, M. (Manuela), Peixoto, A. (Ana), Cardoso, M. (Marta), Silva, M.P. (Maria P.), Santos, C. (Catarina), Eeles, R. (Rosalind), Kote-Jarai, Z., Muir, K.R. (K.), Schleutker, J. (Johanna), Wang, Y. (Ying), Pashayan, N. (Nora), Batra, J. (Jyotsna), Grönberg, H. (Henrik), Neal, D. (David), Nordestgaard, B.G. (Børge), Tangen, C.M. (Catherine M.), Southey, M.C. (Melissa), Wolk, K. (Kerstin), Albanes, D. (Demetrius), Haiman, C.A. (Christopher), Travis, S.P.L. (Simon), Stanford, J.L. (Janet L.), Mucci, L.A. (Lorelei A.), West, C.M.L. (Catharine M. L.), Nielsen, S.F. (Sune F.), Kibel, A. (Adam), Cussenot, O. (Olivier), Berndt, S.I. (Sonja), Koutros, S. (Stella), Sørensen, K.D. (Karina Dalsgaard), Cybulski, C. (Cezary), Grindedal, E.M. (Eli Marie), Park, J.Y. (Jong Y.), Ingles, S.A. (Sue), Maier, C. (Christiane), Hamilton, R.J. (Robert J.), Rosenstein, B.S. (Barry S.), Vega, A. (Ana), Kogevinas, M. (Manolis), Wiklund, F. (Fredrik), Penney, K.L. (Kathryn L.), Brenner, H. (Hermann), John, E.M. (Esther), Kaneva, R. (Radka), Logothetis, N.K. (Nikos), Floris, O.A.M., De Ruyck, K. (Kim), Razack, A. (Azad), Newcomb, L.F. (Lisa F.), Lessel, D. (Davor), Usmani, N. (Nawaid), Claessens, F., Gago-Dominguez, M. (Manuela), Townsend, P.A. (Paul A.), Roobol-Bouts, M.J. (Monique), and Teixeira, P.J.
Abstract: The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case–control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1–3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.
Published: 2020
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47. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

Author: Ramus S.J., Carroll J.S., Schneeweiss A., Schoemaker M.J., Schottker B., Schurmann P., Scott C., Scott R.J., Senter L., Shah M., Sharma P., Shen C.-Y., Shu X.-O., Singer C.F., Slavin T.P., Smichkoska S., Spinelli J.J., Spurdle A.B., Sutter C., Swerdlow A.J., Tamimi R.M., Tan Y.Y., Tapper W.J., Taylor J., Teixeira M.R., Tengstrom M., Teo S.H., Terry M.B., Teule A., Thomassen M., Thull D.L., Toland A.E., Tollenaar R.A.E.M., Tomlinson I., Torres D., Torres-Mejia G., Troester M.A., Truong T., Tung N., Tzardi M., Ulmer H.-U., Vachon C.M., van der Kolk L.E., van Rensburg E.J., Vega A., Viel A., Vijai J., Vogel M.J., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Wildiers H., Winqvist R., Wolk A., Wu A.H., Yannoukakos D., Zhang Y., Zheng W., Hunter D., Pharoah P.D.P., Chang-Claude J., Garcia-Closas M., Schmidt M.K., Kristensen V.N., French J.D., Antoniou A.C., Chenevix-Trench G., Simard J., Easton D.F., Kraft P., Allen J., Harris M., Fachal L., Aschard H., Beesley J., Barnes D.R., Kar S., Pooley K.A., Dennis J., Michailidou K., Turman C., Soucy P., Lemacon A., Lush M., Tyrer J.P., Ghoussaini M., Marjaneh M.M., Jiang X., Agata S., Aittomaki K., Alonso M.R., Andrulis I.L., Anton-Culver H., Antonenkova N.N., Arason A., Arndt V., Aronson K.J., Arun B.K., Auber B., Auer P.L., Azzollini J., Balmana J., Barkardottir R.B., Barrowdale D., Beeghly-Fadiel A., Benitez J., Bermisheva M., Bialkowska K., Blanco A.M., Blomqvist C., Blot W., Bogdanova N.V., Bojesen S.E., Bolla M.K., Bonanni B., Borg A., Bosse K., Brauch H., Brenner H., Briceno I., Brock I.W., Brooks-Wilson A., Bruning T., Burwinkel B., Buys S.S., Cai Q., Caldes T., Caligo M.A., Camp N.J., Campbell I., Carter B.D., Castelao J.E., Chiquette J., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Mari V., Berthet P., Castera L., Vaur D., Lallaoui H., Bignon Y.-J., Uhrhammer N., Bonadona V., Lasset C., Revillion F., Vennin P., Muller D., Gomes D.M., Ingster O., Coupier I., Pujol P., Collonge-Rame M.-A., Mortemousque I., Bera O., Rose M., Baurand A., Bertolone G., Faivre L., Dreyfus H., Leroux D., Venat-Bouvet L., Bezieau S., Delnatte C., Chiesa J., Gilbert-Dussardier B., Gesta P., Prieur F.P., Bronner M., Sokolowska J., Coulet F., Boutry-Kryza N., Calender A., Giraud S., Leone M., Fert-Ferrer S., Stoppa-Lyonnet D., Jiao Y., Lesueur F.L., Mebirouk N., Barouk-Simonet E., Bubien V., Longy M., Sevenet N., Gladieff L., Toulas C., Reimineras A., Sobol H., Paillerets B.B.-D., Cabaret O., Caron O., Guillaud-Bataille M., Rouleau E., Belotti M., Buecher B., Caputo S., Colas C., Pauw A.D., Fourme E., Gauthier-Villars M., Golmard L., Moncoutier V., Saule C., Donaldson A., Murray A., Brady A., Brewer C., Pottinger C., Miller C., Gallagher D., Gregory H., Cook J., Eason J., Adlard J., Barwell J., Ong K.-R., Snape K., Walker L., Izatt L., Side L., Tischkowitz M., Rogers M.T., Porteous M.E., Ahmed M., Morrison P.J., Brennan P., Eeles R., Davidson R., Collee J.M., Cornelissen S., Couch F.J., Cox A., Cross S.S., Cybulski C., Czene K., Daly M.B., de la Hoya M., Devilee P., Diez O., Ding Y.C., Dite G.S., Domchek S.M., Dork T., dos-Santos-Silva I., Droit A., Dubois S., Dumont M., Duran M., Durcan L., Dwek M., Eccles D.M., Engel C., Eriksson M., Evans D.G., Fasching P.A., Fletcher O., Floris G., Flyger H., Foretova L., Foulkes W.D., Friedman E., Fritschi L., Frost D., Gabrielson M., Gago-Dominguez M., Gambino G., Ganz P.A., Gapstur S.M., Garber J., Garcia-Saenz J.A., Gaudet M.M., Georgoulias V., Giles G., Glendon G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Tibiletti M.G., Greene M.H., Grip M., Gronwald J., Grundy A., Guenel P., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Harrington P.A., Hartikainen J.M., Hartman M., He W., Healey C.S., Heemskerk-Gerritsen B.A.M., Heyworth J., Hillemanns P., Hogervorst F.B.L., Hollestelle A., Hooning M., Hopper J., Howell A., Huang G., Hulick P.J., Imyanitov E.N., Sexton A., Christian A., Trainer A., Spigelman A., Fellows A., Shelling A., Fazio A.D., Blackburn A., Crook A., Meiser B., Patterson B., Clarke C., Saunders C., Hunt C., Amor D., Marsh D., Edkins E., Salisbury E., Haan E., Neidermayr E., Macrea F., Farshid G., Lindeman G., Trench G., Mann G., Gill G., Thorne H., Hickie I., Winship I., Flanagan J., Kollias J., Visvader J., Stone J., Burke J., Saunus J., Forbes J., French J., Tucker K., Wu K., Phillips K., Lipton L., Andrews L., Lobb L., Kentwell M., Spurdle M., Cummings M., Gleeson M., Jenkins M., Young M.A., Delatycki M., Wallis M., Burgess M., Price M., Brown M., Southey M., Bogwitz M., Field M., Friedlander M., Gattas M., Saleh M., Hayward N., Pachter N., Cohen P., Duijf P., James P., Simpson P., Fong P., Butow P., Williams R., Kefford R., Scott R., Milne R.L., Balleine R., Dawson S.-J., Lok S., O'Connell S., Greening S., Nightingale S., Edwards S., Fox S., McLachlan S.-A., Lakhani S., Antill Y., Aalfs C., Meijers-Heijboer H., van Engelen K., Gille H., Boere I., Collee M., van Deurzen C., Obdeijn I.-M., van den Ouweland A., Seynaeve C., Siesling S., Verloop J., van Asperen C., van Cronenburg T., Blok R., de Boer M., Garcia E.G., Adank M., Hogervorst F., Jenner D., van Leeuwen F., Rookus M., Russell N., Schmidt M., van den Belt-Dusebout S., Kets C., Mensenkamp A., de Bock T., van der Hout A., Mourits M., Oosterwijk J., Ausems M., Koudijs M., Baxter R., Yip D., Carpenter J., Davis A., Pathmanathan N., Graham D., Sachchithananthan M., Isaacs C., Iwasaki M., Jager A., Jakimovska M., Jakubowska A., Janavicius R., Jankowitz R.C., John E.M., Johnson N., Jones M.E., Jukkola-Vuorinen A., Jung A., Kaaks R., Kang D., Kapoor P.M., Karlan B.Y., Keeman R., Kerin M.J., Khusnutdinova E., Kiiski J.I., Kirk J., Kitahara C.M., Ko Y.-D., Konstantopoulou I., Kosma V.-M., Koutros S., Kubelka-Sabit K., Kwong A., Kyriacou K., Laitman Y., Lambrechts D., Lee E., Leslie G., Lester J., Lesueur F., Lindblom A., Lo W.-Y., Long J., Lophatananon A., Loud J.T., Lubinski J., MacInnis R.J., Maishman T., Makalic E., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Matsuo K., Maurer T., Mavroudis D., Mayes R., McGuffog L., McLean C., Meindl A., Miller A., Miller N., Montagna M., Moreno F., Muir K., Mulligan A.M., Munoz-Garzon V.M., Muranen T.A., Narod S.A., Nassir R., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Neven P., Nielsen F.C., Nikitina-Zake L., Norman A., Offit K., Olah E., Olopade O.I., Olsson H., Orr N., Osorio A., Pankratz V.S., Papp J., Park S.K., Park-Simon T.-W., Parsons M.T., Paul J., Pedersen I.S., Peissel B., Peshkin B., Peterlongo P., Peto J., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Presneau N., Prokofyeva D., Pujana M.A., Pylkas K., Radice P., Canzian F., Rantala J., Rau-Murthy R., Rennert G., Risch H.A., Robson M., Romero A., Rossing M., Saloustros E., Sanchez-Herrero E., Sandler D.P., Santamarina M., Sawyer E.J., Scheuner M.T., Schmidt D.F., Schmutzler R.K., Ramus S.J., Carroll J.S., Schneeweiss A., Schoemaker M.J., Schottker B., Schurmann P., Scott C., Scott R.J., Senter L., Shah M., Sharma P., Shen C.-Y., Shu X.-O., Singer C.F., Slavin T.P., Smichkoska S., Spinelli J.J., Spurdle A.B., Sutter C., Swerdlow A.J., Tamimi R.M., Tan Y.Y., Tapper W.J., Taylor J., Teixeira M.R., Tengstrom M., Teo S.H., Terry M.B., Teule A., Thomassen M., Thull D.L., Toland A.E., Tollenaar R.A.E.M., Tomlinson I., Torres D., Torres-Mejia G., Troester M.A., Truong T., Tung N., Tzardi M., Ulmer H.-U., Vachon C.M., van der Kolk L.E., van Rensburg E.J., Vega A., Viel A., Vijai J., Vogel M.J., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Wildiers H., Winqvist R., Wolk A., Wu A.H., Yannoukakos D., Zhang Y., Zheng W., Hunter D., Pharoah P.D.P., Chang-Claude J., Garcia-Closas M., Schmidt M.K., Kristensen V.N., French J.D., Antoniou A.C., Chenevix-Trench G., Simard J., Easton D.F., Kraft P., Allen J., Harris M., Fachal L., Aschard H., Beesley J., Barnes D.R., Kar S., Pooley K.A., Dennis J., Michailidou K., Turman C., Soucy P., Lemacon A., Lush M., Tyrer J.P., Ghoussaini M., Marjaneh M.M., Jiang X., Agata S., Aittomaki K., Alonso M.R., Andrulis I.L., Anton-Culver H., Antonenkova N.N., Arason A., Arndt V., Aronson K.J., Arun B.K., Auber B., Auer P.L., Azzollini J., Balmana J., Barkardottir R.B., Barrowdale D., Beeghly-Fadiel A., Benitez J., Bermisheva M., Bialkowska K., Blanco A.M., Blomqvist C., Blot W., Bogdanova N.V., Bojesen S.E., Bolla M.K., Bonanni B., Borg A., Bosse K., Brauch H., Brenner H., Briceno I., Brock I.W., Brooks-Wilson A., Bruning T., Burwinkel B., Buys S.S., Cai Q., Caldes T., Caligo M.A., Camp N.J., Campbell I., Carter B.D., Castelao J.E., Chiquette J., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Mari V., Berthet P., Castera L., Vaur D., Lallaoui H., Bignon Y.-J., Uhrhammer N., Bonadona V., Lasset C., Revillion F., Vennin P., Muller D., Gomes D.M., Ingster O., Coupier I., Pujol P., Collonge-Rame M.-A., Mortemousque I., Bera O., Rose M., Baurand A., Bertolone G., Faivre L., Dreyfus H., Leroux D., Venat-Bouvet L., Bezieau S., Delnatte C., Chiesa J., Gilbert-Dussardier B., Gesta P., Prieur F.P., Bronner M., Sokolowska J., Coulet F., Boutry-Kryza N., Calender A., Giraud S., Leone M., Fert-Ferrer S., Stoppa-Lyonnet D., Jiao Y., Lesueur F.L., Mebirouk N., Barouk-Simonet E., Bubien V., Longy M., Sevenet N., Gladieff L., Toulas C., Reimineras A., Sobol H., Paillerets B.B.-D., Cabaret O., Caron O., Guillaud-Bataille M., Rouleau E., Belotti M., Buecher B., Caputo S., Colas C., Pauw A.D., Fourme E., Gauthier-Villars M., Golmard L., Moncoutier V., Saule C., Donaldson A., Murray A., Brady A., Brewer C., Pottinger C., Miller C., Gallagher D., Gregory H., Cook J., Eason J., Adlard J., Barwell J., Ong K.-R., Snape K., Walker L., Izatt L., Side L., Tischkowitz M., Rogers M.T., Porteous M.E., Ahmed M., Morrison P.J., Brennan P., Eeles R., Davidson R., Collee J.M., Cornelissen S., Couch F.J., Cox A., Cross S.S., Cybulski C., Czene K., Daly M.B., de la Hoya M., Devilee P., Diez O., Ding Y.C., Dite G.S., Domchek S.M., Dork T., dos-Santos-Silva I., Droit A., Dubois S., Dumont M., Duran M., Durcan L., Dwek M., Eccles D.M., Engel C., Eriksson M., Evans D.G., Fasching P.A., Fletcher O., Floris G., Flyger H., Foretova L., Foulkes W.D., Friedman E., Fritschi L., Frost D., Gabrielson M., Gago-Dominguez M., Gambino G., Ganz P.A., Gapstur S.M., Garber J., Garcia-Saenz J.A., Gaudet M.M., Georgoulias V., Giles G., Glendon G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Tibiletti M.G., Greene M.H., Grip M., Gronwald J., Grundy A., Guenel P., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Harrington P.A., Hartikainen J.M., Hartman M., He W., Healey C.S., Heemskerk-Gerritsen B.A.M., Heyworth J., Hillemanns P., Hogervorst F.B.L., Hollestelle A., Hooning M., Hopper J., Howell A., Huang G., Hulick P.J., Imyanitov E.N., Sexton A., Christian A., Trainer A., Spigelman A., Fellows A., Shelling A., Fazio A.D., Blackburn A., Crook A., Meiser B., Patterson B., Clarke C., Saunders C., Hunt C., Amor D., Marsh D., Edkins E., Salisbury E., Haan E., Neidermayr E., Macrea F., Farshid G., Lindeman G., Trench G., Mann G., Gill G., Thorne H., Hickie I., Winship I., Flanagan J., Kollias J., Visvader J., Stone J., Burke J., Saunus J., Forbes J., French J., Tucker K., Wu K., Phillips K., Lipton L., Andrews L., Lobb L., Kentwell M., Spurdle M., Cummings M., Gleeson M., Jenkins M., Young M.A., Delatycki M., Wallis M., Burgess M., Price M., Brown M., Southey M., Bogwitz M., Field M., Friedlander M., Gattas M., Saleh M., Hayward N., Pachter N., Cohen P., Duijf P., James P., Simpson P., Fong P., Butow P., Williams R., Kefford R., Scott R., Milne R.L., Balleine R., Dawson S.-J., Lok S., O'Connell S., Greening S., Nightingale S., Edwards S., Fox S., McLachlan S.-A., Lakhani S., Antill Y., Aalfs C., Meijers-Heijboer H., van Engelen K., Gille H., Boere I., Collee M., van Deurzen C., Obdeijn I.-M., van den Ouweland A., Seynaeve C., Siesling S., Verloop J., van Asperen C., van Cronenburg T., Blok R., de Boer M., Garcia E.G., Adank M., Hogervorst F., Jenner D., van Leeuwen F., Rookus M., Russell N., Schmidt M., van den Belt-Dusebout S., Kets C., Mensenkamp A., de Bock T., van der Hout A., Mourits M., Oosterwijk J., Ausems M., Koudijs M., Baxter R., Yip D., Carpenter J., Davis A., Pathmanathan N., Graham D., Sachchithananthan M., Isaacs C., Iwasaki M., Jager A., Jakimovska M., Jakubowska A., Janavicius R., Jankowitz R.C., John E.M., Johnson N., Jones M.E., Jukkola-Vuorinen A., Jung A., Kaaks R., Kang D., Kapoor P.M., Karlan B.Y., Keeman R., Kerin M.J., Khusnutdinova E., Kiiski J.I., Kirk J., Kitahara C.M., Ko Y.-D., Konstantopoulou I., Kosma V.-M., Koutros S., Kubelka-Sabit K., Kwong A., Kyriacou K., Laitman Y., Lambrechts D., Lee E., Leslie G., Lester J., Lesueur F., Lindblom A., Lo W.-Y., Long J., Lophatananon A., Loud J.T., Lubinski J., MacInnis R.J., Maishman T., Makalic E., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Matsuo K., Maurer T., Mavroudis D., Mayes R., McGuffog L., McLean C., Meindl A., Miller A., Miller N., Montagna M., Moreno F., Muir K., Mulligan A.M., Munoz-Garzon V.M., Muranen T.A., Narod S.A., Nassir R., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Neven P., Nielsen F.C., Nikitina-Zake L., Norman A., Offit K., Olah E., Olopade O.I., Olsson H., Orr N., Osorio A., Pankratz V.S., Papp J., Park S.K., Park-Simon T.-W., Parsons M.T., Paul J., Pedersen I.S., Peissel B., Peshkin B., Peterlongo P., Peto J., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Presneau N., Prokofyeva D., Pujana M.A., Pylkas K., Radice P., Canzian F., Rantala J., Rau-Murthy R., Rennert G., Risch H.A., Robson M., Romero A., Rossing M., Saloustros E., Sanchez-Herrero E., Sandler D.P., Santamarina M., Sawyer E.J., Scheuner M.T., Schmidt D.F., and Schmutzler R.K.
Abstract: Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.Copyright © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
Published: 2020

48. Transcriptome-wide association study of breast cancer risk by estrogen-receptor status.

Author: Eriksson M., Peterlongo P., Peto J., Pharoah P.D.P., Phillips K.-A., Plaseska-Karanfilska D., Poppe B., Pradhan N., Prajzendanc K., Presneau N., Punie K., Pylkas K., Radice P., Rantala J., Rashid M.U., Rennert G., Risch H.A., Robson M., Romero A., Saloustros E., Sandler D.P., Santos C., Sawyer E.J., Schmidt M.K., Schmidt D.F., Schmutzler R.K., Schoemaker M.J., Scott R.J., Sharma P., Shu X.-O., Simard J., Singer C.F., Skytte A.-B., Soucy P., Southey M.C., Spinelli J.J., Spurdle A.B., Stone J., Swerdlow A.J., Tapper W.J., Taylor J.A., Teixeira M.R., Terry M.B., Teule A., Thomassen M., Thone K., Thull D.L., Tischkowitz M., Toland A.E., Tollenaar R.A.E.M., Torres D., Truong T., Tung N., Vachon C.M., van Asperen C.J., van den Ouweland A.M.W., van Rensburg E.J., Vega A., Viel A., Vieiro-Balo P., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Winqvist R., Yang X.R., Yannoukakos D., Ziogas A., Milne R.L., Easton D.F., Chenevix-Trench G., Zheng W., Kraft P., Jiang X., Feng H., Gusev A., Pasaniuc B., Wu L., Long J., Abu-full Z., Aittomaki K., Andrulis I.L., Anton-Culver H., Antoniou A.C., Arason A., Arndt V., Aronson K.J., Arun B.K., Asseryanis E., Auer P.L., Azzollini J., Balmana J., Barkardottir R.B., Barnes D.R., Barrowdale D., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bialkowska K., Blanco A., Blomqvist C., Boeckx B., Bogdanova N.V., Bojesen S.E., Bolla M.K., Bonanni B., Borg A., Brauch H., Brenner H., Briceno I., Broeks A., Bruning T., Burwinkel B., Cai Q., Caldes T., Caligo M.A., Campbell I., Canisius S., Campa D., Carter B.D., Carter J., Castelao J.E., Chang-Claude J., Chanock S.J., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Couch F.J., Cox A., Cross S.S., Cybulski C., Czene K., Daly M.B., de la Hoya M., De Leeneer K., Dennis J., Devilee P., Diez O., Domchek S.M., Dork T., dos-Santos-Silva I., Dunning A.M., Dwek M., Eccles D.M., Ejlertsen B., Ellberg C., Engel C., Fasching P.A., Fletcher O., Flyger H., Fostira F., Friedman E., Fritschi L., Frost D., Gabrielson M., Ganz P.A., Gapstur S.M., Garber J., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Giles G.G., Glendon G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Gronwald J., Guenel P., Haiman C.A., Hall P., Hamann U., Hake C., He W., Heyworth J., Hogervorst F.B.L., Hollestelle A., Hooning M.J., Hoover R.N., Hopper J.L., Huang G., Hulick P.J., Humphreys K., Imyanitov E.N., Isaacs C., Jakimovska M., Jakubowska A., James P., Janavicius R., Jankowitz R.C., John E.M., Johnson N., Joseph V., Jung A., Karlan B.Y., Khusnutdinova E., Kiiski J.I., Konstantopoulou I., Kristensen V.N., Laitman Y., Lambrechts D., Lazaro C., Leroux D., Leslie G., Lester J., Lesueur F., Lindor N., Lindstrom S., Lo W.-Y., Loud J.T., Lubinski J., Makalic E., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martens J.W.M., Martinez M.E., Matricardi L., Maurer T., Mavroudis D., McGuffog L., Meindl A., Menon U., Michailidou K., Kapoor P.M., Miller A., Montagna M., Moreno F., Moserle L., Mulligan A.M., Muranen T.A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nevelsteen I., Nielsen F.C., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Olsson H., Osorio A., Papp J., Park-Simon T.-W., Parsons M.T., Pedersen I.S., Peixoto A., Eriksson M., Peterlongo P., Peto J., Pharoah P.D.P., Phillips K.-A., Plaseska-Karanfilska D., Poppe B., Pradhan N., Prajzendanc K., Presneau N., Punie K., Pylkas K., Radice P., Rantala J., Rashid M.U., Rennert G., Risch H.A., Robson M., Romero A., Saloustros E., Sandler D.P., Santos C., Sawyer E.J., Schmidt M.K., Schmidt D.F., Schmutzler R.K., Schoemaker M.J., Scott R.J., Sharma P., Shu X.-O., Simard J., Singer C.F., Skytte A.-B., Soucy P., Southey M.C., Spinelli J.J., Spurdle A.B., Stone J., Swerdlow A.J., Tapper W.J., Taylor J.A., Teixeira M.R., Terry M.B., Teule A., Thomassen M., Thone K., Thull D.L., Tischkowitz M., Toland A.E., Tollenaar R.A.E.M., Torres D., Truong T., Tung N., Vachon C.M., van Asperen C.J., van den Ouweland A.M.W., van Rensburg E.J., Vega A., Viel A., Vieiro-Balo P., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Winqvist R., Yang X.R., Yannoukakos D., Ziogas A., Milne R.L., Easton D.F., Chenevix-Trench G., Zheng W., Kraft P., Jiang X., Feng H., Gusev A., Pasaniuc B., Wu L., Long J., Abu-full Z., Aittomaki K., Andrulis I.L., Anton-Culver H., Antoniou A.C., Arason A., Arndt V., Aronson K.J., Arun B.K., Asseryanis E., Auer P.L., Azzollini J., Balmana J., Barkardottir R.B., Barnes D.R., Barrowdale D., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bialkowska K., Blanco A., Blomqvist C., Boeckx B., Bogdanova N.V., Bojesen S.E., Bolla M.K., Bonanni B., Borg A., Brauch H., Brenner H., Briceno I., Broeks A., Bruning T., Burwinkel B., Cai Q., Caldes T., Caligo M.A., Campbell I., Canisius S., Campa D., Carter B.D., Carter J., Castelao J.E., Chang-Claude J., Chanock S.J., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Couch F.J., Cox A., Cross S.S., Cybulski C., Czene K., Daly M.B., de la Hoya M., De Leeneer K., Dennis J., Devilee P., Diez O., Domchek S.M., Dork T., dos-Santos-Silva I., Dunning A.M., Dwek M., Eccles D.M., Ejlertsen B., Ellberg C., Engel C., Fasching P.A., Fletcher O., Flyger H., Fostira F., Friedman E., Fritschi L., Frost D., Gabrielson M., Ganz P.A., Gapstur S.M., Garber J., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Giles G.G., Glendon G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Gronwald J., Guenel P., Haiman C.A., Hall P., Hamann U., Hake C., He W., Heyworth J., Hogervorst F.B.L., Hollestelle A., Hooning M.J., Hoover R.N., Hopper J.L., Huang G., Hulick P.J., Humphreys K., Imyanitov E.N., Isaacs C., Jakimovska M., Jakubowska A., James P., Janavicius R., Jankowitz R.C., John E.M., Johnson N., Joseph V., Jung A., Karlan B.Y., Khusnutdinova E., Kiiski J.I., Konstantopoulou I., Kristensen V.N., Laitman Y., Lambrechts D., Lazaro C., Leroux D., Leslie G., Lester J., Lesueur F., Lindor N., Lindstrom S., Lo W.-Y., Loud J.T., Lubinski J., Makalic E., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martens J.W.M., Martinez M.E., Matricardi L., Maurer T., Mavroudis D., McGuffog L., Meindl A., Menon U., Michailidou K., Kapoor P.M., Miller A., Montagna M., Moreno F., Moserle L., Mulligan A.M., Muranen T.A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nevelsteen I., Nielsen F.C., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Olsson H., Osorio A., Papp J., Park-Simon T.-W., Parsons M.T., Pedersen I.S., and Peixoto A.
Abstract: Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.Copyright © 2020 The Authors. Genetic Epidemiology published by Wiley Periodicals, Inc.
Published: 2020

49. An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk

Author: Wu, L. (Lang), Yang, Y. (Yaohua), Guo, X. (Xingyi), Shu, X.-O. (Xiao-Ou), Cai, Q. (Qiuyin), Shu, X. (Xiang), Li, B. (Bingshan), Tao, R. (Ran), Wu, C. (Chong), Nikas, J.B. (Jason B.), Sun, Y. (Yanfa), Zhu, J. (Jingjing), Roobol-Bouts, M.J. (Monique), Giles, G.G. (Graham G.), Brenner, H. (Hermann), John, E.M. (Esther M.), Clements, J. (Judith), Grindedal, E.M. (Eli Marie), Park, J.Y. (Jong Y.), Stanford, J.L. (Janet L.), Kote-Jarai, Z. (Zsofia), Haiman, C.A. (Christopher), Eeles, R.A. (Rosalind A.), Zheng, W. (Wei), Long, J. (Jirong), Henderson, B.E. (Brian E.), Haiman, C.A. (Christopher A.), Kote-Jarai, Z., Schumacher, F.R. (Fredrick R), Easton, D. (Douglas), Benlloch, S. (Sara), Olama, A.A.A. (Ali Amin Al), Muir, K.R. (K.), Berndt, S.I. (Sonja I.), Conti, G. (Giario), Wiklund, F. (Fredrik), Chanock, S.J. (Stephen), Gapstur, S.M. (Susan M.), Stevens, V.L. (Victoria L.), Tangen, C.M. (Catherine M.), Batra, J. (Jyotsna), Grönberg, H. (Henrik), Pashayan, N. (Nora), Schleutker, J. (Johanna), Albanes, D. (Demetrius), Weinstein, S. (Stephanie), Wolk, K. (Kerstin), West, C. (Catharine), Mucci, L. (Lorelei), Cancel-Tassin, G. (Géraldine), Koutros, S. (Stella), Sorensen, K.D. (Karina Dalsgaard), Neal, D. (David), Hamdy, F.C. (Freddie C.), Donovan, J. (Jenny), Travis, R.C. (Ruth C.), Hamilton, R.J. (Robert J.), Ingles, S.A. (Sue), Rosenstein, B.S. (Barry S.), Lu, Y.-J. (Yong-Jie), Kibel, A. (Adam), Vega, A. (Ana), Kogevinas, M. (Manolis), Penney, K.L. (Kathryn L.), Cybulski, C. (Cezary), Nordestgaard, B.G. (Børge), Maier, C. (Christiane), Kim, J. (Jongoh), John, E.M. (Esther), Teixeira, P.J., Floris, O.A.M., De Ruyck, K. (Kim), Razack, A. (Azad), Newcomb, L.F. (Lisa F.), Gamulin, M. (Marija), Kaneva, R. (Radka), Usmani, N. (Nawaid), Claessens, F. (Frank), Townsend, P.A. (Paul A.), Dominguez, M.G. (Manuela Gago), Menegaux, F. (Florence), Khaw, K.-T. (Kay-Tee), Cannon-Albright, L.A. (Lisa), Pandha, H. (Hardev), Thibodeau, S.N. (Stephen), Hunter, D.J. (David), Blot, W.J. (William), Riboli, E. (Elio), Eeles, R. (Rosalind), Neal, D.E. (David E.), Hamdy, F. (Freddie), Donovan, J.L. (Jenny L.), Schumacher, F.R. (Fredrick R.), Berndt, S.I. (Sonja), Chanock, S. (Stephen), Travis, S.P.L. (Simon), Hunter, D.J. (David J.), Gronberg, H. (Henrik), Wu, L. (Lang), Yang, Y. (Yaohua), Guo, X. (Xingyi), Shu, X.-O. (Xiao-Ou), Cai, Q. (Qiuyin), Shu, X. (Xiang), Li, B. (Bingshan), Tao, R. (Ran), Wu, C. (Chong), Nikas, J.B. (Jason B.), Sun, Y. (Yanfa), Zhu, J. (Jingjing), Roobol-Bouts, M.J. (Monique), Giles, G.G. (Graham G.), Brenner, H. (Hermann), John, E.M. (Esther M.), Clements, J. (Judith), Grindedal, E.M. (Eli Marie), Park, J.Y. (Jong Y.), Stanford, J.L. (Janet L.), Kote-Jarai, Z. (Zsofia), Haiman, C.A. (Christopher), Eeles, R.A. (Rosalind A.), Zheng, W. (Wei), Long, J. (Jirong), Henderson, B.E. (Brian E.), Haiman, C.A. (Christopher A.), Kote-Jarai, Z., Schumacher, F.R. (Fredrick R), Easton, D. (Douglas), Benlloch, S. (Sara), Olama, A.A.A. (Ali Amin Al), Muir, K.R. (K.), Berndt, S.I. (Sonja I.), Conti, G. (Giario), Wiklund, F. (Fredrik), Chanock, S.J. (Stephen), Gapstur, S.M. (Susan M.), Stevens, V.L. (Victoria L.), Tangen, C.M. (Catherine M.), Batra, J. (Jyotsna), Grönberg, H. (Henrik), Pashayan, N. (Nora), Schleutker, J. (Johanna), Albanes, D. (Demetrius), Weinstein, S. (Stephanie), Wolk, K. (Kerstin), West, C. (Catharine), Mucci, L. (Lorelei), Cancel-Tassin, G. (Géraldine), Koutros, S. (Stella), Sorensen, K.D. (Karina Dalsgaard), Neal, D. (David), Hamdy, F.C. (Freddie C.), Donovan, J. (Jenny), Travis, R.C. (Ruth C.), Hamilton, R.J. (Robert J.), Ingles, S.A. (Sue), Rosenstein, B.S. (Barry S.), Lu, Y.-J. (Yong-Jie), Kibel, A. (Adam), Vega, A. (Ana), Kogevinas, M. (Manolis), Penney, K.L. (Kathryn L.), Cybulski, C. (Cezary), Nordestgaard, B.G. (Børge), Maier, C. (Christiane), Kim, J. (Jongoh), John, E.M. (Esther), Teixeira, P.J., Floris, O.A.M., De Ruyck, K. (Kim), Razack, A. (Azad), Newcomb, L.F. (Lisa F.), Gamulin, M. (Marija), Kaneva, R. (Radka), Usmani, N. (Nawaid), Claessens, F. (Frank), Townsend, P.A. (Paul A.), Dominguez, M.G. (Manuela Gago), Menegaux, F. (Florence), Khaw, K.-T. (Kay-Tee), Cannon-Albright, L.A. (Lisa), Pandha, H. (Hardev), Thibodeau, S.N. (Stephen), Hunter, D.J. (David), Blot, W.J. (William), Riboli, E. (Elio), Eeles, R. (Rosalind), Neal, D.E. (David E.), Hamdy, F. (Freddie), Donovan, J.L. (Jenny L.), Schumacher, F.R. (Fredrick R.), Berndt, S.I. (Sonja), Chanock, S. (Stephen), Travis, S.P.L. (Simon), Hunter, D.J. (David J.), and Gronberg, H. (Henrik)
Abstract: It remains elusive whether some of the associations identified in genome-wide association studies of prostate cancer (PrCa) may be due to regulatory effects of genetic variants on CpG sites, which may further influence expression of PrCa target genes. To search for CpG
Published: 2020
Full Text: View/download PDF

50. Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

Author: Feng, H. (Helian), Gusev, A. (Alexander), Pasaniuc, B. (Bogdan), Wu, L. (Lang), Long, J. (Jirong), Abu-full, Z. (Zomoroda), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene L.), Anton-Culver, H. (Hoda), Antoniou, A.C. (Antonis C.), Arason, A. (Adalgeir), Arndt, V. (Volker), Aronson, K.J. (Kristan J.), Arun, B.K. (Banu), Asseryanis, E. (Ella), Auer, P.L. (Paul L.), Azzollini, J., Balmaña, J. (Judith), Barkardottir, R.B. (Rosa B.), Barnes, D. (Daniel), Barrowdale, D. (Daniel), Beckmann, M.W. (Matthias), Behrens, T.W. (Timothy), Benítez, J. (Javier), Bermisheva, M. (Marina), Białkowska, K. (Katarzyna), Blanco, A. (Ana), Blomqvist, C. (Carl), Boeckx, B. (Bram), Bogdanova, N.V. (Natalia V.), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet K.), Bonnani, B. (Bernardo), Borg, Å. (Åke), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Briceno, I. (Ignacio), Broeks, A. (Annegien), Brüning, T. (Thomas), Burwinkel, B. (Barbara), Cai, Q. (Qiuyin), Caldes, T. (Trinidad), Caligo, M.A. (Maria A.), Campbell, I. (Ian), Canisius, S. (Sander), Campa, D. (Daniele), Carter, B.D. (Brian D.), Carter, J. (Jonathan), Castelao, J.E. (Jose ), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen), Christiansen, H. (Hans), Chung, W. (Wendy), Claes, K.B.M. (Kathleen B. M.), Clarke, C. (Christine), Couch, F.J. (Fergus), Cox, A. (Angela), Cross, S.S. (Simon S.), Cybulski, C. (Cezary), Czene, K. (Kamila), Daly, M.B. (Mary), de la Hoya, M. (Miguel), De Leeneer, K. (Kim), Dennis, J. (Joe), Devilee, P. (Peter), Diez, O. (Orland), Domchek, S.M. (Susan), Dörk, T. (Thilo), Santos Silva, I. (Isabel) dos, Dunning, A.M. (Alison M.), Dwek, M. (Miriam), Eccles, D.M. (Diana M.), Ejlertsen, B. (Bent), Ellberg, C. (Carolina), Engel, C. (Christoph), Eriksson, M. (Mikael), Fasching, P.A. (Peter), Fletcher, O. (Olivia), Flyger, H. (Henrik), Fostira, F. (Florentia), Friedman, E. (Eitan), Fritschi, L. (Lin), Frost, D. (Debra), Gabrielson, M. (Marike), Ganz, P.A. (Patricia A.), Gapstur, S.M. (Susan M.), Garber, J. (Judy), García-Closas, M. (Montserrat), García-Sáenz, J.A. (José A.), Gaudet, M.M. (Mia M.), Giles, G.G. (Graham G.), Glendon, G. (Gord), Godwin, A.K. (Andrew), Goldberg, M.S. (Mark), Radice, P. (Paolo), González-Neira, A. (Anna), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Guénel, P. (Pascal), Haiman, C.A. (Christopher), Hall, P. (Per), Hamann, U. (Ute), Hake, C. (Christopher), He, W. (Wei), Heyworth, J. (Jane), Hogervorst, F.B.L. (Frans B.L.), Hollestelle, A. (Antoinette), Hooning, M.J. (Maartje J.), Hoover, R.N. (Robert), Hopper, J.L. (John), Huang, G. (Guanmengqian), Hulick, P.J. (Peter J.), Humphreys, K. (Keith), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Jakimovska, M. (Milena), Jakubowska, A. (Anna), James, M. (Margaret), Janavicius, R. (Ramunas), Jankowitz, R.C. (Rachel C.), John, E.M. (Esther), Johnson, N. (Nichola), Joseph, V. (Vijai), Jung, A. (Audrey), Karlan, B.Y. (Beth), Khusnutdinova, E.K. (Elza), Kiiski, J.I. (Johanna I.), Konstantopoulou, I. (Irene), Kristensen, V. (Vessela), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lázaro, C. (Conxi), Leroux, D. (Dominique), Leslie, G. (Goska), Lester, J. (Jenny), Lesueur, F. (Fabienne), Lindor, N.M. (Noralane), Lindström, S. (Sara), Lo, W.-Y. (Wing-Yee), Loud, J.T. (Jennifer T.), Lubinski, J. (Jan), Makalic, E. (Enes), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Manoukian, S. (Siranoush), Margolin, S. (Sara), Martens, J.W.M. (John), Martinez, M.E. (Maria E.), Matricardi, L. (Laura), Maurer, T. (Tabea), Mavroudis, D. (Dimitris), McGuffog, L. (Lesley), Meindl, A. (Alfons), Menon, U. (Usha), Michailidou, K. (Kyriaki), Kapoor, P.M. (Pooja M.), Miller, A. (Austin), Montagna, M. (Marco), Moreno, F. (Fernando), Moserle, L. (Lidia), Mulligan, A.-M. (Anna-Marie), Muranen, T.A. (Taru A.), Nathanson, K.L. (Katherine), Floris, O.A.M., Nevanlinna, H. (Heli), Nevelsteen, I. (Ines), Nielsen, F. (Finn), Nikitina-Zake, L. (Liene), Offit, K. (Kenneth), Olah, E., Olopade, O.I. (Olofunmilayo), Olsson, H. (Håkan), Osorio, A. (Ana), Papp, J. (Janos), Park-Simon, T.-W. (Tjoung-Won), Parsons, M. (Marilyn), Pedersen, I.S. (Inge S.), Peixoto, A. (Ana), Peterlongo, P. (Paolo), Peto, J. (Julian), Pharoah, P.D.P. (Paul), Phillips, K.-A. (Kelly-Anne), Plaseska-Karanfilska, D. (Dijana), Poppe, B. (Bruce), Pradhan, N. (Nisha), Prajzendanc, K. (Karolina), Presneau, N. (Nadege), Punie, K. (Kevin), Pylkäs, K. (Katri), Rantala, J. (Johanna), Rashid, M.U. (Muhammad), Rennert, G. (Gad), Risch, H.A. (Harvey A.), Robson, M. (Mark), Romero, A. (Atocha), Saloustros, E. (Emmanouil), Sandler, D.P. (Dale P.), Santos, C. (Catarina), Sawyer, E.J. (Elinor), Schmidt, M.K. (Marjanka), Schmidt, D.F. (Daniel), Schmutzler, R.K. (Rita), Schoemaker, M.J. (Minouk J.), Scott, R.J. (Rodney), Sharma, P. (Priyanka), Shu, X.-O. (Xiao-Ou), Simard, J. (Jacques), Singer, C.F. (Christian), Skytte, A.-B. (Anne-Bine), Soucy, P. (Penny), Southey, M.C. (Melissa), Spinelli, J.J. (John J.), Spurdle, A.B. (Amanda), Stone, J. (Jennifer), Swerdlow, A.J. (Anthony ), Tapper, W.J. (William J.), Taylor, J.A. (Jack A.), Teixeira, P.J., Terry, M.B. (Mary Beth), Teulé, A. (Alex), Thomassen, M. (Mads), Thöne, K. (Kathrin), Thull, D.L. (Darcy L.), Tischkowitz, M. (Marc), Toland, A.E. (Amanda), Tollenaar, R.A.E.M. (Rob), Torres, D. (Diana), Truong, T. (Thérèse), Tung, N. (Nadine), Vachon, C. (Celine), van Asperen, C.J. (Christi J.), Ouweland, A.M.W. (Ans) van den, Rensburg, E.J. (Elizabeth) van, Vega, A. (Ana), Viel, A. (Alessandra), Vieiro-Balo, P. (Paula), Wang, Q. (Qin), Wappenschmidt, B. (Barbara), Weinberg, C.R. (Clarice R.), Weitzel, J.N. (Jeffrey), Wendt, C. (Camilla), Winqvist, R. (Robert), Yang, X.R. (Xiaohong R.), Yannoukakos, D. (Drakoulis), Ziogas, A. (Argyrios), Milne, R.L. (Roger), Adamo, P. (Pio) d', Chenevix-Trench, G. (Georgia), Zheng, W. (Wei), Kraft, P. (Peter), Jiang, X. (Xia), Feng, H. (Helian), Gusev, A. (Alexander), Pasaniuc, B. (Bogdan), Wu, L. (Lang), Long, J. (Jirong), Abu-full, Z. (Zomoroda), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene L.), Anton-Culver, H. (Hoda), Antoniou, A.C. (Antonis C.), Arason, A. (Adalgeir), Arndt, V. (Volker), Aronson, K.J. (Kristan J.), Arun, B.K. (Banu), Asseryanis, E. (Ella), Auer, P.L. (Paul L.), Azzollini, J., Balmaña, J. (Judith), Barkardottir, R.B. (Rosa B.), Barnes, D. (Daniel), Barrowdale, D. (Daniel), Beckmann, M.W. (Matthias), Behrens, T.W. (Timothy), Benítez, J. (Javier), Bermisheva, M. (Marina), Białkowska, K. (Katarzyna), Blanco, A. (Ana), Blomqvist, C. (Carl), Boeckx, B. (Bram), Bogdanova, N.V. (Natalia V.), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet K.), Bonnani, B. (Bernardo), Borg, Å. (Åke), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Briceno, I. (Ignacio), Broeks, A. (Annegien), Brüning, T. (Thomas), Burwinkel, B. (Barbara), Cai, Q. (Qiuyin), Caldes, T. (Trinidad), Caligo, M.A. (Maria A.), Campbell, I. (Ian), Canisius, S. (Sander), Campa, D. (Daniele), Carter, B.D. (Brian D.), Carter, J. (Jonathan), Castelao, J.E. (Jose ), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen), Christiansen, H. (Hans), Chung, W. (Wendy), Claes, K.B.M. (Kathleen B. M.), Clarke, C. (Christine), Couch, F.J. (Fergus), Cox, A. (Angela), Cross, S.S. (Simon S.), Cybulski, C. (Cezary), Czene, K. (Kamila), Daly, M.B. (Mary), de la Hoya, M. (Miguel), De Leeneer, K. (Kim), Dennis, J. (Joe), Devilee, P. (Peter), Diez, O. (Orland), Domchek, S.M. (Susan), Dörk, T. (Thilo), Santos Silva, I. (Isabel) dos, Dunning, A.M. (Alison M.), Dwek, M. (Miriam), Eccles, D.M. (Diana M.), Ejlertsen, B. (Bent), Ellberg, C. (Carolina), Engel, C. (Christoph), Eriksson, M. (Mikael), Fasching, P.A. (Peter), Fletcher, O. (Olivia), Flyger, H. (Henrik), Fostira, F. (Florentia), Friedman, E. (Eitan), Fritschi, L. (Lin), Frost, D. (Debra), Gabrielson, M. (Marike), Ganz, P.A. (Patricia A.), Gapstur, S.M. (Susan M.), Garber, J. (Judy), García-Closas, M. (Montserrat), García-Sáenz, J.A. (José A.), Gaudet, M.M. (Mia M.), Giles, G.G. (Graham G.), Glendon, G. (Gord), Godwin, A.K. (Andrew), Goldberg, M.S. (Mark), Radice, P. (Paolo), González-Neira, A. (Anna), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Guénel, P. (Pascal), Haiman, C.A. (Christopher), Hall, P. (Per), Hamann, U. (Ute), Hake, C. (Christopher), He, W. (Wei), Heyworth, J. (Jane), Hogervorst, F.B.L. (Frans B.L.), Hollestelle, A. (Antoinette), Hooning, M.J. (Maartje J.), Hoover, R.N. (Robert), Hopper, J.L. (John), Huang, G. (Guanmengqian), Hulick, P.J. (Peter J.), Humphreys, K. (Keith), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Jakimovska, M. (Milena), Jakubowska, A. (Anna), James, M. (Margaret), Janavicius, R. (Ramunas), Jankowitz, R.C. (Rachel C.), John, E.M. (Esther), Johnson, N. (Nichola), Joseph, V. (Vijai), Jung, A. (Audrey), Karlan, B.Y. (Beth), Khusnutdinova, E.K. (Elza), Kiiski, J.I. (Johanna I.), Konstantopoulou, I. (Irene), Kristensen, V. (Vessela), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lázaro, C. (Conxi), Leroux, D. (Dominique), Leslie, G. (Goska), Lester, J. (Jenny), Lesueur, F. (Fabienne), Lindor, N.M. (Noralane), Lindström, S. (Sara), Lo, W.-Y. (Wing-Yee), Loud, J.T. (Jennifer T.), Lubinski, J. (Jan), Makalic, E. (Enes), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Manoukian, S. (Siranoush), Margolin, S. (Sara), Martens, J.W.M. (John), Martinez, M.E. (Maria E.), Matricardi, L. (Laura), Maurer, T. (Tabea), Mavroudis, D. (Dimitris), McGuffog, L. (Lesley), Meindl, A. (Alfons), Menon, U. (Usha), Michailidou, K. (Kyriaki), Kapoor, P.M. (Pooja M.), Miller, A. (Austin), Montagna, M. (Marco), Moreno, F. (Fernando), Moserle, L. (Lidia), Mulligan, A.-M. (Anna-Marie), Muranen, T.A. (Taru A.), Nathanson, K.L. (Katherine), Floris, O.A.M., Nevanlinna, H. (Heli), Nevelsteen, I. (Ines), Nielsen, F. (Finn), Nikitina-Zake, L. (Liene), Offit, K. (Kenneth), Olah, E., Olopade, O.I. (Olofunmilayo), Olsson, H. (Håkan), Osorio, A. (Ana), Papp, J. (Janos), Park-Simon, T.-W. (Tjoung-Won), Parsons, M. (Marilyn), Pedersen, I.S. (Inge S.), Peixoto, A. (Ana), Peterlongo, P. (Paolo), Peto, J. (Julian), Pharoah, P.D.P. (Paul), Phillips, K.-A. (Kelly-Anne), Plaseska-Karanfilska, D. (Dijana), Poppe, B. (Bruce), Pradhan, N. (Nisha), Prajzendanc, K. (Karolina), Presneau, N. (Nadege), Punie, K. (Kevin), Pylkäs, K. (Katri), Rantala, J. (Johanna), Rashid, M.U. (Muhammad), Rennert, G. (Gad), Risch, H.A. (Harvey A.), Robson, M. (Mark), Romero, A. (Atocha), Saloustros, E. (Emmanouil), Sandler, D.P. (Dale P.), Santos, C. (Catarina), Sawyer, E.J. (Elinor), Schmidt, M.K. (Marjanka), Schmidt, D.F. (Daniel), Schmutzler, R.K. (Rita), Schoemaker, M.J. (Minouk J.), Scott, R.J. (Rodney), Sharma, P. (Priyanka), Shu, X.-O. (Xiao-Ou), Simard, J. (Jacques), Singer, C.F. (Christian), Skytte, A.-B. (Anne-Bine), Soucy, P. (Penny), Southey, M.C. (Melissa), Spinelli, J.J. (John J.), Spurdle, A.B. (Amanda), Stone, J. (Jennifer), Swerdlow, A.J. (Anthony ), Tapper, W.J. (William J.), Taylor, J.A. (Jack A.), Teixeira, P.J., Terry, M.B. (Mary Beth), Teulé, A. (Alex), Thomassen, M. (Mads), Thöne, K. (Kathrin), Thull, D.L. (Darcy L.), Tischkowitz, M. (Marc), Toland, A.E. (Amanda), Tollenaar, R.A.E.M. (Rob), Torres, D. (Diana), Truong, T. (Thérèse), Tung, N. (Nadine), Vachon, C. (Celine), van Asperen, C.J. (Christi J.), Ouweland, A.M.W. (Ans) van den, Rensburg, E.J. (Elizabeth) van, Vega, A. (Ana), Viel, A. (Alessandra), Vieiro-Balo, P. (Paula), Wang, Q. (Qin), Wappenschmidt, B. (Barbara), Weinberg, C.R. (Clarice R.), Weitzel, J.N. (Jeffrey), Wendt, C. (Camilla), Winqvist, R. (Robert), Yang, X.R. (Xiaohong R.), Yannoukakos, D. (Drakoulis), Ziogas, A. (Argyrios), Milne, R.L. (Roger), Adamo, P. (Pio) d', Chenevix-Trench, G. (Georgia), Zheng, W. (Wei), Kraft, P. (Peter), and Jiang, X. (Xia)
Abstract: Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.
Published: 2020
Full Text: View/download PDF

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