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5. History of hypertension, heart disease, and diabetes and ovarian cancer patient survival: evidence from the ovarian cancer association consortium

Author

Minlikeeva, AN, Freudenheim, JL, Cannioto, RA, Szender, JB, Eng, KH, Modugno, F, Ness, RB, LaMonte, MJ, Friel, G, Segal, BH, Odunsi, K, Mayor, P, Zsiros, E, Schmalfeldt, B, Klapdor, R, Doerk, T, Hillemanns, P, Kelemen, LE, Kobel, M, Steed, H, de Fazio, A, Jordan, SJ, Nagle, CM, Risch, HA, Rossing, MA, Doherty, JA, Goodman, MT, Edwards, R, Matsuo, K, Mizuno, M, Karlan, BY, Kjaer, SK, Hogdall, E, Jensen, A, Schildkraut, JM, Terry, KL, Cramer, DW, Bandera, EV, Paddock, LE, Kiemeney, LA, Massuger, LF, Kupryjanczyk, J, Berchuck, A, Chang-Claude, J, Diergaarde, B, Webb, PM, Moysich, KB, Grp, AOCS, and Consortium, OCA

Subjects
Australian Ovarian Cancer Study Group, Risk, Adult, Heart Diseases, Epidemiology, Ovarian Cancer Association Consortium, Adrenergic beta-Antagonists, Oncology and Carcinogenesis, Medications, Cardiovascular, Disease-Free Survival, Rare Diseases, Clinical Research, Diabetes Mellitus, Genetics, Humans, Insulin, Hypoglycemic Agents, Mortality, Aged, Cancer, Ovarian Neoplasms, screening and diagnosis, Beta blockers, Ovarian cancer prognosis, Diabetes, Middle Aged, Ovarian Cancer, 4.1 Discovery and preclinical testing of markers and technologies, Survival Rate, Detection, Good Health and Well Being, Hypertension, Public Health and Health Services, Female
Abstract

PurposeSurvival following ovarian cancer diagnosis is generally low; understanding factors related to prognosis could be important to optimize treatment. The role of previously diagnosed comorbidities and use of medications for those conditions in relation to prognosis for ovarian cancer patients has not been studied extensively, particularly according to histological subtype.MethodsUsing pooled data from fifteen studies participating in the Ovarian Cancer Association Consortium, we examined the associations between history of hypertension, heart disease, diabetes, and medications taken for these conditions and overall survival (OS) and progression-free survival (PFS) among patients diagnosed with invasive epithelial ovarian carcinoma. We used Cox proportional hazards regression models adjusted for age and stage to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and within strata of histological subtypes.ResultsHistory of diabetes was associated with increased risk of mortality (n = 7,674; HR = 1.12; 95% CI = 1.01-1.25). No significant mortality associations were observed for hypertension (n = 6,482; HR = 0.95; 95% CI = 0.88-1.02) or heart disease (n = 4,252; HR = 1.05; 95% CI = 0.87-1.27). No association of these comorbidities was found with PFS in the overall study population. However, among patients with endometrioid tumors, hypertension was associated with lower risk of progression (n = 339, HR = 0.54; 95% CI = 0.35-0.84). Comorbidity was not associated with OS or PFS for any of the other histological subtypes. Ever use of beta blockers, oral antidiabetic medications, and insulin was associated with increased mortality, HR = 1.20; 95% CI = 1.03-1.40, HR = 1.28; 95% CI = 1.05-1.55, and HR = 1.63; 95% CI = 1.20-2.20, respectively. Ever use of diuretics was inversely associated with mortality, HR = 0.71; 95% CI = 0.53-0.94.ConclusionsHistories of hypertension, diabetes, and use of diuretics, beta blockers, insulin, and oral antidiabetic medications may influence the survival of ovarian cancer patients. Understanding mechanisms for these observations could provide insight regarding treatment.

Published
2017

6. Risk of Ovarian Cancer and the NF-? B Pathway: Genetic Association with IL1A and TNFSF10

Author

Charbonneau, B., Block, M. S., Bamlet, W. R., Vierkant, R. A., Kalli, K. R., Fogarty, Z., Rider, D. N., Sellers, T. A., Tworoger, S. S., Poole, E., Risch, H. A., Salvesen, H. B., Kiemeney, L. A., Baglietto, L., Giles, G. G., Severi, G., Trabert, B., Wentzensen, N., Chenevix-Trench, G., Whittemore, A. S., Sieh, W., Chang-Claude, J., Bandera, E. V., Orlow, I., Terry, K., Goodman, M. T., Thompson, P. J., Cook, L. S., Rossing, M. A., Ness, R. B., Narod, S. A., Kupryjanczyk, J., Lu, K., Butzow, R., Dork, T., Pejovic, T., Campbell, I., Le, N. D., Bunker, C. H., Bogdanova, N., Runnebaum, I. B., Eccles, D., Paul, J., Wu, A. H., Gayther, S. A., Hogdall, E., Heitz, F., Kaye, S. B., Karlan, B. Y., Anton-Culver, H., Gronwald, J., Hogdall, C. K., Lambrechts, D., Fasching, P. A., Menon, U., Schildkraut, J., Pearce, C. L., Levine, D. A., Kjaer, S. K., Cramer, D., Flanagan, J. M., Phelan, C. M., Brown, R., Massuger, L. F. A. G., Song, H., Doherty, J. A., Krakstad, C., Liang, D., Odunsi, K., Berchuck, A., Jensen, A., Lubinski, J., Nevanlinna, H., Bean, Y. T., Lurie, G., Ziogas, A., Walsh, C., Despierre, E., Brinton, L., Hein, A., Rudolph, A., Dansonka-Mieszkowska, A., Olson, S. H., Harter, P., Tyrer, J., Vitonis, A. F., Brooks-Wilson, A., Aben, K. K., Pike, M. C., Ramus, S. J., Wik, E., Cybulski, C., Lin, J., Sucheston, L., Edwards, R., McGuire, V., Lester, J., du Bois, A., Lundvall, L., Wang-Gohrke, S., Szafron, L. M., Lambrechts, S., Yang, H., Beckmann, M. W., Pelttari, L. M., Van Altena, A. M., van den Berg, D., Halle, M. K., Gentry-Maharaj, A., Schwaab, I., Chandran, U., Menkiszak, J., Ekici, A. B., Wilkens, L. R., Leminen, A., Modugno, F., Friel, G., Rothstein, J. H., Vergote, I., Garcia-Closas, M., Hildebrandt, M. A. T., Sobiczewski, P., Kelemen, L. E., Pharoah, P. D. P., Moysich, K., Knutson, K. L., Cunningham, J. M., Fridley, B. L., and Goode, E. L.

Published
2014
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7. History of Comorbidities and Survival of Ovarian Cancer Patients, Results from the Ovarian Cancer Association Consortium

Author

Minlikeeva, A.N., Freudenheim, J.L., Eng, K.H., Cannioto, R.A., Friel, G., Szender, J.B., Segal, B., Odunsi, K., Mayor, P., Diergaarde, B., Zsiros, E., Kelemen, L.E., Kobel, M., Steed, H., Defazio, A., Jordan, S.J., Fasching, P.A., Beckmann, M.W., Risch, H.A., Rossing, M.A., Doherty, J.A., Chang-Claude, J., Goodman, M.T., Dork, T., Edwards, R., Modugno, F., Ness, R.B., Matsuo, K., Mizuno, M., Karlan, B.Y., Goode, E.L., Kjaer, S.K., Hogdall, E., Schildkraut, J.M., Terry, K.L., Cramer, D.W, Bandera, E.V., Paddock, L.E., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Sutphen, R., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S.A., Ramus, S.J., Gentry-Maharaj, A., Pearce, C.L., Wu, A.H., Kupryjanczyk, J., Jensen, A., Webb, P.M., Moysich, K.B., Minlikeeva, A.N., Freudenheim, J.L., Eng, K.H., Cannioto, R.A., Friel, G., Szender, J.B., Segal, B., Odunsi, K., Mayor, P., Diergaarde, B., Zsiros, E., Kelemen, L.E., Kobel, M., Steed, H., Defazio, A., Jordan, S.J., Fasching, P.A., Beckmann, M.W., Risch, H.A., Rossing, M.A., Doherty, J.A., Chang-Claude, J., Goodman, M.T., Dork, T., Edwards, R., Modugno, F., Ness, R.B., Matsuo, K., Mizuno, M., Karlan, B.Y., Goode, E.L., Kjaer, S.K., Hogdall, E., Schildkraut, J.M., Terry, K.L., Cramer, D.W, Bandera, E.V., Paddock, L.E., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Sutphen, R., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S.A., Ramus, S.J., Gentry-Maharaj, A., Pearce, C.L., Wu, A.H., Kupryjanczyk, J., Jensen, A., Webb, P.M., and Moysich, K.B.

Abstract

Contains fulltext : 177359.pdf (publisher's version ) (Closed access), Background: Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between individual concurrent comorbidities and prognosis in ovarian cancer patients.Methods: Among patients diagnosed with invasive ovarian carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival. Using Cox proportional hazards regression models adjusted for age at diagnosis, stage of disease, histology, and study site, we estimated pooled HRs and 95% confidence intervals to assess associations between each comorbidity and ovarian cancer outcomes.Results: None of the comorbidities were associated with ovarian cancer outcome in the overall sample nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced).Conclusions: Histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, or neurologic diseases were not associated with ovarian cancer overall or progression-free survival.Impact: These previously diagnosed chronic diseases do not appear to affect ovarian cancer prognosis. Cancer Epidemiol Biomarkers Prev; 26(9); 1470-3. (c)2017 AACR.

Published
2017

8. History of hypertension, heart disease, and diabetes and ovarian cancer patient survival: evidence from the ovarian cancer association consortium

Author

Minlikeeva, A.N., Freudenheim, J.L., Cannioto, R.A., Szender, J.B., Eng, K.H., Modugno, F., Ness, R.B., LaMonte, M.J., Friel, G., Segal, B.H., Odunsi, K., Mayor, P., Zsiros, E., Schmalfeldt, B., Klapdor, R., Drk, T., Hillemanns, P., Kelemen, L.E., Kbel, M., Steed, H., Fazio, A. de, Jordan, S.J., Nagle, C.M., Risch, H.A., Rossing, M.A., Doherty, J.A., Goodman, M.T., Edwards, R., Matsuo, K., Mizuno, M., Karlan, B.Y., Kjaer, S.K., Hogdall, E., Jensen, A., Schildkraut, J.M., Terry, K.L., Cramer, D.W, Bandera, E.V., Paddock, L.E., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Kupryjanczyk, J., Berchuck, A., Chang-Claude, J., Diergaarde, B., Webb, P.M., Moysich, K.B., Minlikeeva, A.N., Freudenheim, J.L., Cannioto, R.A., Szender, J.B., Eng, K.H., Modugno, F., Ness, R.B., LaMonte, M.J., Friel, G., Segal, B.H., Odunsi, K., Mayor, P., Zsiros, E., Schmalfeldt, B., Klapdor, R., Drk, T., Hillemanns, P., Kelemen, L.E., Kbel, M., Steed, H., Fazio, A. de, Jordan, S.J., Nagle, C.M., Risch, H.A., Rossing, M.A., Doherty, J.A., Goodman, M.T., Edwards, R., Matsuo, K., Mizuno, M., Karlan, B.Y., Kjaer, S.K., Hogdall, E., Jensen, A., Schildkraut, J.M., Terry, K.L., Cramer, D.W, Bandera, E.V., Paddock, L.E., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Kupryjanczyk, J., Berchuck, A., Chang-Claude, J., Diergaarde, B., Webb, P.M., and Moysich, K.B.

Abstract

Contains fulltext : 174140.pdf (publisher's version ) (Closed access), PURPOSE: Survival following ovarian cancer diagnosis is generally low; understanding factors related to prognosis could be important to optimize treatment. The role of previously diagnosed comorbidities and use of medications for those conditions in relation to prognosis for ovarian cancer patients has not been studied extensively, particularly according to histological subtype. METHODS: Using pooled data from fifteen studies participating in the Ovarian Cancer Association Consortium, we examined the associations between history of hypertension, heart disease, diabetes, and medications taken for these conditions and overall survival (OS) and progression-free survival (PFS) among patients diagnosed with invasive epithelial ovarian carcinoma. We used Cox proportional hazards regression models adjusted for age and stage to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and within strata of histological subtypes. RESULTS: History of diabetes was associated with increased risk of mortality (n = 7,674; HR = 1.12; 95% CI = 1.01-1.25). No significant mortality associations were observed for hypertension (n = 6,482; HR = 0.95; 95% CI = 0.88-1.02) or heart disease (n = 4,252; HR = 1.05; 95% CI = 0.87-1.27). No association of these comorbidities was found with PFS in the overall study population. However, among patients with endometrioid tumors, hypertension was associated with lower risk of progression (n = 339, HR = 0.54; 95% CI = 0.35-0.84). Comorbidity was not associated with OS or PFS for any of the other histological subtypes. Ever use of beta blockers, oral antidiabetic medications, and insulin was associated with increased mortality, HR = 1.20; 95% CI = 1.03-1.40, HR = 1.28; 95% CI = 1.05-1.55, and HR = 1.63; 95% CI = 1.20-2.20, respectively. Ever use of diuretics was inversely associated with mortality, HR = 0.71; 95% CI = 0.53-0.94. CONCLUSIONS: Histories of hypertension, diabetes, and use of diuretics, beta blockers, insulin, and oral antidi

Published
2017

9. History of thyroid disease and survival of ovarian cancer patients: results from the Ovarian Cancer Association Consortium, a brief report.

Author

Minlikeeva, AN, Freudenheim, JL, Cannioto, RA, Eng, KH, Szender, JB, Mayor, P, Etter, JL, Cramer, DW, Diergaarde, B, Doherty, JA, Dörk, T, Edwards, R, deFazio, A, Friel, G, Goodman, MT, Hillemanns, P, Høgdall, E, Jensen, A, Jordan, SJ, Karlan, BY, Kjær, SK, Klapdor, R, Matsuo, K, Mizuno, M, Nagle, CM, Odunsi, K, Paddock, L, Rossing, MA, Schildkraut, JM, Schmalfeldt, B, Segal, BH, Starbuck, K, Terry, KL, Webb, PM, Zsiros, E, Ness, RB, Modugno, F, Bandera, EV, Chang-Claude, J, Moysich, KB, Minlikeeva, AN, Freudenheim, JL, Cannioto, RA, Eng, KH, Szender, JB, Mayor, P, Etter, JL, Cramer, DW, Diergaarde, B, Doherty, JA, Dörk, T, Edwards, R, deFazio, A, Friel, G, Goodman, MT, Hillemanns, P, Høgdall, E, Jensen, A, Jordan, SJ, Karlan, BY, Kjær, SK, Klapdor, R, Matsuo, K, Mizuno, M, Nagle, CM, Odunsi, K, Paddock, L, Rossing, MA, Schildkraut, JM, Schmalfeldt, B, Segal, BH, Starbuck, K, Terry, KL, Webb, PM, Zsiros, E, Ness, RB, Modugno, F, Bandera, EV, Chang-Claude, J, and Moysich, KB

Abstract

BACKGROUND: Findings from in vitro studies suggest that increased exposure to thyroid hormones can influence progression of ovarian tumours. However, epidemiologic evidence on this topic is limited. METHODS: We pooled data from 11 studies from the Ovarian Cancer Association Consortium. Using multivariate Cox proportional hazards models, we estimated associations between hyper- and hypothyroidism and medications prescribed for these conditions with 5-year all-cause survival among women diagnosed with invasive ovarian cancer. RESULTS: Overall, there was a nonsignificant association with history of hyperthyroidism (n=160 cases) and mortality (HR=1.22; 95% CI=0.97-1.53). Furthermore, diagnosis of hyperthyroidism within the 5 years before ovarian cancer diagnosis was associated with an increased risk of death (HR=1.94; 95% CI=1.19-3.18). A more modest association was observed with history of hypothyroidism (n=624 cases) and mortality (HR=1.16; 95% CI=1.03-1.31). Neither duration of hypothyroidism nor use of thyroid medications was associated with survival. CONCLUSIONS: In this large study of women with ovarian cancer, we found that recent history of hyperthyroidism and overall history of hypothyroidism were associated with worse 5-year survival.

Published
2017

10. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Author

Hampras, SS, Sucheston-Campbell, LE, Cannioto, R, Chang-Claude, J, Modugno, F, Dörk, T, Hillemanns, P, Preus, L, Knutson, KL, Wallace, PK, Hong, CC, Friel, G, Davis, W, Nesline, M, Pearce, CL, Kelemen, LE, Goodman, MT, Bandera, EV, Terry, KL, Schoof, N, Eng, KH, Clay, A, Singh, PK, Joseph, JM, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bean, Y, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Cook, LS, Cramer, DW, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Despierre, E, Dicks, E, Doherty, JA, du Bois, A, Dürst, M, Easton, D, Eccles, D, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Gronwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hogdall, C, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, BT, Karlan, BY, Kellar, M, Kelley, JL, Kiemeney, LA, Klapdor, R, Kolomeyevskaya, N, Krakstad, C, Kjaer, SK, Kruszka, B, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lissowska, J, Liu, S, and Lu, K

Subjects
endocrine system diseases, female genital diseases and pregnancy complications
Abstract

Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. Results: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). Conclusions: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Published
2016

11. PALB2, CHEK2 and ATM rare variants and cancer risk:data from COGS

Author

Southey, M. C. (Melissa C.), Goldgar, D. E. (David E.), Winqvist, R. (Robert), Pylkäs, K. (Katri), Couch, F. (Fergus), Tischkowitz, M. (Marc), Foulkes, W. D. (William D.), Dennis, J. (Joe), Michailidou, K. (Kyriaki), van Rensburg, E. J. (Elizabeth J.), Heikkinen, T. (Tuomas), Nevanlinna, H. (Heli), Hopper, J. L. (John L.), Doerk, T. (Thilo), Claes, K. B. (Kathleen B. M.), Reis-Filho, J. (Jorge), Teo, Z. L. (Zhi Ling), Radice, P. (Paolo), Catucci, I. (Irene), Peterlongo, P. (Paolo), Tsimiklis, H. (Helen), Odefrey, F. A. (Fabrice A.), Dowty, J. G. (James G.), Schmidt, M. K. (Marjanka K.), Broeks, A. (Annegien), Hogervorst, F. B. (Frans B.), Verhoef, S. (Senno), Carpenter, J. (Jane), Clarke, C. (Christine), Scott, R. J. (Rodney J.), Fasching, P. A. (Peter A.), Haeberle, L. (Lothar), Ekici, A. B. (Arif B.), Beckmann, M. W. (Matthias W.), Peto, J. (Julian), dos-Santos-Silva, I. (Isabel), Fletcher, O. (Olivia), Johnson, N. (Nichola), Bolla, M. K. (Manjeet K.), Sawyer, E. J. (Elinor J.), Tomlinson, I. (Ian), Kerin, M. J. (Michael J.), Miller, N. (Nicola), Marme, F. (Federik), Burwinkel, B. (Barbara), Yang, R. (Rongxi), Guenel, P. (Pascal), Menegaux, F. (Florence), Sanchez, M. (Marie), Bojesen, S. (Stig), Nielsen, S. F. (Sune F.), Flyger, H. (Henrik), Benitez, J. (Javier), Pilar Zamora, M. (M.), Arias Perez, J. I. (Jose Ignacio), Menendez, P. (Primitiva), Anton-Culver, H. (Hoda), Neuhausen, S. (Susan), Ziogas, A. (Argyrios), Clarke, C. A. (Christina A.), Brenner, H. (Hermann), Arndt, V. (Volker), Stegmaier, C. (Christa), Brauch, H. (Hiltrud), Bruening, T. (Thomas), Ko, Y.-D. (Yon-Dschun), Muranen, T. A. (Taru A.), Aittomaki, K. (Kristiina), Blomqvist, C. (Carl), Bogdanova, N. V. (Natalia V.), Antonenkova, N. N. (Natalia N.), Lindblom, A. (Annika), Margolin, S. (Sara), Mannermaa, A. (Arto), Kataja, V. (Vesa), Kosma, V.-M. (Veli-Matti), Hartikainen, J. M. (Jaana M.), Spurdle, A. B. (Amanda B.), Wauters, E. (Els), Smeets, D. (Dominiek), Beuselinck, B. (Benoit), Floris, G. (Giuseppe), Chang-Claude, J. (Jenny), Rudolph, A. (Anja), Seibold, P. (Petra), Flesch-Janys, D. (Dieter), Olson, J. E. (Janet E.), Vachon, C. (Celine), Pankratz, V. S. (Vernon S.), McLean, C. (Catriona), Haiman, C. A. (Christopher A.), Henderson, B. E. (Brian E.), Schumacher, F. (Fredrick), Le Marchand, L. (Loic), Kristensen, V. (Vessela), Alnaes, G. G. (Grethe Grenaker), Zheng, W. (Wei), Hunter, D. J. (David J.), Lindstrom, S. (Sara), Hankinson, S. E. (Susan E.), Kraft, P. (Peter), Andrulis, I. (Irene), Knight, J. A. (Julia A.), Glendon, G. (Gord), Mulligan, A. M. (Anna Marie), Jukkola-Vuorinen, A. (Arja), Grip, M. (Mervi), Kauppila, S. (Saila), Devilee, P. (Peter), Tollenaar, R. A. (Robert A. E. M.), Seynaeve, C. (Caroline), Hollestelle, A. (Antoinette), Garcia-Closas, M. (Montserrat), Figueroa, J. (Jonine), Chanock, S. J. (Stephen J.), Lissowska, J. (Jolanta), Czene, K. (Kamila), Darabi, H. (Hatef), Eriksson, M. (Mikael), Eccles, D. M. (Diana M.), Rafiq, S. (Sajjad), Tapper, W. J. (William J.), Gerty, S. M. (Sue M.), Hooning, M. J. (Maartje J.), Martens, J. W. (John W. M.), Collee, J. M. (J. Margriet), Tilanus-Linthorst, M. (Madeleine), Hall, P. (Per), Li, J. (Jingmei), Brand, J. S. (Judith S.), Humphreys, K. (Keith), Cox, A. (Angela), Reed, M. W. (Malcolm W. R.), Luccarini, C. (Craig), Baynes, C. (Caroline), Dunning, A. M. (Alison M.), Hamann, U. (Ute), Torres, D. (Diana), Ulmer, H. U. (Hans Ulrich), Ruediger, T. (Thomas), Jakubowska, A. (Anna), Lubinski, J. (Jan), Jaworska, K. (Katarzyna), Durda, K. (Katarzyna), Slager, S. (Susan), Toland, A. E. (Amanda E.), Ambrosone, C. B. (Christine B.), Yannoukakos, D. (Drakoulis), Swerdlow, A. (Anthony), Ashworth, A. (Alan), Orr, N. (Nick), Jones, M. (Michael), Gonzalez-Neira, A. (Anna), Pita, G. (Guillermo), Rosario Alonso, M. (M.), Alvarez, N. (Nuria), Herrero, D. (Daniel), Tessier, D. C. (Daniel C.), Vincent, D. (Daniel), Bacot, F. (Francois), Simard, J. (Jacques), Dumont, M. (Martine), Soucy, P. (Penny), Eeles, R. (Rosalind), Muir, K. (Kenneth), Wiklund, F. (Fredrik), Gronberg, H. (Henrik), Schleutker, J. (Johanna), Nordestgaard, B. G. (Borge G.), Weischer, M. (Maren), Travis, R. C. (Ruth C.), Neal, D. (David), Donovan, J. L. (Jenny L.), Hamdy, F. C. (Freddie C.), Khaw, K.-T. (Kay-Tee), Stanford, J. L. (Janet L.), Blot, W. J. (William J.), Thibodeau, S. (Stephen), Schaid, D. J. (Daniel J.), Kelley, J. L. (Joseph L.), Maier, C. (Christiane), Kibel, A. S. (Adam S.), Cybulski, C. (Cezary), Cannon-Albright, L. (Lisa), Butterbach, K. (Katja), Park, J. (Jong), Kaneva, R. (Radka), Batra, J. (Jyotsna), Teixeira, M. R. (Manuel R.), Kote-Jarai, Z. (Zsofia), Al Olama, A. A. (Ali Amin), Benlloch, S. (Sara), Renner, S. P. (Stefan P.), Hartmann, A. (Arndt), Hein, A. (Alexander), Ruebner, M. (Matthias), Lambrechts, D. (Diether), Van Nieuwenhuysen, E. (Els), Vergote, I. (Ignace), Lambretchs, S. (Sandrina), Doherty, J. A. (Jennifer A.), Rossing, M. A. (Mary Anne), Nickels, S. (Stefan), Eilber, U. (Ursula), Wang-Gohrke, S. (Shan), Odunsi, K. (Kunle), Sucheston-Campbell, L. E. (Lara E.), Friel, G. (Grace), Lurie, G. (Galina), Killeen, J. L. (Jeffrey L.), Wilkens, L. R. (Lynne R.), Goodman, M. T. (Marc T.), Runnebaum, I. (Ingo), Hillemanns, P. A. (Peter A.), Pelttari, L. M. (Liisa M.), Butzow, R. (Ralf), Modugno, F. (Francesmary), Edwards, R. P. (Robert P.), Ness, R. B. (Roberta B.), Moysich, K. B. (Kirsten B.), du Bois, A. (Andreas), Heitz, F. (Florian), Harter, P. (Philipp), Kommoss, S. (Stefan), Karlan, B. Y. (Beth Y.), Walsh, C. (Christine), Lester, J. (Jenny), Jensen, A. (Allan), Kjaer, S. K. (Susanne Kruger), Hogdall, E. (Estrid), Peissel, B. (Bernard), Bonanni, B. (Bernardo), Bernard, L. (Loris), Goode, E. L. (Ellen L.), Fridley, B. L. (Brooke L.), Vierkant, R. A. (Robert A.), Cunningham, J. M. (Julie M.), Larson, M. C. (Melissa C.), Fogarty, Z. C. (Zachary C.), Kalli, K. R. (Kimberly R.), Liang, D. (Dong), Lu, K. H. (Karen H.), Hildebrandt, M. A. (Michelle A. T.), Wu, X. (Xifeng), Levine, D. A. (Douglas A.), Dao, F. (Fanny), Bisogna, M. (Maria), Berchuck, A. (Andrew), Iversen, E. S. (Edwin S.), Marks, J. R. (Jeffrey R.), Akushevich, L. (Lucy), Cramer, D. W. (Daniel W.), Schildkraut, J. (Joellen), Terry, K. L. (Kathryn L.), Poole, E. M. (Elizabeth M.), Stampfer, M. (Meir), Tworoger, S. S. (Shelley S.), Bandera, E. V. (Elisa V.), Orlow, I. (Irene), Olson, S. H. (Sara H.), Bjorge, L. (Line), Salvesen, H. B. (Helga B.), van Altena, A. M. (Anne M.), Aben, K. K. (Katja K. H.), Kiemeney, L. A. (Lambertus A.), Massuger, L. F. (Leon F. A. G.), Pejovic, T. (Tanja), Bean, Y. (Yukie), Brooks-Wilson, A. (Angela), Kelemen, L. E. (Linda E.), Cook, L. S. (Linda S.), Le, N. D. (Nhu D.), Grski, B. (Bohdan), Gronwald, J. (Jacek), Menkiszak, J. (Janusz), Hogdall, C. K. (Claus K.), Lundvall, L. (Lene), Nedergaard, L. (Lotte), Engelholm, S. A. (Svend Aage), Dicks, E. (Ed), Tyrer, J. (Jonathan), Campbell, I. (Ian), McNeish, I. (Iain), Paul, J. (James), Siddiqui, N. (Nadeem), Glasspool, R. (Rosalind), Whittemore, A. S. (Alice S.), Rothstein, J. H. (Joseph H.), McGuire, V. (Valerie), Sieh, W. (Weiva), Cai, H. (Hui), Shu, X.-O. (Xiao-Ou), Teten, R. T. (Rachel T.), Sutphen, R. (Rebecca), McLaughlin, J. R. (John R.), Narod, S. A. (Steven A.), Phelan, C. M. (Catherine M.), Monteiro, A. N. (Alvaro N.), Fenstermacher, D. (David), Lin, H.-Y. (Hui-Yi), Permuth, J. B. (Jennifer B.), Sellers, T. A. (Thomas A.), Chen, Y. A. (Y. Ann), Tsai, Y.-Y. (Ya-Yu), Chen, Z. (Zhihua), Gentry-Maharaj, A. (Aleksandra), Gayther, S. A. (Simon A.), Ramus, S. J. (Susan J.), Menon, U. (Usha), Wu, A. H. (Anna H.), Pearce, C. L. (Celeste L.), Van den Berg, D. (David), Pike, M. C. (Malcolm C.), Dansonka-Mieszkowska, A. (Agnieszka), Plisiecka-Halasa, J. (Joanna), Moes-Sosnowska, J. (Joanna), Kupryjanczyk, J. (Jolanta), Pharoah, P. D. (Paul D. P.), Song, H. (Honglin), Winship, I. (Ingrid), Chenevix-Trench, G. (Georgia), Giles, G. G. (Graham G.), Tavtigian, S. V. (Sean V.), Easton, D. F. (Doug F.), and Milne, R. L. (Roger L.)

Subjects
skin and connective tissue diseases
Abstract

Background: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p = 7.1 × 10⁻⁵), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p = 6.9 × 10⁻⁸) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p = 0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p ≤ 0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p = 0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p = 0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

Published
2016

12. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Author

Hampras, S.S., Sucheston-Campbell, L.E., Cannioto, R., Chang-Claude, J., Modugno, F., Dork, T., Hillemanns, P., Preus, L., Knutson, K.L., Wallace, P.K., Hong, C.C., Friel, G., Davis, W., Nesline, M., Pearce, C.L., Kelemen, L.E., Goodman, M.T., Bandera, E.V., Terry, K.L., Schoof, N., Eng, K.H., Clay, A., Singh, P.K., Joseph, J.M., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Baker, H., Bean, Y., Beckmann, M.W., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Bruinsma, F., Butzow, R., Campbell, I.G., Carty, K., Cook, L.S., Cramer, D.W, Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Despierre, E., Dicks, E., Doherty, J.A., Bois, A. du, Durst, M., Easton, D., Eccles, D., Edwards, R.P., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Gronwald, J., Harrington, P., Harter, P., Hasmad, H.N., Hein, A., Heitz, F., Hildebrandt, M.A.T., Hogdall, C., Hogdall, E., Hosono, S., Iversen, E.S., Jakubowska, A., Jensen, A., Ji, B.T., Karlan, B.Y., Kellar, M., Kelley, J.L., Kiemeney, L.A.L.M., Klapdor, R., Kolomeyevskaya, N., Krakstad, C., Kjaer, S.K., Kruszka, B., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, A.W., Lele, S., Leminen, A., Lester, J., Levine, D.A., Liang, D., Lissowska, J., Liu, S., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F.A.G., Matsuo, K., McGuire, V., et al., Hampras, S.S., Sucheston-Campbell, L.E., Cannioto, R., Chang-Claude, J., Modugno, F., Dork, T., Hillemanns, P., Preus, L., Knutson, K.L., Wallace, P.K., Hong, C.C., Friel, G., Davis, W., Nesline, M., Pearce, C.L., Kelemen, L.E., Goodman, M.T., Bandera, E.V., Terry, K.L., Schoof, N., Eng, K.H., Clay, A., Singh, P.K., Joseph, J.M., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Baker, H., Bean, Y., Beckmann, M.W., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Bruinsma, F., Butzow, R., Campbell, I.G., Carty, K., Cook, L.S., Cramer, D.W, Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Despierre, E., Dicks, E., Doherty, J.A., Bois, A. du, Durst, M., Easton, D., Eccles, D., Edwards, R.P., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Gronwald, J., Harrington, P., Harter, P., Hasmad, H.N., Hein, A., Heitz, F., Hildebrandt, M.A.T., Hogdall, C., Hogdall, E., Hosono, S., Iversen, E.S., Jakubowska, A., Jensen, A., Ji, B.T., Karlan, B.Y., Kellar, M., Kelley, J.L., Kiemeney, L.A.L.M., Klapdor, R., Kolomeyevskaya, N., Krakstad, C., Kjaer, S.K., Kruszka, B., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, A.W., Lele, S., Leminen, A., Lester, J., Levine, D.A., Liang, D., Lissowska, J., Liu, S., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F.A.G., Matsuo, K., McGuire, V., and et al.

Abstract

Contains fulltext : 167177.pdf (publisher's version ) (Open Access), BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Published
2016

13. No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer

Author

Hollestelle, A. (Antoinette), Baan, F.H. (Frederieke) van der, Berchuck, A. (Andrew), Johnatty, S.E. (Sharon), Aben, K.K.H. (Katja), Agnarsson, B.A. (Bjarni), Aittomäki, K. (Kristiina), Alducci, E. (Elisa), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Antonenkova, N.N. (Natalia), Antoniou, A.C. (Antonis), Apicella, C. (Carmel), Arndt, V. (Volker), Arnold, N. (Norbert), Arun, B.K. (Banu), Arver, B. (Brita Wasteson), Ashworth, A. (Alan), Baglietto, L. (Laura), Balleine, R. (Rosemary), Bandera, E.V. (Elisa), Barrowdale, D. (Daniel), Bean, Y.T. (Yukie), Beckmann, L. (Lars), Beckmann, M.W. (Matthias), Benítez, J. (Javier), Berger, A. (Andreas), Berger, R. (Raanan), Beuselinck, B. (B.), Bisogna, M. (Maria), Bjorge, L. (Line), Blomqvist, C. (Carl), Bogdanova, N.V. (Natalia), Bojesen, A. (Anders), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet), Bonnani, B. (Bernardo), Brand, J.S. (Judith S.), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brinton, L.A. (Louise), Brooks-Wilson, A. (Angela), Bruinsma, F. (Fiona), Brunet, J. (Joan), Brüning, T. (Thomas), Budzilowska, A. (Agnieszka), Bunker, C.H. (Clareann H.), Burwinkel, B. (Barbara), Butzow, R. (Ralf), Buys, S.S. (Saundra S.), Caligo, M.A. (Maria), Campbell, I. (Ian), Carter, J. (Jonathan), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen J.), Claes, K.B.M. (Kathleen B.M.), Collée, J.M. (Margriet), Cook, L.S. (Linda S.), Couch, F.J. (Fergus), Cox, A. (Angela), Cramer, D.W. (Daniel), Cross, S.S. (Simon), Cunningham, J.M. (Julie), Cybulski, C. (Cezary), Czene, K. (Kamila), Damiola, F. (Francesca), Dansonka-Mieszkowska, A. (Agnieszka), Darabi, H. (Hatef), Hoya, M. (Miguel) de La, DeFazio, A. (Anna), Dennis, J. (Joe), Devilee, P. (Peter), Dicks, E. (Ed), Díez, O. (Orland), Doherty, J.A. (Jennifer A.), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Santos Silva, I. (Isabel) dos, Du Bois, A. (Andreas), Dumont, M. (Martine), Dunning, A.M. (Alison), Duran, M. (Mercedes), Easton, D.F. (Douglas F.), Eccles, D. (Diana), Edwards, R. (Robert), Ehrencrona, H. (Hans), Ejlertsen, B. (Bent), Ekici, A.B. (Arif), Ellis, S.D. (Steve), Engel, C. (Christoph), Eriksson, M. (Mikael), Fasching, P.A. (Peter), Feliubadaló, L. (L.), Figueroa, J.D. (Jonine), Flesch-Janys, D. (Dieter), Fletcher, O. (Olivia), Fontaine, A. (Annette), Fortuzzi, S. (S.), Fostira, F. (Florentia), Fridley, B.L. (Brooke), Friebel, M.O.W. (Mark ), Friedman, E. (Eitan), Friel, G. (Grace), Frost, D. (Debra), Garber, J. (Judy), García-Closas, M. (Montserrat), Gayther, S.A. (Simon), Gentry-Maharaj, A. (Aleksandra), Gerdes, A-M. (Anne-Marie), Giles, G.G. (Graham), Glasspool, R. (Rosalind), Glendon, G. (Gord), Godwin, A.K. (Andrew K.), Goodman, M.T. (Marc T.), Gore, M. (Martin), Greene, M.H. (Mark H.), Grip, M. (Mervi), Gronwald, J. (Jacek), Gschwantler-Kaulich, D. (Daphne), Guénel, P. (Pascal), Guzman, S.R. (Starr R.), Haeberle, L. (Lothar), Haiman, C.A. (Christopher A.), Hall, P. (Per), Halverson, S.L. (Sandra L.), Hamann, U. (Ute), Hansen, T.V.O. (Thomas), Harter, P. (Philipp), Hartikainen, J.M. (J.), Healey, S. (Sue), Hein, R. (Rebecca), Heitz, P.U., Henderson, B.E. (Brian), Herzog, J. (Josef), Hildebrandt, M.A.T. (Michelle), Høgdall, C.K. (Claus), Høgdall, E. (Estrid), Hogervorst, F.B.L. (Frans), Hopper, J.L. (John), Humphreys, K. (Keith), Huzarski, T. (Tomasz), Imyanitov, E.N. (Evgeny N.), Isaacs, C. (Claudine), Jakubowska, A. (Anna), Janavicius, R. (Ramunas), Jaworska, K. (Katarzyna), Jensen, A. (Allan), Jensen, U.B., Johnson, N. (Nichola), Jukkola-Vuorinen, A. (Arja), Kabisch, M. (Maria), Karlan, B.Y. (Beth Y.), Kataja, V. (Vesa), Kauff, N. (Noah), Kelemen, L.E. (Linda), Kerin, M. (Michael), Kiemeney, L.A.L.M. (Bart), Kjaer, M. (Michael), Knight, J.A. (Julia), Knol-Bout, J.P. (Jacoba P.), Konstantopoulou, I. (I.), Kosma, V-M. (Veli-Matti), Krakstad, C. (Camilla), Kristensen, V. (Vessela), Kuchenbaecker, K.B. (Karoline), Kupryjanczyk, J. (Jolanta), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lambrechts, S. (Sandrina), Larson, M.C. (Melissa), Lasa, A. (Adriana), Laurent-Puig, P. (Pierre), Lázaro, C. (Conxi), Le, N. (Nhu), Le Marchand, L. (Loic), Leminen, A. (Arto), Lester, K.J. (Kathryn), Levine, D.A. (Douglas), Li, J. (Jingmei), Liang, D. (Dong), Lindblom, A. (Annika), Lindor, N.M. (Noralane), Lissowska, J. (Jolanta), Long, J. (Jirong), Lu, K.H. (Karen), Lubinski, J. (Jan), Lundvall, L. (Lene), Lurie, G. (Galina), Mai, P.L. (Phuong), Mannermaa, A. (Arto), Margolin, S. (Sara), Mariette, F. (F.), Marme, F. (Federick), Martens, J.W.M. (John), Massuger, L.F. (Leon), Maugard, C., Mazoyer, S. (Sylvie), McGuffog, L. (Lesley), McGuire, W.P., McLean, C.A. (Catriona Ann), McNeish, I. (Iain), Meindl, A. (Alfons), Menegaux, F. (Florence), Menéndez, P. (Primitiva), Menkiszak, J. (Janusz), Menon, U. (Usha), Mensenkamp, A.R. (Arjen), Miller, N. (Nicola), Milne, R.L. (Roger), Modugno, F. (Francesmary), Montagna, M. (Marco), Moysich, K.B. (Kirsten B.), Müller, H. (Heiko), Mulligan, A.-M. (Anna-Marie), Muranen, T.A. (Taru), Narod, S.A. (Steven A.), Nathanson, K.L. (Katherine), Ness, R.B. (Roberta B.), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Neven, P. (Patrick), Nielsen, F. (Finn), Nielsen, S.F. (Sune), Nordestgaard, B.G. (Børge), Nussbaum, R. (Robert), Odunsi, K. (Kunle), Offit, K. (Kenneth), Olah, E., Olopade, O.I. (Olufunmilayo I.), Olson, J.E. (Janet), Olson, S.H. (Sara), Oosterwijk, J.C. (Jan), Orlow, I. (Irene), Orr, N. (Nick), Orsulic, S. (Sandra), Osorio, A. (Ana), Ottini, L. (Laura), Paul, J. (James), Pearce, C.L. (Celeste), Pedersen, I.S. (Inge Sokilde), Peissel, B. (Bernard), Pejovic, T. (Tanja), Pelttari, L.M. (Liisa), Perkins, J. (Jo), Permuth-Wey, J. (Jenny), Peterlongo, P. (Paolo), Peto, J. (Julian), Phelan, C. (Catherine), Phillips, K.-A. (Kelly-Anne), Piedmonte, M. (Marion), Pike, M.C. (Malcolm C.), Platte, R. (Radka), Plisiecka-Halasa, J. (Joanna), Poole, E.M. (Elizabeth), Poppe, B. (Bruce), Pykäs, K. (Katri), Radice, P. (Paolo), Ramus, S.J. (Susan), Rebbeck, R. (Timothy), Reed, M.W.R. (Malcolm W.R.), Rennert, G. (Gad), Risch, H. (Harvey), Robson, M. (Mark), Rodriguez, G. (Gustavo), Romero, A. (Atocha), Rossing, M.A. (Mary Anne), Rothstein, J.H. (Joseph H.), Rudolph, A. (Anja), Runnebaum, I.B. (Ingo), Salani, R. (Ritu), Salvesen, H.B. (Helga), Sawyer, E.J. (Elinor), Schildkraut, J.M. (Joellen), Schmidt, M.K. (Marjanka), Schmutzler, R.K. (Rita), Schneeweiss, A. (Andreas), Schoemaker, M. (Minouk), Schrauder, A. (André), Schumacher, F.R. (Fredrick), Schwaab, I. (Ira), Scuvera, G. (Giulietta), Sellers, T.A. (Thomas A.), Severi, G. (Gianluca), Seynaeve, C.M. (Caroline), Shah, M. (Mitul), Shrubsole, M. (Martha), Siddiqui, N. (Nadeem), Sieh, W. (Weiva), Simard, J. (Jacques), Singer, C.F. (Christian), Sinilnikova, O. (Olga), Smeets, D. (Dominiek), Sohn, C. (Christof), Soller, M. (Maria), Song, H. (Honglin), Soucy, P. (Penny), Southey, M.C. (Melissa), Stegmaier, C. (Christa), Stoppa-Lyonnet, D. (Dominique), Sucheston, L. (Lara), Swerdlow, A.J. (Anthony ), Tangen, I.L. (Ingvild L.), Tea, M.-K., Teixeira, P.J., Terry, K.L. (Kathryn), Terry, M.B. (Mary Beth), Thomassen, M. (Mads), Thompson, P.J. (Pamela J.), Tihomirova, L. (Laima), Tischkowitz, M. (Marc), Toland, A.E. (Amanda), Tollenaar, R.A.E.M. (Rob), Tomlinson, I. (Ian), Torres, D. (Diana), Truong, T. (Thérèse), Tsimiklis, H. (Helen), Tung, N. (Nadine), Tworoger, S. (Shelley), Tyrer, J.P. (Jonathan), Vachon, C. (Celine), Veer, L.J. (Laura) van 't, Altena, A.M. (Anne) van, Asperen, C.J. (Christi) van, Van Den Berg, D. (David), Ouweland, A.M.W. (Ans) van den, Doorn, H.C. (Lena) van, Van Nieuwenhuysen, E. (Els), Rensburg, E.J. (Elizabeth) van, Vergote, I. (Ignace), Verhoef, S., Vierkant, R.A. (Robert), Vijai, J. (Joseph), Vitonis, A.F. (Allison), Wachenfeldt, A. (Anna) von, Walsh, C.S. (Christine), Wang, Q. (Qing), Wang-Gohrke, S. (Shan), Wapenschmidt, B. (Barbara), Weischer, M. (Maren), Weitzel, J.N. (Jeffrey), Weltens, C. (Caroline), Wentzensen, N. (N.), Whittemore, A.S. (Alice S.), Wilkens, L.R. (Lynne R.), Winqvist, R. (Robert), Wu, A.H. (Anna), Wu, X. (Xifeng), Yang, H.P. (Hannah P.), Zaffaroni, D. (Daniela), Zamora, M.P. (Pilar), Zheng, W. (Wei), Ziogas, A. (Argyrios), Chenevix-Trench, G. (Georgia), Pharoah, P.D.P. (Paul), Rookus, M.A. (Matti), Hooning, M.J. (Maartje), Goode, E.L. (Ellen L.), Breast Cancer Family Register, EMBRACE, GENICA Network, HEBON, SWE-BRCA, Hollestelle, A. (Antoinette), Baan, F.H. (Frederieke) van der, Berchuck, A. (Andrew), Johnatty, S.E. (Sharon), Aben, K.K.H. (Katja), Agnarsson, B.A. (Bjarni), Aittomäki, K. (Kristiina), Alducci, E. (Elisa), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Antonenkova, N.N. (Natalia), Antoniou, A.C. (Antonis), Apicella, C. (Carmel), Arndt, V. (Volker), Arnold, N. (Norbert), Arun, B.K. (Banu), Arver, B. (Brita Wasteson), Ashworth, A. (Alan), Baglietto, L. (Laura), Balleine, R. (Rosemary), Bandera, E.V. (Elisa), Barrowdale, D. (Daniel), Bean, Y.T. (Yukie), Beckmann, L. (Lars), Beckmann, M.W. (Matthias), Benítez, J. (Javier), Berger, A. (Andreas), Berger, R. (Raanan), Beuselinck, B. (B.), Bisogna, M. (Maria), Bjorge, L. (Line), Blomqvist, C. (Carl), Bogdanova, N.V. (Natalia), Bojesen, A. (Anders), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet), Bonnani, B. (Bernardo), Brand, J.S. (Judith S.), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brinton, L.A. (Louise), Brooks-Wilson, A. (Angela), Bruinsma, F. (Fiona), Brunet, J. (Joan), Brüning, T. (Thomas), Budzilowska, A. (Agnieszka), Bunker, C.H. (Clareann H.), Burwinkel, B. (Barbara), Butzow, R. (Ralf), Buys, S.S. (Saundra S.), Caligo, M.A. (Maria), Campbell, I. (Ian), Carter, J. (Jonathan), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen J.), Claes, K.B.M. (Kathleen B.M.), Collée, J.M. (Margriet), Cook, L.S. (Linda S.), Couch, F.J. (Fergus), Cox, A. (Angela), Cramer, D.W. (Daniel), Cross, S.S. (Simon), Cunningham, J.M. (Julie), Cybulski, C. (Cezary), Czene, K. (Kamila), Damiola, F. (Francesca), Dansonka-Mieszkowska, A. (Agnieszka), Darabi, H. (Hatef), Hoya, M. (Miguel) de La, DeFazio, A. (Anna), Dennis, J. (Joe), Devilee, P. (Peter), Dicks, E. (Ed), Díez, O. (Orland), Doherty, J.A. (Jennifer A.), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Santos Silva, I. (Isabel) dos, Du Bois, A. (Andreas), Dumont, M. (Martine), Dunning, A.M. (Alison), Duran, M. (Mercedes), Easton, D.F. (Douglas F.), Eccles, D. (Diana), Edwards, R. (Robert), Ehrencrona, H. (Hans), Ejlertsen, B. (Bent), Ekici, A.B. (Arif), Ellis, S.D. (Steve), Engel, C. (Christoph), Eriksson, M. (Mikael), Fasching, P.A. (Peter), Feliubadaló, L. (L.), Figueroa, J.D. (Jonine), Flesch-Janys, D. (Dieter), Fletcher, O. (Olivia), Fontaine, A. (Annette), Fortuzzi, S. (S.), Fostira, F. (Florentia), Fridley, B.L. (Brooke), Friebel, M.O.W. (Mark ), Friedman, E. (Eitan), Friel, G. (Grace), Frost, D. (Debra), Garber, J. (Judy), García-Closas, M. (Montserrat), Gayther, S.A. (Simon), Gentry-Maharaj, A. (Aleksandra), Gerdes, A-M. (Anne-Marie), Giles, G.G. (Graham), Glasspool, R. (Rosalind), Glendon, G. (Gord), Godwin, A.K. (Andrew K.), Goodman, M.T. (Marc T.), Gore, M. (Martin), Greene, M.H. (Mark H.), Grip, M. (Mervi), Gronwald, J. (Jacek), Gschwantler-Kaulich, D. (Daphne), Guénel, P. (Pascal), Guzman, S.R. (Starr R.), Haeberle, L. (Lothar), Haiman, C.A. (Christopher A.), Hall, P. (Per), Halverson, S.L. (Sandra L.), Hamann, U. (Ute), Hansen, T.V.O. (Thomas), Harter, P. (Philipp), Hartikainen, J.M. (J.), Healey, S. (Sue), Hein, R. (Rebecca), Heitz, P.U., Henderson, B.E. (Brian), Herzog, J. (Josef), Hildebrandt, M.A.T. (Michelle), Høgdall, C.K. (Claus), Høgdall, E. (Estrid), Hogervorst, F.B.L. (Frans), Hopper, J.L. (John), Humphreys, K. (Keith), Huzarski, T. (Tomasz), Imyanitov, E.N. (Evgeny N.), Isaacs, C. (Claudine), Jakubowska, A. (Anna), Janavicius, R. (Ramunas), Jaworska, K. (Katarzyna), Jensen, A. (Allan), Jensen, U.B., Johnson, N. (Nichola), Jukkola-Vuorinen, A. (Arja), Kabisch, M. (Maria), Karlan, B.Y. (Beth Y.), Kataja, V. (Vesa), Kauff, N. (Noah), Kelemen, L.E. (Linda), Kerin, M. (Michael), Kiemeney, L.A.L.M. (Bart), Kjaer, M. (Michael), Knight, J.A. (Julia), Knol-Bout, J.P. (Jacoba P.), Konstantopoulou, I. (I.), Kosma, V-M. (Veli-Matti), Krakstad, C. (Camilla), Kristensen, V. (Vessela), Kuchenbaecker, K.B. (Karoline), Kupryjanczyk, J. (Jolanta), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lambrechts, S. (Sandrina), Larson, M.C. (Melissa), Lasa, A. (Adriana), Laurent-Puig, P. (Pierre), Lázaro, C. (Conxi), Le, N. (Nhu), Le Marchand, L. (Loic), Leminen, A. (Arto), Lester, K.J. (Kathryn), Levine, D.A. (Douglas), Li, J. (Jingmei), Liang, D. (Dong), Lindblom, A. (Annika), Lindor, N.M. (Noralane), Lissowska, J. (Jolanta), Long, J. (Jirong), Lu, K.H. (Karen), Lubinski, J. (Jan), Lundvall, L. (Lene), Lurie, G. (Galina), Mai, P.L. (Phuong), Mannermaa, A. (Arto), Margolin, S. (Sara), Mariette, F. (F.), Marme, F. (Federick), Martens, J.W.M. (John), Massuger, L.F. (Leon), Maugard, C., Mazoyer, S. (Sylvie), McGuffog, L. (Lesley), McGuire, W.P., McLean, C.A. (Catriona Ann), McNeish, I. (Iain), Meindl, A. (Alfons), Menegaux, F. (Florence), Menéndez, P. (Primitiva), Menkiszak, J. (Janusz), Menon, U. (Usha), Mensenkamp, A.R. (Arjen), Miller, N. (Nicola), Milne, R.L. (Roger), Modugno, F. (Francesmary), Montagna, M. (Marco), Moysich, K.B. (Kirsten B.), Müller, H. (Heiko), Mulligan, A.-M. (Anna-Marie), Muranen, T.A. (Taru), Narod, S.A. (Steven A.), Nathanson, K.L. (Katherine), Ness, R.B. (Roberta B.), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Neven, P. (Patrick), Nielsen, F. (Finn), Nielsen, S.F. (Sune), Nordestgaard, B.G. (Børge), Nussbaum, R. (Robert), Odunsi, K. (Kunle), Offit, K. (Kenneth), Olah, E., Olopade, O.I. (Olufunmilayo I.), Olson, J.E. (Janet), Olson, S.H. (Sara), Oosterwijk, J.C. (Jan), Orlow, I. (Irene), Orr, N. (Nick), Orsulic, S. (Sandra), Osorio, A. (Ana), Ottini, L. (Laura), Paul, J. (James), Pearce, C.L. (Celeste), Pedersen, I.S. (Inge Sokilde), Peissel, B. (Bernard), Pejovic, T. (Tanja), Pelttari, L.M. (Liisa), Perkins, J. (Jo), Permuth-Wey, J. (Jenny), Peterlongo, P. (Paolo), Peto, J. (Julian), Phelan, C. (Catherine), Phillips, K.-A. (Kelly-Anne), Piedmonte, M. (Marion), Pike, M.C. (Malcolm C.), Platte, R. (Radka), Plisiecka-Halasa, J. (Joanna), Poole, E.M. (Elizabeth), Poppe, B. (Bruce), Pykäs, K. (Katri), Radice, P. (Paolo), Ramus, S.J. (Susan), Rebbeck, R. (Timothy), Reed, M.W.R. (Malcolm W.R.), Rennert, G. (Gad), Risch, H. (Harvey), Robson, M. (Mark), Rodriguez, G. (Gustavo), Romero, A. (Atocha), Rossing, M.A. (Mary Anne), Rothstein, J.H. (Joseph H.), Rudolph, A. (Anja), Runnebaum, I.B. (Ingo), Salani, R. (Ritu), Salvesen, H.B. (Helga), Sawyer, E.J. (Elinor), Schildkraut, J.M. (Joellen), Schmidt, M.K. (Marjanka), Schmutzler, R.K. (Rita), Schneeweiss, A. (Andreas), Schoemaker, M. (Minouk), Schrauder, A. (André), Schumacher, F.R. (Fredrick), Schwaab, I. (Ira), Scuvera, G. (Giulietta), Sellers, T.A. (Thomas A.), Severi, G. (Gianluca), Seynaeve, C.M. (Caroline), Shah, M. (Mitul), Shrubsole, M. (Martha), Siddiqui, N. (Nadeem), Sieh, W. (Weiva), Simard, J. (Jacques), Singer, C.F. (Christian), Sinilnikova, O. (Olga), Smeets, D. (Dominiek), Sohn, C. (Christof), Soller, M. (Maria), Song, H. (Honglin), Soucy, P. (Penny), Southey, M.C. (Melissa), Stegmaier, C. (Christa), Stoppa-Lyonnet, D. (Dominique), Sucheston, L. (Lara), Swerdlow, A.J. (Anthony ), Tangen, I.L. (Ingvild L.), Tea, M.-K., Teixeira, P.J., Terry, K.L. (Kathryn), Terry, M.B. (Mary Beth), Thomassen, M. (Mads), Thompson, P.J. (Pamela J.), Tihomirova, L. (Laima), Tischkowitz, M. (Marc), Toland, A.E. (Amanda), Tollenaar, R.A.E.M. (Rob), Tomlinson, I. (Ian), Torres, D. (Diana), Truong, T. (Thérèse), Tsimiklis, H. (Helen), Tung, N. (Nadine), Tworoger, S. (Shelley), Tyrer, J.P. (Jonathan), Vachon, C. (Celine), Veer, L.J. (Laura) van 't, Altena, A.M. (Anne) van, Asperen, C.J. (Christi) van, Van Den Berg, D. (David), Ouweland, A.M.W. (Ans) van den, Doorn, H.C. (Lena) van, Van Nieuwenhuysen, E. (Els), Rensburg, E.J. (Elizabeth) van, Vergote, I. (Ignace), Verhoef, S., Vierkant, R.A. (Robert), Vijai, J. (Joseph), Vitonis, A.F. (Allison), Wachenfeldt, A. (Anna) von, Walsh, C.S. (Christine), Wang, Q. (Qing), Wang-Gohrke, S. (Shan), Wapenschmidt, B. (Barbara), Weischer, M. (Maren), Weitzel, J.N. (Jeffrey), Weltens, C. (Caroline), Wentzensen, N. (N.), Whittemore, A.S. (Alice S.), Wilkens, L.R. (Lynne R.), Winqvist, R. (Robert), Wu, A.H. (Anna), Wu, X. (Xifeng), Yang, H.P. (Hannah P.), Zaffaroni, D. (Daniela), Zamora, M.P. (Pilar), Zheng, W. (Wei), Ziogas, A. (Argyrios), Chenevix-Trench, G. (Georgia), Pharoah, P.D.P. (Paul), Rookus, M.A. (Matti), Hooning, M.J. (Maartje), Goode, E.L. (Ellen L.), Breast Cancer Family Register, EMBRACE, GENICA Network, HEBON, and SWE-BRCA

Abstract

Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and br

Published
2016
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14. Recreational physical inactivity and mortality in women with invasive epithelial ovarian cancer: evidence from the Ovarian Cancer Association Consortium.

Author

Cannioto, RA, LaMonte, MJ, Kelemen, LE, Risch, HA, Eng, KH, Minlikeeva, AN, Hong, C-C, Szender, JB, Sucheston-Campbell, L, Joseph, JM, Berchuck, A, Chang-Claude, J, Cramer, DW, DeFazio, A, Diergaarde, B, Dörk, T, Doherty, JA, Edwards, RP, Fridley, BL, Friel, G, Goode, EL, Goodman, MT, Hillemanns, P, Hogdall, E, Hosono, S, Kelley, JL, Kjaer, SK, Klapdor, R, Matsuo, K, Odunsi, K, Nagle, CM, Olsen, CM, Paddock, LE, Pearce, CL, Pike, MC, Rossing, MA, Schmalfeldt, B, Segal, BH, Szamreta, EA, Thompson, PJ, Tseng, C-C, Vierkant, R, Schildkraut, JM, Wentzensen, N, Wicklund, KG, Winham, SJ, Wu, AH, Modugno, F, Ness, RB, Jensen, A, Webb, PM, Terry, K, Bandera, EV, Moysich, KB, Cannioto, RA, LaMonte, MJ, Kelemen, LE, Risch, HA, Eng, KH, Minlikeeva, AN, Hong, C-C, Szender, JB, Sucheston-Campbell, L, Joseph, JM, Berchuck, A, Chang-Claude, J, Cramer, DW, DeFazio, A, Diergaarde, B, Dörk, T, Doherty, JA, Edwards, RP, Fridley, BL, Friel, G, Goode, EL, Goodman, MT, Hillemanns, P, Hogdall, E, Hosono, S, Kelley, JL, Kjaer, SK, Klapdor, R, Matsuo, K, Odunsi, K, Nagle, CM, Olsen, CM, Paddock, LE, Pearce, CL, Pike, MC, Rossing, MA, Schmalfeldt, B, Segal, BH, Szamreta, EA, Thompson, PJ, Tseng, C-C, Vierkant, R, Schildkraut, JM, Wentzensen, N, Wicklund, KG, Winham, SJ, Wu, AH, Modugno, F, Ness, RB, Jensen, A, Webb, PM, Terry, K, Bandera, EV, and Moysich, KB

Abstract

BACKGROUND: Little is known about modifiable behaviours that may be associated with epithelial ovarian cancer (EOC) survival. We conducted a pooled analysis of 12 studies from the Ovarian Cancer Association Consortium to investigate the association between pre-diagnostic physical inactivity and mortality. METHODS: Participants included 6806 women with a primary diagnosis of invasive EOC. In accordance with the Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. We utilised Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) representing the associations of inactivity with mortality censored at 5 years. RESULTS: In multivariate analysis, inactive women had significantly higher mortality risks, with (HR=1.34, 95% CI: 1.18-1.52) and without (HR=1.22, 95% CI: 1.12-1.33) further adjustment for residual disease, respectively. CONCLUSION: In this large pooled analysis, lack of recreational physical activity was associated with increased mortality among women with invasive EOC.

Published
2016

15. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

Author

Southey, MC, Goldgar, DE, Winqvist, R, Pylkas, K, Couch, F, Tischkowitz, M, Foulkes, WD, Dennis, J, Michailidou, K, van Rensburg, EJ, Heikkinen, T, Nevanlinna, H, Hopper, JL, Doerk, T, Claes, KBM, Reis-Filho, J, Teo, ZL, Radice, P, Catucci, I, Peterlongo, P, Tsimiklis, H, Odefrey, FA, Dowty, JG, Schmidt, MK, Broeks, A, Hogervorst, FB, Verhoef, S, Carpenter, J, Clarke, C, Scott, RJ, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Fletcher, O, Johnson, N, Bolla, MK, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Marme, F, Burwinkel, B, Yang, R, Guenel, P, Therese, T, Menegaux, F, Sanchez, M, Bojesen, S, Nielsen, SF, Flyger, H, Benitez, J, Pilar Zamora, M, Arias Perez, JI, Menendez, P, Anton-Culver, H, Neuhausen, S, Ziogas, A, Clarke, CA, Brenner, H, Arndt, V, Stegmaier, C, Brauch, H, Bruening, T, Ko, Y-D, Muranen, TA, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Antonenkova, NN, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Spurdle, AB, Wauters, E, Smeets, D, Beuselinck, B, Floris, G, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Olson, JE, Vachon, C, Pankratz, VS, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Kristensen, V, Alnaes, GG, Zheng, W, Hunter, DJ, Lindstrom, S, Hankinson, SE, Kraft, P, Andrulis, I, Knight, JA, Glendon, G, Mulligan, AM, Jukkola-Vuorinen, A, Grip, M, Kauppila, S, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Hollestelle, A, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Darabi, H, Eriksson, M, Eccles, DM, Rafiq, S, Tapper, WJ, Gerty, SM, Hooning, MJ, Martens, JWM, Collee, JM, Tilanus-Linthorst, M, Hall, P, Li, J, Brand, JS, Humphreys, K, Cox, A, Reed, MWR, Luccarini, C, Baynes, C, Dunning, AM, Hamann, U, Torres, D, Ulmer, HU, Ruediger, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Gonzalez-Neira, A, Pita, G, Rosario Alonso, M, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Simard, J, Dumont, M, Soucy, P, Eeles, R, Muir, K, Wiklund, F, Gronberg, H, Schleutker, J, Nordestgaard, BG, Weischer, M, Travis, RC, Neal, D, Donovan, JL, Hamdy, FC, Khaw, K-T, Stanford, JL, Blot, WJ, Thibodeau, S, Schaid, DJ, Kelley, JL, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Butterbach, K, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Renner, SP, Hartmann, A, Hein, A, Ruebner, M, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambretchs, S, Doherty, JA, Rossing, MA, Nickels, S, Eilber, U, Wang-Gohrke, S, Odunsi, K, Sucheston-Campbell, LE, Friel, G, Lurie, G, Killeen, JL, Wilkens, LR, Goodman, MT, Runnebaum, I, Hillemanns, PA, Pelttari, LM, Butzow, R, Modugno, F, Edwards, RP, Ness, RB, Moysich, KB, du Bois, A, Heitz, F, Harter, P, Kommoss, S, Karlan, BY, Walsh, C, Lester, J, Jensen, A, Kjaer, SK, Hogdall, E, Peissel, B, Bonanni, B, Bernard, L, Goode, EL, Fridley, BL, Vierkant, RA, Cunningham, JM, Larson, MC, Fogarty, ZC, Kalli, KR, Liang, D, Lu, KH, Hildebrandt, MAT, Wu, X, Levine, DA, Dao, F, Bisogna, M, Berchuck, A, Iversen, ES, Marks, JR, Akushevich, L, Cramer, DW, Schildkraut, J, Terry, KL, Poole, EM, Stampfer, M, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Bjorge, L, Salvesen, HB, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bean, Y, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Grski, B, Gronwald, J, Menkiszak, J, Hogdall, CK, Lundvall, L, Nedergaard, L, Engelholm, SA, Dicks, E, Tyrer, J, Campbell, I, McNeish, I, Paul, J, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Cai, H, Shu, X-O, Teten, RT, Sutphen, R, McLaughlin, JR, Narod, SA, Phelan, CM, Monteiro, AN, Fenstermacher, D, Lin, H-Y, Permuth, JB, Sellers, TA, Chen, YA, Tsai, Y-Y, Chen, Z, Gentry-Maharaj, A, Gayther, SA, Ramus, SJ, Menon, U, Wu, AH, Pearce, CL, Van den Berg, D, Pike, MC, Dansonka-Mieszkowska, A, Plisiecka-Halasa, J, Moes-Sosnowska, J, Kupryjanczyk, J, Pharoah, PDP, Song, H, Winship, I, Chenevix-Trench, G, Giles, GG, Tavtigian, SV, Easton, DF, Milne, RL, Southey, MC, Goldgar, DE, Winqvist, R, Pylkas, K, Couch, F, Tischkowitz, M, Foulkes, WD, Dennis, J, Michailidou, K, van Rensburg, EJ, Heikkinen, T, Nevanlinna, H, Hopper, JL, Doerk, T, Claes, KBM, Reis-Filho, J, Teo, ZL, Radice, P, Catucci, I, Peterlongo, P, Tsimiklis, H, Odefrey, FA, Dowty, JG, Schmidt, MK, Broeks, A, Hogervorst, FB, Verhoef, S, Carpenter, J, Clarke, C, Scott, RJ, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Fletcher, O, Johnson, N, Bolla, MK, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Marme, F, Burwinkel, B, Yang, R, Guenel, P, Therese, T, Menegaux, F, Sanchez, M, Bojesen, S, Nielsen, SF, Flyger, H, Benitez, J, Pilar Zamora, M, Arias Perez, JI, Menendez, P, Anton-Culver, H, Neuhausen, S, Ziogas, A, Clarke, CA, Brenner, H, Arndt, V, Stegmaier, C, Brauch, H, Bruening, T, Ko, Y-D, Muranen, TA, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Antonenkova, NN, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Spurdle, AB, Wauters, E, Smeets, D, Beuselinck, B, Floris, G, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Olson, JE, Vachon, C, Pankratz, VS, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Kristensen, V, Alnaes, GG, Zheng, W, Hunter, DJ, Lindstrom, S, Hankinson, SE, Kraft, P, Andrulis, I, Knight, JA, Glendon, G, Mulligan, AM, Jukkola-Vuorinen, A, Grip, M, Kauppila, S, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Hollestelle, A, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Darabi, H, Eriksson, M, Eccles, DM, Rafiq, S, Tapper, WJ, Gerty, SM, Hooning, MJ, Martens, JWM, Collee, JM, Tilanus-Linthorst, M, Hall, P, Li, J, Brand, JS, Humphreys, K, Cox, A, Reed, MWR, Luccarini, C, Baynes, C, Dunning, AM, Hamann, U, Torres, D, Ulmer, HU, Ruediger, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Gonzalez-Neira, A, Pita, G, Rosario Alonso, M, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Simard, J, Dumont, M, Soucy, P, Eeles, R, Muir, K, Wiklund, F, Gronberg, H, Schleutker, J, Nordestgaard, BG, Weischer, M, Travis, RC, Neal, D, Donovan, JL, Hamdy, FC, Khaw, K-T, Stanford, JL, Blot, WJ, Thibodeau, S, Schaid, DJ, Kelley, JL, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Butterbach, K, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Renner, SP, Hartmann, A, Hein, A, Ruebner, M, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambretchs, S, Doherty, JA, Rossing, MA, Nickels, S, Eilber, U, Wang-Gohrke, S, Odunsi, K, Sucheston-Campbell, LE, Friel, G, Lurie, G, Killeen, JL, Wilkens, LR, Goodman, MT, Runnebaum, I, Hillemanns, PA, Pelttari, LM, Butzow, R, Modugno, F, Edwards, RP, Ness, RB, Moysich, KB, du Bois, A, Heitz, F, Harter, P, Kommoss, S, Karlan, BY, Walsh, C, Lester, J, Jensen, A, Kjaer, SK, Hogdall, E, Peissel, B, Bonanni, B, Bernard, L, Goode, EL, Fridley, BL, Vierkant, RA, Cunningham, JM, Larson, MC, Fogarty, ZC, Kalli, KR, Liang, D, Lu, KH, Hildebrandt, MAT, Wu, X, Levine, DA, Dao, F, Bisogna, M, Berchuck, A, Iversen, ES, Marks, JR, Akushevich, L, Cramer, DW, Schildkraut, J, Terry, KL, Poole, EM, Stampfer, M, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Bjorge, L, Salvesen, HB, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bean, Y, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Grski, B, Gronwald, J, Menkiszak, J, Hogdall, CK, Lundvall, L, Nedergaard, L, Engelholm, SA, Dicks, E, Tyrer, J, Campbell, I, McNeish, I, Paul, J, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Cai, H, Shu, X-O, Teten, RT, Sutphen, R, McLaughlin, JR, Narod, SA, Phelan, CM, Monteiro, AN, Fenstermacher, D, Lin, H-Y, Permuth, JB, Sellers, TA, Chen, YA, Tsai, Y-Y, Chen, Z, Gentry-Maharaj, A, Gayther, SA, Ramus, SJ, Menon, U, Wu, AH, Pearce, CL, Van den Berg, D, Pike, MC, Dansonka-Mieszkowska, A, Plisiecka-Halasa, J, Moes-Sosnowska, J, Kupryjanczyk, J, Pharoah, PDP, Song, H, Winship, I, Chenevix-Trench, G, Giles, GG, Tavtigian, SV, Easton, DF, and Milne, RL

Abstract

BACKGROUND: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. METHODS: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. RESULTS: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. CONCLUSIONS: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

Published
2016

16. Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

Author

Earp, MA, Kelemen, LE, Magliocco, AM, Swenerton, KD, Chenevix-Trench, G, Lu, Y, Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Despierre, E, Vergote, I, Lambrechts, S, Doherty, JA, Rossing, MA, Chang-Claude, J, Rudolph, A, Friel, G, Moysich, KB, Odunsi, K, Sucheston-Campbell, L, Lurie, G, Goodman, MT, Carney, ME, Thompson, PJ, Runnebaum, IB, Dürst, M, Hillemanns, P, Dörk, T, Antonenkova, N, Bogdanova, N, Leminen, A, Nevanlinna, H, Pelttari, LM, Butzow, R, Bunker, CH, Modugno, F, Edwards, RP, Ness, RB, Du Bois, A, Heitz, F, Schwaab, I, Harter, P, Karlan, BY, Walsh, C, Lester, J, Jensen, A, Kjær, SK, Høgdall, CK, Høgdall, E, Lundvall, L, Sellers, TA, Fridley, BL, Goode, EL, Cunningham, JM, Vierkant, RA, Giles, GG, Baglietto, L, Severi, G, Southey, MC, Liang, D, Wu, X, Lu, K, Hildebrandt, MAT, Levine, DA, Bisogna, M, Schildkraut, JM, Iversen, ES, Weber, RP, Berchuck, A, Cramer, DW, Terry, KL, Poole, EM, Tworoger, SS, Bandera, EV, and Chandran, U

Subjects
endocrine system diseases, female genital diseases and pregnancy complications
Abstract

Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes. © 2013 Springer-Verlag Berlin Heidelberg.

Published
2014

17. Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

Author

Earp, M.A., Kelemen, L.E., Magliocco, A.M., Swenerton, K.D., Chenevix-Trench, G., Lu, Y., Hein, A., Ekici, A.B., Beckmann, M.W., Fasching, P.A., Lambrechts, D., Despierre, E., Vergote, I., Lambrechts, S., Doherty, J.A., Rossing, M.A., Chang-Claude, J., Rudolph, A., Friel, G., Moysich, K.B., Odunsi, K., Sucheston-Campbell, L., Lurie, G., Goodman, M.T., Carney, M.E., Thompson, P.J., Runnebaum, I.B., Durst, M., Hillemanns, P., Dork, T., Antonenkova, N., Bogdanova, N., Leminen, A., Nevanlinna, H., Pelttari, L.M., Butzow, R., Bunker, C.H., Modugno, F., Edwards, R.P., Ness, R.B., Bois, A. du, Heitz, F., Schwaab, I., Harter, P., Karlan, B.Y., Walsh, C., Lester, J., Jensen, A., Kjaer, S.K., Hogdall, C.K., Hogdall, E., Lundvall, L., Sellers, T.A., Fridley, B.L., Goode, E.L., Cunningham, J.M., Vierkant, R.A., Giles, G.G., Baglietto, L., Severi, G., Southey, M.C., Liang, D., Wu, X., Lu, K., Hildebrandt, M.A.T., Levine, D.A., Bisogna, M., Schildkraut, J.M., Iversen, E.S., Weber, R.P., Berchuck, A., Cramer, D.W, Terry, K.L., Poole, E.M., Tworoger, S.S., Bandera, E.V., Chandran, U., Orlow, I., Olson, S.H., Wik, E., Salvesen, H.B., Bjorge, L., Halle, M.K., Altena, A.M. van, Aben, K.K.H., Kiemeney, B., Massuger, L.F.A.G., Pejovic, T., Bean, Y.T., Cybulski, C., Gronwald, J., Lubinski, J., Wentzensen, N., Brinton, L.A., Lissowska, J., Garcia-Closas, M., Dicks, E., et al., Earp, M.A., Kelemen, L.E., Magliocco, A.M., Swenerton, K.D., Chenevix-Trench, G., Lu, Y., Hein, A., Ekici, A.B., Beckmann, M.W., Fasching, P.A., Lambrechts, D., Despierre, E., Vergote, I., Lambrechts, S., Doherty, J.A., Rossing, M.A., Chang-Claude, J., Rudolph, A., Friel, G., Moysich, K.B., Odunsi, K., Sucheston-Campbell, L., Lurie, G., Goodman, M.T., Carney, M.E., Thompson, P.J., Runnebaum, I.B., Durst, M., Hillemanns, P., Dork, T., Antonenkova, N., Bogdanova, N., Leminen, A., Nevanlinna, H., Pelttari, L.M., Butzow, R., Bunker, C.H., Modugno, F., Edwards, R.P., Ness, R.B., Bois, A. du, Heitz, F., Schwaab, I., Harter, P., Karlan, B.Y., Walsh, C., Lester, J., Jensen, A., Kjaer, S.K., Hogdall, C.K., Hogdall, E., Lundvall, L., Sellers, T.A., Fridley, B.L., Goode, E.L., Cunningham, J.M., Vierkant, R.A., Giles, G.G., Baglietto, L., Severi, G., Southey, M.C., Liang, D., Wu, X., Lu, K., Hildebrandt, M.A.T., Levine, D.A., Bisogna, M., Schildkraut, J.M., Iversen, E.S., Weber, R.P., Berchuck, A., Cramer, D.W, Terry, K.L., Poole, E.M., Tworoger, S.S., Bandera, E.V., Chandran, U., Orlow, I., Olson, S.H., Wik, E., Salvesen, H.B., Bjorge, L., Halle, M.K., Altena, A.M. van, Aben, K.K.H., Kiemeney, B., Massuger, L.F.A.G., Pejovic, T., Bean, Y.T., Cybulski, C., Gronwald, J., Lubinski, J., Wentzensen, N., Brinton, L.A., Lissowska, J., Garcia-Closas, M., Dicks, E., and et al.

Abstract

Contains fulltext : 138102.pdf (publisher's version ) (Closed access), Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.

Published
2014

27. Risk of Ovarian Cancer and the NF- B Pathway: Genetic Association with IL1A and TNFSF10

Author

Charbonneau, B., Block, M. S., Bamlet, W. R., Vierkant, R. A., Kalli, K. R., Fogarty, Z., Rider, D. N., Sellers, T. A., Tworoger, Shelley Slate, Poole, Elizabeth M., Risch, H. A., Salvesen, H. B., Kiemeney, L. A., Baglietto, L., Giles, G. G., Severi, G., Trabert, B., Wentzensen, N., Chenevix-Trench, G., Whittemore, A. S., Sieh, W., Chang-Claude, J., Bandera, E. V., Orlow, I., Terry, Kathryn Lynne, Goodman, M. T., Thompson, P. J., Cook, L. S., Rossing, M. A., Ness, R. B., Narod, S. A., Kupryjanczyk, J., Lu, K., Butzow, R., Dork, T., Pejovic, T., Campbell, I., Le, N. D., Bunker, C. H., Bogdanova, N., Runnebaum, I. B., Eccles, D., Paul, J., Wu, A. H., Gayther, S. A., Hogdall, E., Heitz, F., Kaye, S. B., Karlan, B. Y., Anton-Culver, H., Gronwald, J., Hogdall, C. K., Lambrechts, D., Fasching, P. A., Menon, U., Schildkraut, J., Pearce, C. L., Levine, D. A., Kjaer, S. K., Cramer, Daniel William, Flanagan, J. M., Phelan, C. M., Brown, Robert, Massuger, L. F. A. G., Song, H., Doherty, J. A., Krakstad, C., Liang, D., Odunsi, K., Berchuck, A., Jensen, A., Lubinski, J., Nevanlinna, H., Bean, Y. T., Lurie, G., Ziogas, A., Walsh, C., Despierre, E., Brinton, L., Hein, A., Rudolph, A., Dansonka-Mieszkowska, A., Olson, S. H., Harter, P., Tyrer, J., Vitonis, A. F., Brooks-Wilson, A., Aben, K. K., Pike, M. C., Ramus, S. J., Wik, E., Cybulski, C., Lin, J., Sucheston, L., Edwards, Robert R, McGuire, V., Lester, J., du Bois, A., Lundvall, L., Wang-Gohrke, S., Szafron, L. M., Lambrechts, S., Yang, H., Beckmann, M. W., Pelttari, L. M., Van Altena, A. M., van den Berg, D., Halle, M. K., Gentry-Maharaj, A., Schwaab, I., Chandran, U., Menkiszak, J., Ekici, A. B., Wilkens, L. R., Leminen, A., Modugno, F., Friel, G., Rothstein, J. H., Vergote, I., Garcia-Closas, M., Hildebrandt, M. A. T., Sobiczewski, P., Kelemen, L. E., Pharoah, P. D. P., Moysich, K., Knutson, K. L., Cunningham, J. M., Fridley, B. L., and Goode, E. L.

Subjects
clear cell, endometrioid, case-control, single nucleotide polymorphism, IL-1α
Abstract

A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 × 10(-5), only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted., Other Research Unit

Published
2013
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31. Experimental and modeling investigation of the effect of ventilation on smoke rollback in a mine entry.

Author

Edwards, J. C., Franks, R. A., Friel, G. F., and Yuan, L.

Subjects
AIR speed, SMOKE prevention, DIESEL fuels, COAL mining, VENTILATION, FLUID dynamics
Abstract

To determine the critical air velocity for preventing smoke rollback, diesel-fuel fire experiments were conducted in the National Institute for Occupational Safety and Health's (NIOSH) Pittsburgh Research Laboratory's Safety Research Coal Mine. Such information is necessary for preplanning and implementation of ventilation changes during mine fire fighting and rescue operations. The fire intensity varied from 50 to 300 kW depending on the fuel tray area. Airflow in the 2-m-(6.6-ft-) high, 2.9-m-(9.5-ft-) wide coal mine entry was regulated during the course of each experiment. The airflow was measured upwind from the fire as an average over the entry cross-section with an ultrasonic airflow sensor and was recorded dynamically with a mine monitoring system. The extent of smoke reversal was monitored with light-obscuration monitors, ionization smoke sensors and visual observations. Experimental results for the critical air velocity for smoke reversal as a function of fire intensity compared very well with model predictions based upon a computational fluid dynamics fire dynamics simulator.

Published
2006

33. Economic estimates of invasive wild ungulate damage to livestock producers in Hawai'i.

Author

Shwiff SA, Auweloa CL, Caires K, Friel G, Katayama L, Munoz Z, Price MR, Risch D, Shartaj M, Steensma K, Thorne M, and Zifko R

Abstract

Background: Invasive ungulates (hoofed mammals), including deer, feral pigs, feral goats, and feral sheep, are known to cause damage to agriculture, property, natural resources, and many other commodities. Most of the information regarding the economic impacts of wild ungulates is from North America, where some of these species are native. To evaluate invasive ungulate damage to livestock producers in the Hawaiian Islands, which have no native ungulates, a survey was distributed to livestock producers across the state., Results: Survey results described how total annual costs are distributed among damage, control, and repairs for survey respondents, who represented a significant percentage of total ranchland acreage across the islands. The estimates, excluding fixed fence installation, revealed an annual cost to livestock producers who responded to the survey of US$1.42 million, which ranged from $3.6 million to $7.5 million when extrapolated to the entire state. The large cost contributors included damage to property, pastureland repair, control costs (excluding fencing), supplemental feed, and predation of calves by wild pigs. Additionally, producers reported spending more than $2 million in upfront fence installation costs. Most of these costs were reported by respondents on the islands of Hawai'i and Moloka'i., Conclusion: Study results revealed substantial damage to state livestock producers due to wild ungulates and are useful in determining an invasive ungulate management strategy that can appropriately aid the most impacted sectors of Hawai'i. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)

Published
2024
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35. Sepsis now a priority: a quality improvement initiative for early sepsis recognition and care.

Author

McDonald CM, West S, Dushenski D, Lapinsky SE, Soong C, van den Broek K, Ashby M, Wilde-Friel G, Kan C, McIntyre M, and Morris A

Subjects
Aged, Algorithms, Clinical Protocols, Emergency Service, Hospital organization & administration, Female, Hospitals, Teaching, Humans, Intensive Care Units statistics & numerical data, Length of Stay statistics & numerical data, Male, Middle Aged, Ontario, Patient Care Bundles, Retrospective Studies, Sepsis mortality, Triage standards, Quality Improvement organization & administration, Sepsis diagnosis, Sepsis therapy, Triage organization & administration
Abstract

Objective: To develop a triage-based screening algorithm and treatment order-sets aimed at improving the quality of care of all patients with sepsis presenting to our emergency department (ED)., Design: Retrospective cohort study conducted during a pre-intervention period from 1 April 2010 to 31 March 2011 and a post-intervention period from 1 September 2014 to 30 April 2015., Setting: A large teaching hospital located in Toronto, Ontario, Canada with a 35-bed ED., Participants: All patients meeting pre-specified sepsis criteria during the ED encounter., Main Outcome Measures: Process of care measures included time to assessment by emergency physician, lactate measurement, blood culture collection, fluid and antibiotic administration. Intensive care unit (ICU) outcomes including admissions, length of stay (LOS) and deaths were reviewed., Results: There were 346 patients pre-intervention, and 270 patients post-intervention. We significantly improved all process measures including mean time to antibiotics by 60 min (P = 0.003) and proportion of patients receiving fluid resuscitation (64.7% vs. 94.4%, P < 0.001). There was no significant difference in the number of patients admitted to ICU (P = 0.14). The median ICU LOS was shorter in the post-intervention group [2.0 days (interquartile range (IQR) 1.0-4.5 days) vs. 5.0 days (IQR 1.5-10.8 days), P = 0.04], and there was no difference in in-hospital mortality between groups (P = 0.27)., Conclusions: We have demonstrated that a triage-based sepsis screening tool results in expedited and consistent delivery of care, with a significant improvement in initial resuscitation measures.

Published
2018
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36. History of thyroid disease and survival of ovarian cancer patients: results from the Ovarian Cancer Association Consortium, a brief report.

Author

Minlikeeva AN, Freudenheim JL, Cannioto RA, Eng KH, Szender JB, Mayor P, Etter JL, Cramer DW, Diergaarde B, Doherty JA, Dörk T, Edwards R, deFazio A, Friel G, Goodman MT, Hillemanns P, Høgdall E, Jensen A, Jordan SJ, Karlan BY, Kjær SK, Klapdor R, Matsuo K, Mizuno M, Nagle CM, Odunsi K, Paddock L, Rossing MA, Schildkraut JM, Schmalfeldt B, Segal BH, Starbuck K, Terry KL, Webb PM, Zsiros E, Ness RB, Modugno F, Bandera EV, Chang-Claude J, and Moysich KB

Subjects
Aged, Female, Humans, Hyperthyroidism drug therapy, Hypothyroidism drug therapy, Middle Aged, Proportional Hazards Models, Survival Rate, Time Factors, Hyperthyroidism epidemiology, Hypothyroidism epidemiology, Ovarian Neoplasms mortality
Abstract

Background: Findings from in vitro studies suggest that increased exposure to thyroid hormones can influence progression of ovarian tumours. However, epidemiologic evidence on this topic is limited., Methods: We pooled data from 11 studies from the Ovarian Cancer Association Consortium. Using multivariate Cox proportional hazards models, we estimated associations between hyper- and hypothyroidism and medications prescribed for these conditions with 5-year all-cause survival among women diagnosed with invasive ovarian cancer., Results: Overall, there was a nonsignificant association with history of hyperthyroidism (n=160 cases) and mortality (HR=1.22; 95% CI=0.97-1.53). Furthermore, diagnosis of hyperthyroidism within the 5 years before ovarian cancer diagnosis was associated with an increased risk of death (HR=1.94; 95% CI=1.19-3.18). A more modest association was observed with history of hypothyroidism (n=624 cases) and mortality (HR=1.16; 95% CI=1.03-1.31). Neither duration of hypothyroidism nor use of thyroid medications was associated with survival., Conclusions: In this large study of women with ovarian cancer, we found that recent history of hyperthyroidism and overall history of hypothyroidism were associated with worse 5-year survival.

Published
2017
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37. History of Comorbidities and Survival of Ovarian Cancer Patients, Results from the Ovarian Cancer Association Consortium.

Author

Minlikeeva AN, Freudenheim JL, Eng KH, Cannioto RA, Friel G, Szender JB, Segal B, Odunsi K, Mayor P, Diergaarde B, Zsiros E, Kelemen LE, Köbel M, Steed H, deFazio A, Jordan SJ, Fasching PA, Beckmann MW, Risch HA, Rossing MA, Doherty JA, Chang-Claude J, Goodman MT, Dörk T, Edwards R, Modugno F, Ness RB, Matsuo K, Mizuno M, Karlan BY, Goode EL, Kjær SK, Høgdall E, Schildkraut JM, Terry KL, Cramer DW, Bandera EV, Paddock LE, Kiemeney LA, Massuger LFAG, Sutphen R, Anton-Culver H, Ziogas A, Menon U, Gayther SA, Ramus SJ, Gentry-Maharaj A, Pearce CL, Wu AH, Kupryjanczyk J, Jensen A, Webb PM, and Moysich KB

Subjects
Comorbidity, Disease-Free Survival, Female, Humans, Ovarian Neoplasms epidemiology, Survival Analysis, Ovarian Neoplasms mortality
Abstract

Background: Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between individual concurrent comorbidities and prognosis in ovarian cancer patients. Methods: Among patients diagnosed with invasive ovarian carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival. Using Cox proportional hazards regression models adjusted for age at diagnosis, stage of disease, histology, and study site, we estimated pooled HRs and 95% confidence intervals to assess associations between each comorbidity and ovarian cancer outcomes. Results: None of the comorbidities were associated with ovarian cancer outcome in the overall sample nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced). Conclusions: Histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, or neurologic diseases were not associated with ovarian cancer overall or progression-free survival. Impact: These previously diagnosed chronic diseases do not appear to affect ovarian cancer prognosis. Cancer Epidemiol Biomarkers Prev; 26(9); 1470-3. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Published
2017
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38. History of hypertension, heart disease, and diabetes and ovarian cancer patient survival: evidence from the ovarian cancer association consortium.

Author

Minlikeeva AN, Freudenheim JL, Cannioto RA, Szender JB, Eng KH, Modugno F, Ness RB, LaMonte MJ, Friel G, Segal BH, Odunsi K, Mayor P, Zsiros E, Schmalfeldt B, Klapdor R, Dӧrk T, Hillemanns P, Kelemen LE, Kӧbel M, Steed H, de Fazio A, Jordan SJ, Nagle CM, Risch HA, Rossing MA, Doherty JA, Goodman MT, Edwards R, Matsuo K, Mizuno M, Karlan BY, Kjær SK, Høgdall E, Jensen A, Schildkraut JM, Terry KL, Cramer DW, Bandera EV, Paddock LE, Kiemeney LA, Massuger LF, Kupryjanczyk J, Berchuck A, Chang-Claude J, Diergaarde B, Webb PM, and Moysich KB

Subjects
Adrenergic beta-Antagonists therapeutic use, Adult, Aged, Diabetes Mellitus drug therapy, Disease-Free Survival, Female, Heart Diseases drug therapy, Humans, Hypertension drug therapy, Hypoglycemic Agents therapeutic use, Insulin therapeutic use, Middle Aged, Ovarian Neoplasms complications, Ovarian Neoplasms pathology, Risk, Survival Rate, Heart Diseases complications, Hypertension complications, Ovarian Neoplasms mortality
Abstract

Purpose: Survival following ovarian cancer diagnosis is generally low; understanding factors related to prognosis could be important to optimize treatment. The role of previously diagnosed comorbidities and use of medications for those conditions in relation to prognosis for ovarian cancer patients has not been studied extensively, particularly according to histological subtype., Methods: Using pooled data from fifteen studies participating in the Ovarian Cancer Association Consortium, we examined the associations between history of hypertension, heart disease, diabetes, and medications taken for these conditions and overall survival (OS) and progression-free survival (PFS) among patients diagnosed with invasive epithelial ovarian carcinoma. We used Cox proportional hazards regression models adjusted for age and stage to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and within strata of histological subtypes., Results: History of diabetes was associated with increased risk of mortality (n = 7,674; HR = 1.12; 95% CI = 1.01-1.25). No significant mortality associations were observed for hypertension (n = 6,482; HR = 0.95; 95% CI = 0.88-1.02) or heart disease (n = 4,252; HR = 1.05; 95% CI = 0.87-1.27). No association of these comorbidities was found with PFS in the overall study population. However, among patients with endometrioid tumors, hypertension was associated with lower risk of progression (n = 339, HR = 0.54; 95% CI = 0.35-0.84). Comorbidity was not associated with OS or PFS for any of the other histological subtypes. Ever use of beta blockers, oral antidiabetic medications, and insulin was associated with increased mortality, HR = 1.20; 95% CI = 1.03-1.40, HR = 1.28; 95% CI = 1.05-1.55, and HR = 1.63; 95% CI = 1.20-2.20, respectively. Ever use of diuretics was inversely associated with mortality, HR = 0.71; 95% CI = 0.53-0.94., Conclusions: Histories of hypertension, diabetes, and use of diuretics, beta blockers, insulin, and oral antidiabetic medications may influence the survival of ovarian cancer patients. Understanding mechanisms for these observations could provide insight regarding treatment.

Published
2017
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39. The Association of Peripheral Blood Regulatory T-Cell Concentrations With Epithelial Ovarian Cancer: A Brief Report.

Author

Cannioto RA, Sucheston-Campbell LE, Hampras S, Goode EL, Knutson K, Ness R, Modugno F, Wallace P, Szender JB, Mayor P, Hong CC, Joseph JM, Friel G, Davis W, Nesline M, Eng KH, Edwards RP, Kruszka B, Schmitt K, Odunsi K, and Moysich KB

Subjects
Age Factors, Carcinoma, Ovarian Epithelial, Case-Control Studies, Female, Humans, Middle Aged, Neoplasms, Glandular and Epithelial immunology, Ovarian Neoplasms immunology, T-Lymphocytes, Regulatory immunology, Neoplasms, Glandular and Epithelial blood, Ovarian Neoplasms blood, T-Lymphocytes, Regulatory pathology
Abstract

Objective: There is a mounting body of evidence demonstrating higher percentages of regulatory T (Treg) cells in the peripheral blood of patients with cancer in comparison to healthy controls, but there is a paucity of epidemiological literature characterizing circulating Treg cells among patients with epithelial ovarian cancer (EOC). To investigate the role of peripheral Treg cells in ovarian neoplasms, we conducted a case-control study to characterize circulating concentrations of Treg cells among patients with EOC, women with benign ovarian conditions, and healthy controls without a history of cancer., Materials and Methods: Participants were identified for inclusion due to their participation in the Data Bank and BioRepository program at Roswell Park Cancer Institute in Buffalo, NY. Patients included 71 women with a primary diagnosis of EOC and 195 women with a diagnosis of benign ovarian conditions. Controls included 101 age- and race-matched women without a history of cancer. Nonfasting, pretreatment peripheral blood levels of CD3+CD4+CD25+FOXP3+ Treg cells were measured using flow cytometric analyses and expressed as a percentage of total CD3+ cells and as a percentage of total CD3+CD4+ cells., Results: Compared to healthy controls and women with benign ovarian conditions, patients with EOC had significantly higher frequency of Treg cells (P < 0.04). In multivariable logistic regression analyses using Treg frequency expressed as a percentage of CD+3 cells, we observed a significant positive association between Treg cell percentage and EOC risk, with each 1% increase associated with a 37% increased risk of EOC (odds ratio, 1.37; 95% confidence interval, 1.04-1.80). We observed a similar trend when Treg frequency was expressed as a percentage of CD3+CD+4 cells (odds ratio, 1.22; 95% confidence interval, 0.99-1.49)., Conclusions: The current study provides support that peripheral Treg cell frequency is elevated in patients with EOC in comparison to women with benign ovarian conditions and healthy controls.

Published
2017
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40. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.

Author

Southey MC, Goldgar DE, Winqvist R, Pylkäs K, Couch F, Tischkowitz M, Foulkes WD, Dennis J, Michailidou K, van Rensburg EJ, Heikkinen T, Nevanlinna H, Hopper JL, Dörk T, Claes KB, Reis-Filho J, Teo ZL, Radice P, Catucci I, Peterlongo P, Tsimiklis H, Odefrey FA, Dowty JG, Schmidt MK, Broeks A, Hogervorst FB, Verhoef S, Carpenter J, Clarke C, Scott RJ, Fasching PA, Haeberle L, Ekici AB, Beckmann MW, Peto J, Dos-Santos-Silva I, Fletcher O, Johnson N, Bolla MK, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Marme F, Burwinkel B, Yang R, Guénel P, Truong T, Menegaux F, Sanchez M, Bojesen S, Nielsen SF, Flyger H, Benitez J, Zamora MP, Perez JI, Menéndez P, Anton-Culver H, Neuhausen S, Ziogas A, Clarke CA, Brenner H, Arndt V, Stegmaier C, Brauch H, Brüning T, Ko YD, Muranen TA, Aittomäki K, Blomqvist C, Bogdanova NV, Antonenkova NN, Lindblom A, Margolin S, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Spurdle AB, Investigators K, Wauters E, Smeets D, Beuselinck B, Floris G, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Olson JE, Vachon C, Pankratz VS, McLean C, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Kristensen V, Alnæs GG, Zheng W, Hunter DJ, Lindstrom S, Hankinson SE, Kraft P, Andrulis I, Knight JA, Glendon G, Mulligan AM, Jukkola-Vuorinen A, Grip M, Kauppila S, Devilee P, Tollenaar RA, Seynaeve C, Hollestelle A, Garcia-Closas M, Figueroa J, Chanock SJ, Lissowska J, Czene K, Darabi H, Eriksson M, Eccles DM, Rafiq S, Tapper WJ, Gerty SM, Hooning MJ, Martens JW, Collée JM, Tilanus-Linthorst M, Hall P, Li J, Brand JS, Humphreys K, Cox A, Reed MW, Luccarini C, Baynes C, Dunning AM, Hamann U, Torres D, Ulmer HU, Rüdiger T, Jakubowska A, Lubinski J, Jaworska K, Durda K, Slager S, Toland AE, Ambrosone CB, Yannoukakos D, Swerdlow A, Ashworth A, Orr N, Jones M, González-Neira A, Pita G, Alonso MR, Álvarez N, Herrero D, Tessier DC, Vincent D, Bacot F, Simard J, Dumont M, Soucy P, Eeles R, Muir K, Wiklund F, Gronberg H, Schleutker J, Nordestgaard BG, Weischer M, Travis RC, Neal D, Donovan JL, Hamdy FC, Khaw KT, Stanford JL, Blot WJ, Thibodeau S, Schaid DJ, Kelley JL, Maier C, Kibel AS, Cybulski C, Cannon-Albright L, Butterbach K, Park J, Kaneva R, Batra J, Teixeira MR, Kote-Jarai Z, Olama AA, Benlloch S, Renner SP, Hartmann A, Hein A, Ruebner M, Lambrechts D, Van Nieuwenhuysen E, Vergote I, Lambretchs S, Doherty JA, Rossing MA, Nickels S, Eilber U, Wang-Gohrke S, Odunsi K, Sucheston-Campbell LE, Friel G, Lurie G, Killeen JL, Wilkens LR, Goodman MT, Runnebaum I, Hillemanns PA, Pelttari LM, Butzow R, Modugno F, Edwards RP, Ness RB, Moysich KB, du Bois A, Heitz F, Harter P, Kommoss S, Karlan BY, Walsh C, Lester J, Jensen A, Kjaer SK, Høgdall E, Peissel B, Bonanni B, Bernard L, Goode EL, Fridley BL, Vierkant RA, Cunningham JM, Larson MC, Fogarty ZC, Kalli KR, Liang D, Lu KH, Hildebrandt MA, Wu X, Levine DA, Dao F, Bisogna M, Berchuck A, Iversen ES, Marks JR, Akushevich L, Cramer DW, Schildkraut J, Terry KL, Poole EM, Stampfer M, Tworoger SS, Bandera EV, Orlow I, Olson SH, Bjorge L, Salvesen HB, van Altena AM, Aben KK, Kiemeney LA, Massuger LF, Pejovic T, Bean Y, Brooks-Wilson A, Kelemen LE, Cook LS, Le ND, Górski B, Gronwald J, Menkiszak J, Høgdall CK, Lundvall L, Nedergaard L, Engelholm SA, Dicks E, Tyrer J, Campbell I, McNeish I, Paul J, Siddiqui N, Glasspool R, Whittemore AS, Rothstein JH, McGuire V, Sieh W, Cai H, Shu XO, Teten RT, Sutphen R, McLaughlin JR, Narod SA, Phelan CM, Monteiro AN, Fenstermacher D, Lin HY, Permuth JB, Sellers TA, Chen YA, Tsai YY, Chen Z, Gentry-Maharaj A, Gayther SA, Ramus SJ, Menon U, Wu AH, Pearce CL, Van Den Berg D, Pike MC, Dansonka-Mieszkowska A, Plisiecka-Halasa J, Moes-Sosnowska J, Kupryjanczyk J, Pharoah PD, Song H, Winship I, Chenevix-Trench G, Giles GG, Tavtigian SV, Easton DF, and Milne RL

Subjects
Breast Neoplasms epidemiology, Breast Neoplasms genetics, Case-Control Studies, Fanconi Anemia Complementation Group N Protein, Female, Genetic Association Studies, Humans, Male, Ovarian Neoplasms epidemiology, Ovarian Neoplasms genetics, Ovarian Neoplasms metabolism, Prostatic Neoplasms epidemiology, Prostatic Neoplasms genetics, Risk, Ataxia Telangiectasia Mutated Proteins genetics, Breast Neoplasms metabolism, Checkpoint Kinase 2 genetics, Genetic Predisposition to Disease, Mutation, Nuclear Proteins genetics, Prostatic Neoplasms metabolism, Tumor Suppressor Proteins genetics
Abstract

Background: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study., Methods: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant., Results: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10 -5 ), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10 -8 ) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants., Conclusions: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Published
2016
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41. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer.

Author

Hampras SS, Sucheston-Campbell LE, Cannioto R, Chang-Claude J, Modugno F, Dörk T, Hillemanns P, Preus L, Knutson KL, Wallace PK, Hong CC, Friel G, Davis W, Nesline M, Pearce CL, Kelemen LE, Goodman MT, Bandera EV, Terry KL, Schoof N, Eng KH, Clay A, Singh PK, Joseph JM, Aben KK, Anton-Culver H, Antonenkova N, Baker H, Bean Y, Beckmann MW, Bisogna M, Bjorge L, Bogdanova N, Brinton LA, Brooks-Wilson A, Bruinsma F, Butzow R, Campbell IG, Carty K, Cook LS, Cramer DW, Cybulski C, Dansonka-Mieszkowska A, Dennis J, Despierre E, Dicks E, Doherty JA, du Bois A, Dürst M, Easton D, Eccles D, Edwards RP, Ekici AB, Fasching PA, Fridley BL, Gao YT, Gentry-Maharaj A, Giles GG, Glasspool R, Gronwald J, Harrington P, Harter P, Hasmad HN, Hein A, Heitz F, Hildebrandt MA, Hogdall C, Hogdall E, Hosono S, Iversen ES, Jakubowska A, Jensen A, Ji BT, Karlan BY, Kellar M, Kelley JL, Kiemeney LA, Klapdor R, Kolomeyevskaya N, Krakstad C, Kjaer SK, Kruszka B, Kupryjanczyk J, Lambrechts D, Lambrechts S, Le ND, Lee AW, Lele S, Leminen A, Lester J, Levine DA, Liang D, Lissowska J, Liu S, Lu K, Lubinski J, Lundvall L, Massuger LF, Matsuo K, McGuire V, McLaughlin JR, McNeish I, Menon U, Moes-Sosnowska J, Narod SA, Nedergaard L, Nevanlinna H, Nickels S, Olson SH, Orlow I, Weber RP, Paul J, Pejovic T, Pelttari LM, Perkins B, Permuth-Wey J, Pike MC, Plisiecka-Halasa J, Poole EM, Risch HA, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Rzepecka IK, Salvesen HB, Schernhammer E, Schmitt K, Schwaab I, Shu XO, Shvetsov YB, Siddiqui N, Sieh W, Song H, Southey MC, Tangen IL, Teo SH, Thompson PJ, Timorek A, Tsai YY, Tworoger SS, Tyrer J, van Altena AM, Vergote I, Vierkant RA, Walsh C, Wang-Gohrke S, Wentzensen N, Whittemore AS, Wicklund KG, Wilkens LR, Wu AH, Wu X, Woo YL, Yang H, Zheng W, Ziogas A, Gayther SA, Ramus SJ, Sellers TA, Schildkraut JM, Phelan CM, Berchuck A, Chenevix-Trench G, Cunningham JM, Pharoah PP, Ness RB, Odunsi K, Goode EL, and Moysich KB

Subjects
Adenocarcinoma, Clear Cell immunology, Adult, Aged, Carcinoma, Ovarian Epithelial, Female, Gene Expression Regulation, Neoplastic, Gene Frequency, Genotype, Humans, Middle Aged, Neoplasms, Glandular and Epithelial immunology, Ovarian Neoplasms immunology, Receptor, Transforming Growth Factor-beta Type II, Risk Factors, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Adenocarcinoma, Clear Cell genetics, Genetic Predisposition to Disease genetics, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide, Protein Serine-Threonine Kinases genetics, Receptors, Transforming Growth Factor beta genetics
Abstract

Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer., Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients., Results: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively)., Conclusions: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Published
2016
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42. Impact of Physical Inactivity on Risk of Developing Cancer of the Uterine Cervix: A Case-Control Study.

Author

Szender JB, Cannioto R, Gulati NR, Schmitt KL, Friel G, Minlikeeva A, Platek A, Gower EH, Nagy R, Khachatryan E, Mayor PC, Kasza KA, Lele SB, Odunsi K, and Moysich KB

Subjects
Adult, Case-Control Studies, Female, Humans, Risk Assessment, Young Adult, Exercise, Uterine Cervical Neoplasms epidemiology
Abstract

Objective: In this study, we investigated whether physical inactivity was associated with risk of cervical cancer in women treated at an American cancer hospital., Methods: This case-control study included 128 patients with cervical cancer and 512 controls matched on age. Controls were women suspected of having but not ultimately diagnosed with a neoplasm. Physical inactivity was defined in accordance with the 2008 Physical Activity Guidelines for Americans. Thus, participants reporting, on average, no moderate or vigorous recreational physical activity were classified as inactive. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs)., Results: Compared with noncancer controls, those with cervical cancer had significantly increased odds of reporting abstinence from recreational physical activity (OR, 2.43; 95% CI, 1.56-3.80). No association was noted between occupational-related physical inactivity and cervical cancer (OR, 0.88; 95% CI, 0.58-1.36)., Conclusions: Our findings suggest that abstinence from regular recreational physical activity is associated with increased odds of cervical cancer. To our knowledge, this is the first US-based study examining these associations. Given the 2008 Physical Activity Guidelines for Americans, this study has identified yet another potential public health benefit to regular physical activity. Further investigation is needed using a larger sample and prospectively collected data to characterize dose of activity to mitigate risk and the optimal window of susceptibility.

Published
2016
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43. Recreational physical inactivity and mortality in women with invasive epithelial ovarian cancer: evidence from the Ovarian Cancer Association Consortium.

Author

Cannioto RA, LaMonte MJ, Kelemen LE, Risch HA, Eng KH, Minlikeeva AN, Hong CC, Szender JB, Sucheston-Campbell L, Joseph JM, Berchuck A, Chang-Claude J, Cramer DW, DeFazio A, Diergaarde B, Dörk T, Doherty JA, Edwards RP, Fridley BL, Friel G, Goode EL, Goodman MT, Hillemanns P, Hogdall E, Hosono S, Kelley JL, Kjaer SK, Klapdor R, Matsuo K, Odunsi K, Nagle CM, Olsen CM, Paddock LE, Pearce CL, Pike MC, Rossing MA, Schmalfeldt B, Segal BH, Szamreta EA, Thompson PJ, Tseng CC, Vierkant R, Schildkraut JM, Wentzensen N, Wicklund KG, Winham SJ, Wu AH, Modugno F, Ness RB, Jensen A, Webb PM, Terry K, Bandera EV, and Moysich KB

Subjects
Carcinoma, Ovarian Epithelial, Female, Humans, Middle Aged, Proportional Hazards Models, Risk Factors, Exercise physiology, Neoplasms, Glandular and Epithelial mortality, Ovarian Neoplasms mortality, Recreation physiology
Abstract

Background: Little is known about modifiable behaviours that may be associated with epithelial ovarian cancer (EOC) survival. We conducted a pooled analysis of 12 studies from the Ovarian Cancer Association Consortium to investigate the association between pre-diagnostic physical inactivity and mortality., Methods: Participants included 6806 women with a primary diagnosis of invasive EOC. In accordance with the Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. We utilised Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) representing the associations of inactivity with mortality censored at 5 years., Results: In multivariate analysis, inactive women had significantly higher mortality risks, with (HR=1.34, 95% CI: 1.18-1.52) and without (HR=1.22, 95% CI: 1.12-1.33) further adjustment for residual disease, respectively., Conclusion: In this large pooled analysis, lack of recreational physical activity was associated with increased mortality among women with invasive EOC.

Published
2016
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44. No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer.

Author

Hollestelle A, van der Baan FH, Berchuck A, Johnatty SE, Aben KK, Agnarsson BA, Aittomäki K, Alducci E, Andrulis IL, Anton-Culver H, Antonenkova NN, Antoniou AC, Apicella C, Arndt V, Arnold N, Arun BK, Arver B, Ashworth A, Baglietto L, Balleine R, Bandera EV, Barrowdale D, Bean YT, Beckmann L, Beckmann MW, Benitez J, Berger A, Berger R, Beuselinck B, Bisogna M, Bjorge L, Blomqvist C, Bogdanova NV, Bojesen A, Bojesen SE, Bolla MK, Bonanni B, Brand JS, Brauch H, Brenner H, Brinton L, Brooks-Wilson A, Bruinsma F, Brunet J, Brüning T, Budzilowska A, Bunker CH, Burwinkel B, Butzow R, Buys SS, Caligo MA, Campbell I, Carter J, Chang-Claude J, Chanock SJ, Claes KBM, Collée JM, Cook LS, Couch FJ, Cox A, Cramer D, Cross SS, Cunningham JM, Cybulski C, Czene K, Damiola F, Dansonka-Mieszkowska A, Darabi H, de la Hoya M, deFazio A, Dennis J, Devilee P, Dicks EM, Diez O, Doherty JA, Domchek SM, Dorfling CM, Dörk T, Silva IDS, du Bois A, Dumont M, Dunning AM, Duran M, Easton DF, Eccles D, Edwards RP, Ehrencrona H, Ejlertsen B, Ekici AB, Ellis SD, Engel C, Eriksson M, Fasching PA, Feliubadalo L, Figueroa J, Flesch-Janys D, Fletcher O, Fontaine A, Fortuzzi S, Fostira F, Fridley BL, Friebel T, Friedman E, Friel G, Frost D, Garber J, García-Closas M, Gayther SA, Gentry-Maharaj A, Gerdes AM, Giles GG, Glasspool R, Glendon G, Godwin AK, Goodman MT, Gore M, Greene MH, Grip M, Gronwald J, Gschwantler Kaulich D, Guénel P, Guzman SR, Haeberle L, Haiman CA, Hall P, Halverson SL, Hamann U, Hansen TVO, Harter P, Hartikainen JM, Healey S, Hein A, Heitz F, Henderson BE, Herzog J, T Hildebrandt MA, Høgdall CK, Høgdall E, Hogervorst FBL, Hopper JL, Humphreys K, Huzarski T, Imyanitov EN, Isaacs C, Jakubowska A, Janavicius R, Jaworska K, Jensen A, Jensen UB, Johnson N, Jukkola-Vuorinen A, Kabisch M, Karlan BY, Kataja V, Kauff N, Kelemen LE, Kerin MJ, Kiemeney LA, Kjaer SK, Knight JA, Knol-Bout JP, Konstantopoulou I, Kosma VM, Krakstad C, Kristensen V, Kuchenbaecker KB, Kupryjanczyk J, Laitman Y, Lambrechts D, Lambrechts S, Larson MC, Lasa A, Laurent-Puig P, Lazaro C, Le ND, Le Marchand L, Leminen A, Lester J, Levine DA, Li J, Liang D, Lindblom A, Lindor N, Lissowska J, Long J, Lu KH, Lubinski J, Lundvall L, Lurie G, Mai PL, Mannermaa A, Margolin S, Mariette F, Marme F, Martens JWM, Massuger LFAG, Maugard C, Mazoyer S, McGuffog L, McGuire V, McLean C, McNeish I, Meindl A, Menegaux F, Menéndez P, Menkiszak J, Menon U, Mensenkamp AR, Miller N, Milne RL, Modugno F, Montagna M, Moysich KB, Müller H, Mulligan AM, Muranen TA, Narod SA, Nathanson KL, Ness RB, Neuhausen SL, Nevanlinna H, Neven P, Nielsen FC, Nielsen SF, Nordestgaard BG, Nussbaum RL, Odunsi K, Offit K, Olah E, Olopade OI, Olson JE, Olson SH, Oosterwijk JC, Orlow I, Orr N, Orsulic S, Osorio A, Ottini L, Paul J, Pearce CL, Pedersen IS, Peissel B, Pejovic T, Pelttari LM, Perkins J, Permuth-Wey J, Peterlongo P, Peto J, Phelan CM, Phillips KA, Piedmonte M, Pike MC, Platte R, Plisiecka-Halasa J, Poole EM, Poppe B, Pylkäs K, Radice P, Ramus SJ, Rebbeck TR, Reed MWR, Rennert G, Risch HA, Robson M, Rodriguez GC, Romero A, Rossing MA, Rothstein JH, Rudolph A, Runnebaum I, Salani R, Salvesen HB, Sawyer EJ, Schildkraut JM, Schmidt MK, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schrauder MG, Schumacher F, Schwaab I, Scuvera G, Sellers TA, Severi G, Seynaeve CM, Shah M, Shrubsole M, Siddiqui N, Sieh W, Simard J, Singer CF, Sinilnikova OM, Smeets D, Sohn C, Soller M, Song H, Soucy P, Southey MC, Stegmaier C, Stoppa-Lyonnet D, Sucheston L, Swerdlow A, Tangen IL, Tea MK, Teixeira MR, Terry KL, Terry MB, Thomassen M, Thompson PJ, Tihomirova L, Tischkowitz M, Toland AE, Tollenaar RAEM, Tomlinson I, Torres D, Truong T, Tsimiklis H, Tung N, Tworoger SS, Tyrer JP, Vachon CM, Van 't Veer LJ, van Altena AM, Van Asperen CJ, van den Berg D, van den Ouweland AMW, van Doorn HC, Van Nieuwenhuysen E, van Rensburg EJ, Vergote I, Verhoef S, Vierkant RA, Vijai J, Vitonis AF, von Wachenfeldt A, Walsh C, Wang Q, Wang-Gohrke S, Wappenschmidt B, Weischer M, Weitzel JN, Weltens C, Wentzensen N, Whittemore AS, Wilkens LR, Winqvist R, Wu AH, Wu X, Yang HP, Zaffaroni D, Pilar Zamora M, Zheng W, Ziogas A, Chenevix-Trench G, Pharoah PDP, Rookus MA, Hooning MJ, and Goode EL

Subjects
Carcinoma, Ovarian Epithelial, Female, Humans, Breast Neoplasms enzymology, Breast Neoplasms genetics, Neoplasms, Glandular and Epithelial enzymology, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms enzymology, Ovarian Neoplasms genetics, Proto-Oncogene Proteins p21(ras) genetics
Abstract

Objective: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370., Methods: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers)., Results: We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations., Conclusions: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Published
2016
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45. Oral Contraceptive Use and Reproductive Characteristics Affect Survival in Patients With Epithelial Ovarian Cancer: A Cohort Study.

Author

Kolomeyevskaya NV, Szender JB, Zirpoli G, Minlikeeva A, Friel G, Cannioto RA, Brightwell RM, Grzankowski KS, and Moysich KB

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Carcinoma, Ovarian Epithelial, Female, Gravidity, Humans, Kaplan-Meier Estimate, Live Birth, Middle Aged, Parity, Pregnancy, Proportional Hazards Models, Retrospective Studies, Survival Rate, Young Adult, Contraceptives, Oral therapeutic use, Fallopian Tube Neoplasms mortality, Neoplasms, Glandular and Epithelial mortality, Ovarian Neoplasms mortality, Peritoneal Neoplasms mortality
Abstract

Objectives: Prognostic risk factors influencing survival in patients with epithelial ovarian cancer (EOC) include tumor stage, grade, histologic subtype, debulking, and platinum status. Little is known about the impact of hormonal milieu and reproductive factors before cancer diagnosis on clinical outcome. We sought to evaluate whether oral contraceptive (OC) use carries any prognostic significance on overall survival (OS) in patients with EOC., Methods: Newly diagnosed patients with EOC, fallopian tube, and primary peritoneal cancers between 1982 and 1998 were prospectively evaluated with a comprehensive epidemiologic questionnaire. A retrospective chart review was performed to abstract clinicopathologic data, including OS. A Kaplan-Meier analysis was performed to compare survival across various exposures. A Cox regression model was used to compute adjusted hazards ratios (aHRs) and 95% confidence intervals (CIs)., Results: We identified 387 newly diagnosed cancers with evaluable information in this cohort. Decreased risk of death was observed in women who reported prior use of OC (aHR, 0.79; 95% CI, 0.58-1.09), previous pregnancy (aHR, 0.77; 95% CI, 0.57-1.04), or a live birth (aHR, 0.81; 95% CI, 0.60-1.08) after adjusting for age at diagnosis, stage, and histologic subtype. Oral contraceptive use was associated with a crude reduced risk of death (HR, 0.55; 95% CI, 0.42-0.72), with reported median OS of 81 months in OC users versus 46 months in nonusers. Patients who reported a single live birth experienced the largest potential survival advantage (aHR, 0.61; 95% CI, 0.39-0.94). Oral contraceptive use and prior pregnancy were associated with improved survival across all strata., Conclusions: Oral contraceptive use may have lasting effects on epithelial ovarian tumor characteristics conferring favorable prognosis. Putative mechanisms that affect tumor biology include complex interactions between ovarian cells, host immune cells, and hormonal microenvironment during carcinogenesis. Future efforts should be directed to determine the role of reproductive factors in antitumor immunity.

Published
2015
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46. Use of common analgesics is not associated with ovarian cancer survival.

Author

Minlikeeva AN, Freudenheim JL, Lo-Ciganic WH, Eng KH, Friel G, Diergaarde B, Modugno F, Cannioto R, Gower E, Szender JB, Grzankowski K, Odunsi K, Ness RB, and Moysich KB

Subjects
Analgesics pharmacology, Carcinoma, Ovarian Epithelial, Female, Humans, Middle Aged, Neoplasms, Glandular and Epithelial mortality, Ovarian Neoplasms mortality, Survival Analysis, Analgesics therapeutic use, Neoplasms, Glandular and Epithelial drug therapy, Ovarian Neoplasms drug therapy
Abstract

Background: Use of analgesics has been associated with lower risk of ovarian cancer, but, to date, very few studies have explored the association between analgesics and ovarian cancer survival., Methods: We examined the relationship between self-reported prediagnostic use of aspirin, ibuprofen, and acetaminophen and overall survival (OS), progression-free survival (PFS), ascites at the time of primary treatment, and persistence of disease after primary treatment among 699 women diagnosed with epithelial ovarian carcinoma. The associations between use of these medications and OS and PFS were estimated using Cox proportional hazards models. We utilized unconditional logistic regression models to estimate associations between medication use and presence of ascites and persistence of disease., Results: Prediagnostic intake of aspirin, both low-dose and regular-dose, ibuprofen, and acetaminophen was not associated with any of the outcomes of interest., Conclusions: Our results indicate a lack of association between prediagnostic intake of selected analgesics and OS, PFS, presence of ascites at the time of primary treatment, and persistence of disease after primary treatment., Impact: Prediagnostic intake of analgesics may not be associated with ovarian cancer outcomes., (©2015 American Association for Cancer Research.)

Published
2015
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47. Aspirin and Acetaminophen Use and the Risk of Cervical Cancer.

Author

Friel G, Liu CS, Kolomeyevskaya NV, Hampras SS, Kruszka B, Schmitt K, Cannioto RA, Lele SB, Odunsi KO, and Moysich KB

Subjects
Adenocarcinoma pathology, Adult, Aged, Cancer Care Facilities, Carcinoma, Squamous Cell pathology, Case-Control Studies, Female, Humans, Logistic Models, Middle Aged, New York, Risk Factors, Surveys and Questionnaires, Uterine Cervical Neoplasms pathology, Acetaminophen therapeutic use, Analgesics, Non-Narcotic therapeutic use, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Aspirin therapeutic use, Uterine Cervical Neoplasms prevention & control
Abstract

Objective: In this study, we investigated whether regular use of aspirin or acetaminophen was associated with risk of cervical cancer in women treated at an American cancer hospital., Methods: This case-control study included 328 patients with cervical cancer and 1,312 controls matched on age and decade enrolled. Controls were women suspected of having but not ultimately diagnosed with a neoplasm. Analgesic use was defined as regular (at least once per week for ≥6 months), frequent (≥7 tablets/week), very long term (≥11 years), or frequent, long term (≥7 tablets per week for ≥5 years)., Results: Compared to nonusers, frequent aspirin use was associated with decreased odds of cervical cancer (odds ratio, 0.53; 95% confidence interval, 0.29-0.97). A slightly larger association was observed with frequent, long-term use of aspirin (odds ratio, 0.46; 95% confidence interval, 0.22-0.95). Acetaminophen use was not associated with the risk of cervical cancer., Conclusions: Our findings suggest that frequent and frequent, long-term use of aspirin is associated with decreased odds of cervical cancer. To our knowledge, this is the first US-based study examining these associations. Given the widespread use of nonsteroidal anti-inflammatory drugs and acetaminophen worldwide, further investigations of the possible role of analgesics in cervical cancer, using a larger sample size with better-defined dosing regimens, are warranted.

Published
2015
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48. Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA.

Author

Earp MA, Kelemen LE, Magliocco AM, Swenerton KD, Chenevix-Trench G, Lu Y, Hein A, Ekici AB, Beckmann MW, Fasching PA, Lambrechts D, Despierre E, Vergote I, Lambrechts S, Doherty JA, Rossing MA, Chang-Claude J, Rudolph A, Friel G, Moysich KB, Odunsi K, Sucheston-Campbell L, Lurie G, Goodman MT, Carney ME, Thompson PJ, Runnebaum IB, Dürst M, Hillemanns P, Dörk T, Antonenkova N, Bogdanova N, Leminen A, Nevanlinna H, Pelttari LM, Butzow R, Bunker CH, Modugno F, Edwards RP, Ness RB, du Bois A, Heitz F, Schwaab I, Harter P, Karlan BY, Walsh C, Lester J, Jensen A, Kjær SK, Høgdall CK, Høgdall E, Lundvall L, Sellers TA, Fridley BL, Goode EL, Cunningham JM, Vierkant RA, Giles GG, Baglietto L, Severi G, Southey MC, Liang D, Wu X, Lu K, Hildebrandt MA, Levine DA, Bisogna M, Schildkraut JM, Iversen ES, Weber RP, Berchuck A, Cramer DW, Terry KL, Poole EM, Tworoger SS, Bandera EV, Chandran U, Orlow I, Olson SH, Wik E, Salvesen HB, Bjorge L, Halle MK, van Altena AM, Aben KK, Kiemeney LA, Massuger LF, Pejovic T, Bean YT, Cybulski C, Gronwald J, Lubinski J, Wentzensen N, Brinton LA, Lissowska J, Garcia-Closas M, Dicks E, Dennis J, Easton DF, Song H, Tyrer JP, Pharoah PD, Eccles D, Campbell IG, Whittemore AS, McGuire V, Sieh W, Rothstein JH, Flanagan JM, Paul J, Brown R, Phelan CM, Risch HA, McLaughlin JR, Narod SA, Ziogas A, Anton-Culver H, Gentry-Maharaj A, Menon U, Gayther SA, Ramus SJ, Wu AH, Pearce CL, Pike MC, Dansonka-Mieszkowska A, Rzepecka IK, Szafron LM, Kupryjanczyk J, Cook LS, Le ND, and Brooks-Wilson A

Subjects
Carcinoma, Ovarian Epithelial, Female, Humans, Polymorphism, Single Nucleotide, Quality Control, Alleles, DNA genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms genetics
Abstract

Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.

Published
2014
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49. Do mutations causing low HDL-C promote increased carotid intima-media thickness?

Author

Miller M, Rhyne J, Hong SH, Friel G, Dolinar C, and Riley W

Subjects
Contrast Media, Coronary Disease epidemiology, Coronary Disease pathology, Female, Humans, Male, Mutation genetics, Risk Factors, Cholesterol, HDL blood, Coronary Disease blood, Coronary Disease genetics
Abstract

Background: Although observational data support an inverse relationship between high-density lipoprotein (HDL) cholesterol and coronary heart disease (CHD), genetic HDL deficiency states often do not correlate with premature CHD., Methods: Carotid intima-media thickness (cIMT) measurements were obtained in cases comprising 10 different mutations in LCAT, ABCA1 and APOA1 to further evaluate the relationship between low HDL resulting from genetic variation and early atherosclerosis., Results: In a 1:2 case-control study of sex and age-related (+/-5 y) subjects (n=114), cIMT was nearly identical between cases (0.66+/-0.17 cm) and controls (0.65+/-0.18 cm) despite significantly lower HDL cholesterol (0.67 vs. 1.58 mmol/l) and apolipoprotein A-I levels (96.7 vs. 151.4 mg/dl) (P<0.05), Conclusions: Genetic variants identified in the present study may be insufficient to promote early carotid atherosclerosis.

Published
2007
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50. Lack of association between increased carotid intima-media thickening and decreased HDL-cholesterol in a family with a novel ABCA1 variant, G2265T.

Author

Hong SH, Riley W, Rhyne J, Friel G, and Miller M

Subjects
ATP Binding Cassette Transporter 1, Adult, Coronary Artery Disease genetics, Coronary Artery Disease pathology, Humans, Male, Mutation, Pedigree, Polymerase Chain Reaction, Polymorphism, Single-Stranded Conformational, ATP-Binding Cassette Transporters genetics, Carotid Arteries pathology, Cholesterol, HDL blood, Coronary Artery Disease diagnosis, Tunica Intima pathology
Abstract

Low HDL-cholesterol (HDL-C) concentrations are inversely correlated with cardiovascular disease, and previous studies have demonstrated that variants in the ATP-binding cassette transporter, ABCA1, are responsible for a proportion of HDL-C deficiency states. We identified a novel variant in ABCA1 in a kindred with decreased HDL-C. This variant was not identified in >200 chromosomes of healthy individuals. The proband, a heterozygote for G2265T, developed premature coronary artery disease. In addition to low HDL-C, six biological family members heterozygous for the ABCA1 variant exhibited low HDL-C concentrations compared with unaffected family members (0.83 +/- 0.32 vs 1.33 +/- 0.36 mmol/L; P = 0.009). Despite the decreased HDL-C, carotid artery B-mode ultrasound studies failed to reveal increased intima-media thickening in affected individuals compared with age- and sex-matched controls. Although these data extend previous observations that a single defective ABCA1 allele may lead to decreased HDL-C, associated evidence of early atherosclerosis was not confirmed.

Published
2002

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