24 results on '"OCAC"'
Search Results
2. Tortuosity and Pulsatility of the Tibial Artery – Two Case Reports of a Rare Etiology of Tarsal Tunnel Syndrome
- Author
-
Márcio Luís Duarte, Mayara Oliveira da Silva, and Ocacir de Souza Reis Soares
- Subjects
Medicine - Abstract
Tarsal tunnel syndrome is a neuropathic compression of the tibial nerve and its branches on the medial side of the ankle. It is a challenging diagnosis that constitutes symptoms arising from damage to the posterior tibial nerve or its branches as they proceed through the tarsal tunnel below the flexor retinaculum in the medial ankle, easily forgotten and underdiagnosed. Neural compression by vascular structures has been suggested as a possible etiology in some clinical conditions. Tibial artery tortuosity is not that rare, but only that it affects the nerve can cause tarsal tunnel syndrome. Therefore, a study care must be taken to avoid false-positive errors.
- Published
- 2024
- Full Text
- View/download PDF
3. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.
- Author
-
Zhang, Yan Dora, Hurson, Amber N, Zhang, Haoyu, Choudhury, Parichoy Pal, Easton, Douglas F, Milne, Roger L, Simard, Jacques, Hall, Per, Michailidou, Kyriaki, Dennis, Joe, Schmidt, Marjanka K, Chang-Claude, Jenny, Gharahkhani, Puya, Whiteman, David, Campbell, Peter T, Hoffmeister, Michael, Jenkins, Mark, Peters, Ulrike, Hsu, Li, Gruber, Stephen B, Casey, Graham, Schmit, Stephanie L, O'Mara, Tracy A, Spurdle, Amanda B, Thompson, Deborah J, Tomlinson, Ian, De Vivo, Immaculata, Landi, Maria Teresa, Law, Matthew H, Iles, Mark M, Demenais, Florence, Kumar, Rajiv, MacGregor, Stuart, Bishop, D Timothy, Ward, Sarah V, Bondy, Melissa L, Houlston, Richard, Wiencke, John K, Melin, Beatrice, Barnholtz-Sloan, Jill, Kinnersley, Ben, Wrensch, Margaret R, Amos, Christopher I, Hung, Rayjean J, Brennan, Paul, McKay, James, Caporaso, Neil E, Berndt, Sonja I, Birmann, Brenda M, Camp, Nicola J, Kraft, Peter, Rothman, Nathaniel, Slager, Susan L, Berchuck, Andrew, Pharoah, Paul DP, Sellers, Thomas A, Gayther, Simon A, Pearce, Celeste L, Goode, Ellen L, Schildkraut, Joellen M, Moysich, Kirsten B, Amundadottir, Laufey T, Jacobs, Eric J, Klein, Alison P, Petersen, Gloria M, Risch, Harvey A, Stolzenberg-Solomon, Rachel Z, Wolpin, Brian M, Li, Donghui, Eeles, Rosalind A, Haiman, Christopher A, Kote-Jarai, Zsofia, Schumacher, Fredrick R, Al Olama, Ali Amin, Purdue, Mark P, Scelo, Ghislaine, Dalgaard, Marlene D, Greene, Mark H, Grotmol, Tom, Kanetsky, Peter A, McGlynn, Katherine A, Nathanson, Katherine L, Turnbull, Clare, Wiklund, Fredrik, Breast Cancer Association Consortium (BCAC), Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON), Colon Cancer Family Registry (CCFR), Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT), Endometrial Cancer Association Consortium (ECAC), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Melanoma Genetics Consortium (GenoMEL), Glioma International Case-Control Study (GICC), International Lung Cancer Consortium (ILCCO), Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium, International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph), Ovarian Cancer Association Consortium (OCAC), Oral Cancer GWAS, Pancreatic Cancer Case-Control Consortium (PanC4), Pancreatic Cancer Cohort Consortium (PanScan), and Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL)
- Subjects
Breast Cancer Association Consortium ,Barrett’s and Esophageal Adenocarcinoma Consortium ,Colon Cancer Family Registry ,Transdisciplinary Studies of Genetic Variation in Colorectal Cancer ,Endometrial Cancer Association Consortium ,Genetics and Epidemiology of Colorectal Cancer Consortium ,Melanoma Genetics Consortium ,Glioma International Case-Control Study ,International Lung Cancer Consortium ,Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium ,International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies ,Ovarian Cancer Association Consortium ,Oral Cancer GWAS ,Pancreatic Cancer Case-Control Consortium ,Pancreatic Cancer Cohort Consortium ,Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome ,Renal Cancer GWAS ,Testicular Cancer Consortium ,Animals ,Humans ,Neoplasms ,Genetic Predisposition to Disease ,Incidence ,Risk Assessment ,Risk Factors ,Multifactorial Inheritance ,Polymorphism ,Single Nucleotide ,Models ,Genetic ,Female ,Male ,Genome-Wide Association Study ,Human Genome ,Prevention ,Cancer ,Prostate Cancer ,Genetics ,Urologic Diseases ,2.1 Biological and endogenous factors - Abstract
Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.
- Published
- 2020
4. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers
- Author
-
Yan Dora Zhang, Amber N. Hurson, Haoyu Zhang, Parichoy Pal Choudhury, Douglas F. Easton, Roger L. Milne, Jacques Simard, Per Hall, Kyriaki Michailidou, Joe Dennis, Marjanka K. Schmidt, Jenny Chang-Claude, Puya Gharahkhani, David Whiteman, Peter T. Campbell, Michael Hoffmeister, Mark Jenkins, Ulrike Peters, Li Hsu, Stephen B. Gruber, Graham Casey, Stephanie L. Schmit, Tracy A. O’Mara, Amanda B. Spurdle, Deborah J. Thompson, Ian Tomlinson, Immaculata De Vivo, Maria Teresa Landi, Matthew H. Law, Mark M. Iles, Florence Demenais, Rajiv Kumar, Stuart MacGregor, D. Timothy Bishop, Sarah V. Ward, Melissa L. Bondy, Richard Houlston, John K. Wiencke, Beatrice Melin, Jill Barnholtz-Sloan, Ben Kinnersley, Margaret R. Wrensch, Christopher I. Amos, Rayjean J. Hung, Paul Brennan, James McKay, Neil E. Caporaso, Sonja I. Berndt, Brenda M. Birmann, Nicola J. Camp, Peter Kraft, Nathaniel Rothman, Susan L. Slager, Andrew Berchuck, Paul D. P. Pharoah, Thomas A. Sellers, Simon A. Gayther, Celeste L. Pearce, Ellen L. Goode, Joellen M. Schildkraut, Kirsten B. Moysich, Laufey T. Amundadottir, Eric J. Jacobs, Alison P. Klein, Gloria M. Petersen, Harvey A. Risch, Rachel Z. Stolzenberg-Solomon, Brian M. Wolpin, Donghui Li, Rosalind A. Eeles, Christopher A. Haiman, Zsofia Kote-Jarai, Fredrick R. Schumacher, Ali Amin Al Olama, Mark P. Purdue, Ghislaine Scelo, Marlene D. Dalgaard, Mark H. Greene, Tom Grotmol, Peter A. Kanetsky, Katherine A. McGlynn, Katherine L. Nathanson, Clare Turnbull, Fredrik Wiklund, Breast Cancer Association Consortium (BCAC), Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON), Colon Cancer Family Registry (CCFR), Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT), Endometrial Cancer Association Consortium (ECAC), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Melanoma Genetics Consortium (GenoMEL), Glioma International Case-Control Study (GICC), International Lung Cancer Consortium (ILCCO), Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium, International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph), Ovarian Cancer Association Consortium (OCAC), Oral Cancer GWAS, Pancreatic Cancer Case-Control Consortium (PanC4), Pancreatic Cancer Cohort Consortium (PanScan), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL), Renal Cancer GWAS, Testicular Cancer Consortium (TECAC), Stephen J. Chanock, Nilanjan Chatterjee, and Montserrat Garcia-Closas
- Subjects
Science - Abstract
In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size. Here, the authors analyse summary statistics of genome-wide association studies from fourteen cancers, and show the utility of polygenic risk scores may vary depending on cancer type.
- Published
- 2020
- Full Text
- View/download PDF
5. Association between invasive ovarian cancer susceptibility and 11 best candidate SNPs from breast cancer genome-wide association study.
- Author
-
Song, Honglin, Ramus, Susan J, Kjaer, Susanne Krüger, DiCioccio, Richard A, Chenevix-Trench, Georgia, Pearce, Celeste Leigh, Hogdall, Estrid, Whittemore, Alice S, McGuire, Valerie, Hogdall, Claus, Blaakaer, Jan, Wu, Anna H, Van Den Berg, David J, Stram, Daniel O, Menon, Usha, Gentry-Maharaj, Aleksandra, Jacobs, Ian J, Webb, Penny M, Beesley, Jonathan, Chen, Xiaoqing, Australian Cancer (Ovarian) Study, Australian Ovarian Cancer Study Group, Rossing, Mary Anne, Doherty, Jennifer A, Chang-Claude, Jenny, Wang-Gohrke, Shan, Goodman, Marc T, Lurie, Galina, Thompson, Pamela J, Carney, Michael E, Ness, Roberta B, Moysich, Kirsten, Goode, Ellen L, Vierkant, Robert A, Cunningham, Julie M, Anderson, Stephanie, Schildkraut, Joellen M, Berchuck, Andrew, Iversen, Edwin S, Moorman, Patricia G, Garcia-Closas, Montserrat, Chanock, Stephen, Lissowska, Jolanta, Brinton, Louise, Anton-Culver, Hoda, Ziogas, Argyrios, Brewster, Wendy R, Ponder, Bruce AJ, Easton, Douglas F, Gayther, Simon A, Pharoah, Paul DP, and Ovarian Cancer Association Consortium (OCAC)
- Subjects
Australian Cancer (Ovarian) Study ,Australian Ovarian Cancer Study Group ,Ovarian Cancer Association Consortium ,Humans ,Breast Neoplasms ,Ovarian Neoplasms ,Genetic Predisposition to Disease ,Glycoproteins ,Neuropeptides ,Risk Factors ,Case-Control Studies ,Polymorphism ,Single Nucleotide ,European Continental Ancestry Group ,Female ,Genome-Wide Association Study ,Polymorphism ,Single Nucleotide ,Clinical Research ,Breast Cancer ,Aging ,Cancer ,Rare Diseases ,Prevention ,Human Genome ,Genetics ,Ovarian Cancer ,2.1 Biological and endogenous factors ,Biological Sciences ,Medical and Health Sciences ,Genetics & Heredity - Abstract
Because both ovarian and breast cancer are hormone-related and are known to have some predisposition genes in common, we evaluated 11 of the most significant hits (six with confirmed associations with breast cancer) from the breast cancer genome-wide association study for association with invasive ovarian cancer. Eleven SNPs were initially genotyped in 2927 invasive ovarian cancer cases and 4143 controls from six ovarian cancer case-control studies. Genotype frequencies in cases and controls were compared using a likelihood ratio test in a logistic regression model stratified by study. Initially, three SNPs (rs2107425 in MRPL23, rs7313833 in PTHLH, rs3803662 in TNRC9) were weakly associated with ovarian cancer risk and one SNP (rs4954956 in NXPH2) was associated with serous ovarian cancer in non-Hispanic white subjects (P-trend < 0.1). These four SNPs were then genotyped in an additional 4060 cases and 6308 controls from eight independent studies. Only rs4954956 was significantly associated with ovarian cancer risk both in the replication study and in combined analyses. This association was stronger for the serous histological subtype [per minor allele odds ratio (OR) 1.07 95% CI 1.01-1.13, P-trend = 0.02 for all types of ovarian cancer and OR 1.14 95% CI 1.07-1.22, P-trend = 0.00017 for serous ovarian cancer]. In conclusion, we found that rs4954956 was associated with increased ovarian cancer risk, particularly for serous ovarian cancer. However, none of the six confirmed breast cancer susceptibility variants we tested was associated with ovarian cancer risk. Further work will be needed to identify the causal variant associated with rs4954956 or elucidate its function.
- Published
- 2009
6. Correction: Polygenic risk modeling for prediction of epithelial ovarian cancer risk.
- Author
-
Dareng, EO, Tyrer, JP, Barnes, DR, Jones, MR, Yang, X, Aben, KKH, Adank, MA, Agata, S, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Aravantinos, G, Arun, BK, Augustinsson, A, Balmaña, J, Bandera, EV, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, NV, Bonanni, B, Borg, A, Brenton, JD, Budzilowska, A, Butzow, R, Buys, SS, Cai, H, Caligo, MA, Campbell, I, Cannioto, R, Cassingham, H, Chang-Claude, J, Chanock, SJ, Chen, K, Chiew, Y-E, Chung, WK, Claes, KBM, Colonna, S, GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, Cook, LS, Couch, FJ, Daly, MB, Dao, F, Davies, E, de la Hoya, M, de Putter, R, Dennis, J, DePersia, A, Devilee, P, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dörk, T, du Bois, A, Dürst, M, Eccles, DM, Eliassen, HA, Engel, C, Evans, GD, Fasching, PA, Flanagan, JM, Fortner, RT, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, OPAL Study Group, AOCS Group, Hahnen, E, Haiman, CA, Håkansson, N, Hamann, U, Hansen, TVO, Harris, HR, Hartman, M, Heitz, F, Hildebrandt, MAT, Høgdall, E, Høgdall, CK, Hopper, JL, Huang, R-Y, Huff, C, Hulick, PJ, Huntsman, DG, Imyanitov, EN, KConFab Investigators, HEBON Investigators, Isaacs, C, Jakubowska, A, James, PA, Janavicius, R, Jensen, A, Johannsson, OT, John, EM, Jones, ME, Kang, D, Karlan, BY, Karnezis, A, Kelemen, LE, Khusnutdinova, E, Kiemeney, LA, Kim, B-G, Kjaer, SK, Komenaka, I, Kupryjanczyk, J, Kurian, AW, Kwong, A, Lambrechts, D, Larson, MC, Lazaro, C, Le, ND, Leslie, G, Lester, J, Lesueur, F, Levine, DA, Li, L, Li, J, Loud, JT, Lu, KH, Lubiński, J, Mai, PL, Manoukian, S, Marks, JR, Matsuno, RK, Matsuo, K, May, T, McGuffog, L, McLaughlin, JR, McNeish, IA, Mebirouk, N, Menon, U, Miller, A, Milne, RL, Minlikeeva, A, Modugno, F, Montagna, M, Moysich, KB, Munro, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nielsen, HR, Nielsen, FC, Nikitina-Zake, L, Odunsi, K, Offit, K, Olah, E, Olbrecht, S, Olopade, OI, Olson, SH, Olsson, H, Osorio, A, Papi, L, Park, SK, Parsons, MT, Pathak, H, Pedersen, IS, Peixoto, A, Pejovic, T, Perez-Segura, P, Permuth, JB, Peshkin, B, Peterlongo, P, Piskorz, A, Prokofyeva, D, Radice, P, Rantala, J, Riggan, MJ, Risch, HA, Rodriguez-Antona, C, Ross, E, Rossing, MA, Runnebaum, I, Sandler, DP, Santamariña, M, Soucy, P, Schmutzler, RK, Setiawan, VW, Shan, K, Sieh, W, Simard, J, Singer, CF, Sokolenko, AP, Song, H, Southey, MC, Steed, H, Stoppa-Lyonnet, D, Sutphen, R, Swerdlow, AJ, Tan, YY, Teixeira, MR, Teo, SH, Terry, KL, Terry, MB, OCAC Consortium, CIMBA Consortium, Thomassen, M, Thompson, PJ, Thomsen, LCV, Thull, DL, Tischkowitz, M, Titus, L, Toland, AE, Torres, D, Trabert, B, Travis, R, Tung, N, Tworoger, SS, Valen, E, van Altena, AM, van der Hout, AH, Van Nieuwenhuysen, E, van Rensburg, EJ, Vega, A, Edwards, DV, Vierkant, RA, Wang, F, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, White, E, Whittemore, AS, Winham, SJ, Wolk, A, Woo, Y-L, Wu, AH, Yan, L, Yannoukakos, D, Zavaglia, KM, Zheng, W, Ziogas, A, Zorn, KK, Kleibl, Z, Easton, D, Lawrenson, K, DeFazio, A, Sellers, TA, Ramus, SJ, Pearce, CL, Monteiro, AN, Cunningham, J, Goode, EL, Schildkraut, JM, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Antoniou, AC, Pharoah, PDP, Dareng, EO, Tyrer, JP, Barnes, DR, Jones, MR, Yang, X, Aben, KKH, Adank, MA, Agata, S, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Aravantinos, G, Arun, BK, Augustinsson, A, Balmaña, J, Bandera, EV, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, NV, Bonanni, B, Borg, A, Brenton, JD, Budzilowska, A, Butzow, R, Buys, SS, Cai, H, Caligo, MA, Campbell, I, Cannioto, R, Cassingham, H, Chang-Claude, J, Chanock, SJ, Chen, K, Chiew, Y-E, Chung, WK, Claes, KBM, Colonna, S, GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, Cook, LS, Couch, FJ, Daly, MB, Dao, F, Davies, E, de la Hoya, M, de Putter, R, Dennis, J, DePersia, A, Devilee, P, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dörk, T, du Bois, A, Dürst, M, Eccles, DM, Eliassen, HA, Engel, C, Evans, GD, Fasching, PA, Flanagan, JM, Fortner, RT, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, OPAL Study Group, AOCS Group, Hahnen, E, Haiman, CA, Håkansson, N, Hamann, U, Hansen, TVO, Harris, HR, Hartman, M, Heitz, F, Hildebrandt, MAT, Høgdall, E, Høgdall, CK, Hopper, JL, Huang, R-Y, Huff, C, Hulick, PJ, Huntsman, DG, Imyanitov, EN, KConFab Investigators, HEBON Investigators, Isaacs, C, Jakubowska, A, James, PA, Janavicius, R, Jensen, A, Johannsson, OT, John, EM, Jones, ME, Kang, D, Karlan, BY, Karnezis, A, Kelemen, LE, Khusnutdinova, E, Kiemeney, LA, Kim, B-G, Kjaer, SK, Komenaka, I, Kupryjanczyk, J, Kurian, AW, Kwong, A, Lambrechts, D, Larson, MC, Lazaro, C, Le, ND, Leslie, G, Lester, J, Lesueur, F, Levine, DA, Li, L, Li, J, Loud, JT, Lu, KH, Lubiński, J, Mai, PL, Manoukian, S, Marks, JR, Matsuno, RK, Matsuo, K, May, T, McGuffog, L, McLaughlin, JR, McNeish, IA, Mebirouk, N, Menon, U, Miller, A, Milne, RL, Minlikeeva, A, Modugno, F, Montagna, M, Moysich, KB, Munro, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nielsen, HR, Nielsen, FC, Nikitina-Zake, L, Odunsi, K, Offit, K, Olah, E, Olbrecht, S, Olopade, OI, Olson, SH, Olsson, H, Osorio, A, Papi, L, Park, SK, Parsons, MT, Pathak, H, Pedersen, IS, Peixoto, A, Pejovic, T, Perez-Segura, P, Permuth, JB, Peshkin, B, Peterlongo, P, Piskorz, A, Prokofyeva, D, Radice, P, Rantala, J, Riggan, MJ, Risch, HA, Rodriguez-Antona, C, Ross, E, Rossing, MA, Runnebaum, I, Sandler, DP, Santamariña, M, Soucy, P, Schmutzler, RK, Setiawan, VW, Shan, K, Sieh, W, Simard, J, Singer, CF, Sokolenko, AP, Song, H, Southey, MC, Steed, H, Stoppa-Lyonnet, D, Sutphen, R, Swerdlow, AJ, Tan, YY, Teixeira, MR, Teo, SH, Terry, KL, Terry, MB, OCAC Consortium, CIMBA Consortium, Thomassen, M, Thompson, PJ, Thomsen, LCV, Thull, DL, Tischkowitz, M, Titus, L, Toland, AE, Torres, D, Trabert, B, Travis, R, Tung, N, Tworoger, SS, Valen, E, van Altena, AM, van der Hout, AH, Van Nieuwenhuysen, E, van Rensburg, EJ, Vega, A, Edwards, DV, Vierkant, RA, Wang, F, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, White, E, Whittemore, AS, Winham, SJ, Wolk, A, Woo, Y-L, Wu, AH, Yan, L, Yannoukakos, D, Zavaglia, KM, Zheng, W, Ziogas, A, Zorn, KK, Kleibl, Z, Easton, D, Lawrenson, K, DeFazio, A, Sellers, TA, Ramus, SJ, Pearce, CL, Monteiro, AN, Cunningham, J, Goode, EL, Schildkraut, JM, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Antoniou, AC, and Pharoah, PDP
- Published
- 2022
7. Polygenic risk modeling for prediction of epithelial ovarian cancer risk
- Author
-
Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V., Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia V., Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen, Colonna, Sarah, Lesueur, Fabienne, Mebirouk, Noura, Engel, Christoph, Schmutzler, Rita K., Davies, Eleanor, Eccles, Diana M., Evans, D. Gareth, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eliassen, Heather A., Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, Renée T., Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Høgdall, Estrid, Høgdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Chenevix-Trench, Georgia, van der Hout, Annemieke H., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th., John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Lubiński, Jan, Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., Matsuno, Rayna Kim, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo I., Olson, Sara H., Olsson, Håkan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamariña, Marta, Soucy, Penny, Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., Terry, Mary Beth, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Titus, Linda, Trabert, Britton, Travis, Ruth, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., Van Nieuwenhuysen, Els, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Webb, Penelope M., Weinberg, Clarice R., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zheng, Wei, Ziogas, Argyrios, Lawrenson, Kate, deFazio, Anna, Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie M., Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Gayther, Simon A., Pharoah, Paul D. P., Claes, Kathleen B. M., Thomassen, Mads, Thull, Darcy L., Tischkowitz, Marc, Toland, Amanda E., Torres, Diana, Tung, Nadine, van Rensburg, Elizabeth J., Vega, Ana, Wappenschmidt, Barbara, Weitzel, Jeffrey N., Zavaglia, Katia M., Zorn, Kristin K., Sellers, Thomas A., Antoniou, Antonis C., Kleibl, Zdenek, Easton, Douglas, DeFazio, Anna, Cunningham, Julie, GEMO Study Collaborators, [missing], GC-HBOC Study Collaborators, [missing], EMBRACE Collaborators, [missing], OPAL Study Group, [missing], AOCS Group, [missing], KConFab Investigators, [missing], HEBON Investigators, [missing], The OCAC Consortium, [missing], The CIMBA Consortium, [missing], Clinicum, Department of Pathology, HUSLAB, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, Faculteit Medische Wetenschappen/UMCG, Institut Català de la Salut, [Dareng EO, Barnes DR, Yang X] University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Cambridge, UK. [Tyrer JP] University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Oncology, Cambridge, UK. [Jones MR] Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [Aben KKH] Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands. Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands. [Balmaña J] Hereditary cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Ovarian Cancer Action, and National Institute for Health Research
- Subjects
Male ,Biochemistry & Molecular Biology ,OCAC Consortium ,Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES] ,Breast Neoplasms ,Ovaris - Càncer - Aspectes genètics ,Carcinoma, Ovarian Epithelial ,SUSCEPTIBILITY ,Polymorphism, Single Nucleotide ,GEMO Study Collaborators ,Risk Factors ,OPAL Study Group ,Other subheadings::Other subheadings::/genetics [Other subheadings] ,Medicine and Health Sciences ,Genetics ,Ovaris - Càncer - Propensió ,Humans ,Genetic Predisposition to Disease ,Prospective Studies ,EMBRACE Collaborators ,GC-HBOC Study Collaborators ,Genetics (clinical) ,HEBON Investigators ,fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS] ,Medicinsk genetik ,Ovarian Neoplasms ,Genetics & Heredity ,0604 Genetics ,Science & Technology ,Otros calificadores::Otros calificadores::/genética [Otros calificadores] ,1184 Genetics, developmental biology, physiology ,Neoplasms::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms::Carcinoma, Ovarian Epithelial [DISEASES] ,1103 Clinical Sciences ,Bayes Theorem ,AOCS Group ,neoplasias::neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas::carcinoma epitelial de ovario [ENFERMEDADES] ,Women's cancers Radboud Institute for Health Sciences [Radboudumc 17] ,Carcinoma, Ovarian Epithelial/genetics ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,CIMBA Consortium ,1182 Biochemistry, cell and molecular biology ,Female ,KConFab Investigators ,Ovarian Neoplasms/epidemiology ,Medical Genetics ,Life Sciences & Biomedicine - Abstract
Clinical genetics; Genetic markers; Risk factors Genética clínica; Marcadores genéticos; Factores de riesgo Genètica clínica; Marcadors genètics; Factors de risc Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
- Published
- 2022
8. Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals
- Author
-
Chen, H, Majumdar, A, Wang, L, Kar, S, Brown, KM, Feng, H, Turman, C, Dennis, J, Easton, D, Michailidou, K, Simard, J, Breast Cancer Association Consortium (BCAC), Bishop, T, Cheng, IC, Huyghe, JR, Schmit, SL, Colorectal Transdisciplinary Study (CORECT), Colon Cancer Family Registry Study (CCFR), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO, O'Mara, TA, Spurdle, AB, Endometrial Cancer Association Consortium (ECAC), Gharahkhani, P, Schumacher, J, Jankowski, J, Gockel, I, Esophageal Cancer GWAS Consortium, Bondy, ML, Houlston, RS, Jenkins, RB, Melin, B, Glioma International Case Control Consortium (GICC), Lesseur, C, Ness, AR, Diergaarde, B, Olshan, AF, Head-Neck Cancer GWAS Consortium, Amos, CI, Christiani, DC, Landi, MT, McKay, JD, International Lung Cancer Consortium (ILCCO), Brossard, M, Iles, MM, Law, MH, MacGregor, S, Melanoma GWAS Consortium, Beesley, J, Jones, MR, Tyrer, J, Winham, SJ, Ovarian Cancer Association Consortium (OCAC), Klein, AP, Petersen, G, Li, D, Wolpin, BM, Pancreatic Cancer Case-Control Consortium (PANC4), Pancreatic Cancer Cohort Consortium (PanScan), Eeles, RA, Haiman, CA, Kote-Jarai, Z, Schumacher, FR, PRACTICAL consortium, CRUK, BPC3, CAPS, PEGASUS, Brennan, P, Chanock, SJ, Gaborieau, V, Purdue, MP, Renal Cancer GWAS Consortium, Pharoah, P, Hung, RJ, Amundadottir, LT, Kraft, P, Pasaniuc, B, and Lindström, S
- Abstract
Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
- Published
- 2021
9. Cross-cancer GWAS meta-analysis of more than 370,000 cases and 530,000 controls identifies multiple novel cancer risk regions
- Author
-
Lindstrom, S, Kar, S, Wang, L, Turman, C, MacDonald, J, Bammler, T, BCAC, OCAC, PRACTICAL, Huyghe, J, Schmit, S, O'Mara, TA, Thompson, DJ, Gharahkhani, P, MacGregor, S, Brennan, P, Houlston, RS, Melin, BS, Amos, CI, McKay, J, Iles, MM, Law, MH, Klein, A, Amundadottir, L, Pasaniuc, B, Pharoah, P, Hung, RJ, and Kraft, P
- Published
- 2020
10. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers
- Author
-
Montserrat Garcia-Closas, Ellen L. Goode, Mark M. Iles, Brian M. Wolpin, Stephen J. Chanock, Susan L. Slager, Li Hsu, Clare Turnbull, Ccfr, Michael Hoffmeister, Peter T. Campbell, Maria Teresa Landi, Paul D.P. Pharoah, Amber N. Hurson, Melissa L. Bondy, Roger L. Milne, Peter A. Kanetsky, Simon A. Gayther, Christopher A. Haiman, Nicola J. Camp, Mark A. Jenkins, Margaret Wrensch, Bcac, Ulrike Peters, Jill S. Barnholtz-Sloan, Richard S. Houlston, PanScan, Haoyu Zhang, Christopher I. Amos, Ben Kinnersley, GenoMEL, Florence Demenais, Rosalind A. Eeles, Katherine A. McGlynn, Practical, John K. Wiencke, Gicc, Katherine L. Nathanson, Stolzenberg-Solomon R, Brenda M. Birmann, Rayjean J. Hung, Donghui Li, David C. Whiteman, Ghislaine Scelo, Sonja I. Berndt, Alison P. Klein, Sarah V. Ward, Per Hall, D. Timothy Bishop, Tracy A. O'Mara, Kirsten B. Moysich, Corect, Laufey T. Amundadottir, Marjanka K. Schmidt, Ian Tomlinson, Ocac, Yan Zhang, Gloria M. Petersen, Ali Amin Al Olama, Puya Gharahkhani, Deborah J. Thompson, Paul Brennan, Douglas F. Easton, Celeste Leigh Pearce, InterLymph, Jacques Simard, Mark H. Greene, Zsofia Kote-Jarai, Nilanjan Chatterjee, Ecac, Marlene Danner Dalgaard, Mark P. Purdue, Beatrice Melin, Graham Casey, Rajesh Kumar, Jenny Chang-Claude, Thomas A. Sellers, Stephen B. Gruber, Beacon, James D. McKay, Tecac, Stephanie L. Schmit, Tom Grotmol, Kyriaki Michailidou, Immaculata De Vivo, Joellen M. Schildkraut, Eric J. Jacobs, Fredrik Wiklund, Amanda B. Spurdle, Nathaniel Rothman, Parichoy Pal Choudhury, Peter Kraft, Panc, Renal Cancer Gwas, Neil E. Caporaso, Joe Dennis, Matthew Law, Fredrick R. Schumacher, Harvey A. Risch, Stuart MacGregor, Andrew Berchuck, Ilcco, Oral Cancer Gwas, Zhang, Yan Dora [0000-0002-5302-3690], Hurson, Amber N. [0000-0001-7831-6660], Easton, Douglas F. [0000-0003-2444-3247], Milne, Roger L. [0000-0001-5764-7268], Simard, Jacques [0000-0001-6906-3390], Michailidou, Kyriaki [0000-0001-7065-1237], Dennis, Joe [0000-0003-4591-1214], Schmidt, Marjanka K. [0000-0002-2228-429X], Gharahkhani, Puya [0000-0002-4203-5952], Whiteman, David [0000-0003-2563-9559], Jenkins, Mark [0000-0002-8964-6160], Peters, Ulrike [0000-0001-5666-9318], Schmit, Stephanie L. [0000-0001-5931-1194], O’Mara, Tracy A. [0000-0002-5436-3232], Spurdle, Amanda B. [0000-0003-1337-7897], Thompson, Deborah J. [0000-0003-1465-5799], Tomlinson, Ian [0000-0003-3037-1470], Landi, Maria Teresa [0000-0003-4507-329X], Law, Matthew H. [0000-0002-4303-8821], Iles, Mark M. [0000-0002-2603-6509], Demenais, Florence [0000-0001-8361-0936], Kumar, Rajiv [0000-0002-6093-0395], MacGregor, Stuart [0000-0001-6731-8142], Bishop, D. Timothy [0000-0002-8752-8785], Houlston, Richard [0000-0002-5268-0242], Barnholtz-Sloan, Jill [0000-0001-6190-9304], Kinnersley, Ben [0000-0003-1783-6296], Amos, Christopher I. [0000-0002-8540-7023], Hung, Rayjean J. [0000-0002-4486-7496], Brennan, Paul [0000-0002-0518-8714], Birmann, Brenda M. [0000-0002-7550-5498], Camp, Nicola J. [0000-0002-4788-1998], Kraft, Peter [0000-0002-4472-8103], Pharoah, Paul D. P. [0000-0001-8494-732X], Gayther, Simon A. [0000-0001-7937-5443], Amundadottir, Laufey T. [0000-0003-1859-8971], Jacobs, Eric J. [0000-0002-8458-7659], Klein, Alison P. [0000-0003-2737-8399], Eeles, Rosalind A. [0000-0002-3698-6241], Schumacher, Fredrick R. [0000-0002-3073-7463], Greene, Mark H. [0000-0003-1852-9239], Kanetsky, Peter A. [0000-0002-5567-9618], Nathanson, Katherine L. [0000-0002-6740-0901], Wiklund, Fredrik [0000-0002-4623-0544], Chanock, Stephen J. [0000-0002-2324-3393], Garcia-Closas, Montserrat [0000-0003-1033-2650], Apollo - University of Cambridge Repository, Hurson, Amber N [0000-0001-7831-6660], Easton, Douglas F [0000-0003-2444-3247], Milne, Roger L [0000-0001-5764-7268], Schmidt, Marjanka K [0000-0002-2228-429X], Schmit, Stephanie L [0000-0001-5931-1194], O'Mara, Tracy A [0000-0002-5436-3232], Spurdle, Amanda B [0000-0003-1337-7897], Thompson, Deborah J [0000-0003-1465-5799], Law, Matthew H [0000-0002-4303-8821], Iles, Mark M [0000-0002-2603-6509], Bishop, D Timothy [0000-0002-8752-8785], Amos, Christopher I [0000-0002-8540-7023], Hung, Rayjean J [0000-0002-4486-7496], Birmann, Brenda M [0000-0002-7550-5498], Camp, Nicola J [0000-0002-4788-1998], Pharoah, Paul DP [0000-0001-8494-732X], Gayther, Simon A [0000-0001-7937-5443], Amundadottir, Laufey T [0000-0003-1859-8971], Jacobs, Eric J [0000-0002-8458-7659], Klein, Alison P [0000-0003-2737-8399], Eeles, Rosalind A [0000-0002-3698-6241], Schumacher, Fredrick R [0000-0002-3073-7463], Greene, Mark H [0000-0003-1852-9239], Kanetsky, Peter A [0000-0002-5567-9618], Nathanson, Katherine L [0000-0002-6740-0901], and Chanock, Stephen J [0000-0002-2324-3393]
- Subjects
Male ,0301 basic medicine ,Oncology ,Multifactorial Inheritance ,45/43 ,General Physics and Astronomy ,Diseases ,Genome-wide association study ,0302 clinical medicine ,Risk Factors ,Neoplasms ,631/208/68 ,lcsh:Science ,Cancer genetics ,Multidisciplinary ,692/699 ,Incidence ,article ,030220 oncology & carcinogenesis ,Medical genetics ,Female ,Medical Genetics ,medicine.medical_specialty ,Science ,Biology ,Polymorphism, Single Nucleotide ,Risk Assessment ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Breast cancer ,SDG 3 - Good Health and Well-being ,Internal medicine ,medicine ,Genetic predisposition ,Animals ,Humans ,Genetic Predisposition to Disease ,Lung cancer ,Genetic association ,Medicinsk genetik ,Cancer och onkologi ,Models, Genetic ,45 ,Cancer ,General Chemistry ,Heritability ,medicine.disease ,030104 developmental biology ,Sample size determination ,Relative risk ,Cancer and Oncology ,lcsh:Q ,Ovarian cancer ,Genome-Wide Association Study - Abstract
Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence., In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size. Here, the authors analyse summary statistics of genome-wide association studies from fourteen cancers, and show the utility of polygenic risk scores may vary depending on cancer type.
- Published
- 2020
11. Cross-cancer cross-tissue Transcriptome-wide Association Study (TWAS) of 11 cancers identifies 56 novel genes
- Author
-
Feng, H, Majumdar, A, Pasaniuc, B, Chen, H, Lindstrom, S, Huyghe, J, Schmit, SL, O'Mara, TA, Thompson, DJ, MacGregor, S, Brennan, P, Mckay, J, Houlston, RS, Melin, BS, Amos, C, Cus, AE, Iles, MM, Kar, S, Pharoah, P, Hung, RJ, Kraft, P, BCAC, and OCAC
- Published
- 2020
12. Identification of novel epithelial ovarian cancer loci in women of African ancestry
- Author
-
Manichaikul, Ani, Peres, Lauren C, Wang, Xin-Qun, Barnard, Mollie E, Chyn, Deanna, Sheng, Xin, Du, Zhaohui, Tyrer, Jonathan, Dennis, Joseph, Schwartz, Ann G, Cote, Michele L, Peters, Edward, Moorman, Patricia G, Bondy, Melissa, Barnholtz-Sloan, Jill S, Terry, Paul, Alberg, Anthony J, Bandera, Elisa V, Funkhouser, Ellen, Wu, Anna H, Pearce, Celeste Leigh, Pike, Malcom, Setiawan, Veronica Wendy, Haiman, Christopher A, African American Breast Cancer Consortium (AABC), African Ancestry Prostate Cancer Consortium (AAPC), Palmer, Julie R, LeMarchand, Loic, Wilkens, Lynne R, Berchuck, Andrew, Doherty, Jennifer A, Modugno, Francesmary, Ness, Roberta, Moysich, Kirsten, Karlan, Beth Y, Whittemore, Alice S, McGuire, Valerie, Sieh, Weiva, Lawrenson, Kate, Gayther, Simon, Sellers, Thomas A, Pharoah, Paul, Schildkraut, Joellen M, African American Cancer Epidemiology Study (AACES) and the Ovarian Cancer Association Consortium (OCAC), Peres, Lauren C [0000-0002-6620-8600], Du, Zhaohui [0000-0002-7125-8928], Barnholtz-Sloan, Jill S [0000-0001-6190-9304], Pearce, Celeste Leigh [0000-0002-8023-7846], Pike, Malcom [0000-0003-4891-1199], Modugno, Francesmary [0000-0003-0637-1534], Lawrenson, Kate [0000-0002-6469-2515], Schildkraut, Joellen M [0000-0002-0990-9339], and Apollo - University of Cambridge Repository
- Subjects
Follistatin ,endocrine system diseases ,Oncology and Carcinogenesis ,Black People ,Breast Neoplasms ,Carcinoma, Ovarian Epithelial ,Polymorphism, Single Nucleotide ,African Ancestry Prostate Cancer Consortium ,White People ,Rare Diseases ,Antigens, Neoplasm ,Clinical Research ,Ovarian Epithelial ,Genetics ,Humans ,2.1 Biological and endogenous factors ,Genetic Predisposition to Disease ,Oncology & Carcinogenesis ,Antigens ,Polymorphism ,Aetiology ,genome wide association study ,Cancer ,eQTLs ,Prevention ,Carcinoma ,Aldo-Keto Reductase Family 1 Member C3 ,African American Cancer Epidemiology Study (AACES) and the Ovarian Cancer Association Consortium ,African American Breast Cancer Consortium ,Single Nucleotide ,United States ,Neoplasm Proteins ,Ovarian Cancer ,Black or African American ,ovarian cancer ,African ancestry ,gene expression ,Neoplasm ,Female ,Genome-Wide Association Study ,Biotechnology - Abstract
Women of African ancestry have lower incidence of epithelial ovarian cancer (EOC) yet worse survival compared to women of European ancestry. We conducted a genome-wide association study in African ancestry women with 755 EOC cases, including 537 high-grade serous ovarian carcinomas (HGSOC) and 1,235 controls. We identified four novel loci with suggestive evidence of association with EOC (p
- Published
- 2020
13. Abstract 30: Cross-cancer cross-tissue transcriptome-wide association study (TWAS) of 11 cancers identifies 56 novel genes
- Author
-
James Mckay, Hongjie Chen, Paul Brennan, Richard S. Houlston, Stephanie L. Schmit, Christopher I. Amos, Paul D.P. Pharoah, Stuart MacGregor, Tracy A. O'Mara, Bogdan Pasaniuc, Arunabha Majumdar, Rayjean J. Hung, Deborah J. Thompson, Mark M. Iles, Anne E. Cus, Bcac, Ocac, Practical, Jeroen R. Huyghe, Beatrice Melin, Peter Kraft, Siddhartha Kar, Sara Lindström, and Helian Feng
- Subjects
Genetics ,Cancer Research ,DNA repair ,Cancer ,Genome-wide association study ,Biology ,medicine.disease ,medicine.disease_cause ,Transcriptome ,Oncology ,Transcriptional regulation ,medicine ,Carcinogenesis ,Gene ,Genetic association - Abstract
Although cancer is a heterogeneous disease, there are shared hallmark mechanisms across multiple tumor types. Because of this, identifying genes associated with multiple cancer types has the potential to shed light on general oncogenic mechanisms. Conversely, integrating evidence for genetic association across multiple cancers could identify novel genes missed in single-cancer analyses. Transcriptome Wide Association Studies (TWAS) have been successful in identifying genes associated with individual cancers. TWAS test whether genetically-predicted tissue-specific gene expression levels are associated with cancer risk. Although cross-cancer genome-wide association studies (GWAS) analyses have been performed previously, no cross-cancer TWAS has been conducted to date. Here, we implement a pipeline to perform cross-cancer, cross-tissue TWAS analysis. We use newly-developed multi-trait TWAS test statistics to integrate the TWAS results for association between 11 separated cancers and predicted gene expression in each of 43 GTEx tissues; these include a "sum" test and a "variance components" test, analogous to fixed- and random-effects meta-analyses. We then integrated the results across different tissues using the Aggregated Cauchy Association Test (ACAT), a novel powerful and robust test for combining association results under general correlation patterns. A total of 403 genes were significantly associated with at least one cancer type using predicted gene expression for at least one tissue (p250 kb distant). 14 of the 70 novel genes were identified from the single cancer single tissue test; an additional 43 were identified with the cross-cancer test; and another 13 were identified when further combining the results across tissues. The newly identified genes include RBBP8, which regulates cell proliferation and modulates BRCA1-mediated DNA repair, and TP53BP1, which is involved in double-strand break repair. Other newly identified genes are involved in chromatin structure, tumorigenesis, apoptosis, transcriptional regulation, DNA repair, immune system, oxidative damage and cell cycle, proliferation, progression, shape, structure, and migration. Citation Format: Helian Feng, Arunabha Majumdar, Bogdan Pasaniuc, Hongjie Chen, Sara Lindström, BCAC, OCAC, PRACTICAL, Jeroen Huyghe, Stephanie L. Schmit, Tracy A. O'Mara, Deborah J. Thompson, Stuart MacGregor, Paul Brennan, James McKay, Richard S. Houlston, Beatrice S. Melin, Christopher Amos, Anne E. Cus, Mark M. Iles, Siddhartha Kar, Paul Pharoah, Rayjean J. Hung, Peter Kraft. Cross-cancer cross-tissue transcriptome-wide association study (TWAS) of 11 cancers identifies 56 novel genes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 30.
- Published
- 2020
14. Abstract 1194: Cross-cancer GWAS meta-analysis of more than 370,000 cases and 530,000 controls identifies multiple novel cancer risk regions
- Author
-
James McKay, Christopher I. Amos, Puya Gharahkhani, Matthew Law, Bogdan Pasaniuc, Mark M. Iles, Richard S. Houlston, Deborah J. Thompson, James W. MacDonald, Bcac, Ocac, Practical, Lu Wang, Stephanie L. Schmit, Theo K. Bammler, Constance Turman, Beatrice Melin, Alison P. Klein, Tracy A. O'Mara, Paul D.P. Pharoah, Stuart MacGregor, Rayjean J. Hung, Jeroen R. Huyghe, Peter Kraft, Paul Brennan, Siddhartha Kar, Sara Lindström, and Laufey T. Amundadottir
- Subjects
Oncology ,Subset Analysis ,Cancer Research ,medicine.medical_specialty ,Haplotype ,Cancer ,Genome-wide association study ,Biology ,medicine.disease ,Meta-analysis ,Relative risk ,Internal medicine ,medicine ,Multiple Cancer Sites ,Genetic association - Abstract
Genome-wide association studies (GWAS) have identified hundreds of common, low-penetrance alleles associated with cancer risk. However, known rare and common risk alleles only explain between 10% and 30% of the familial relative risk for different cancers and multiple lines of evidence indicate that many more risk alleles remain to be discovered. We have demonstrated genetic correlations between cancers, reflecting a shared genetic origin for solid tumors. These results suggest that jointly analyzing multiple cancer sites will lead to the discovery of novel risk regions. We conducted a cross-cancer GWAS meta-analysis by leveraging GWAS summary statistics from 12 solid cancers (breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate and renal cancers) with a total of 373,818 cases and 532,382 controls of European ancestry. All studies had been imputed to either 1,000 Genomes or the Haplotype Reference Consortium panel. We conducted four meta-analysis using (1) fixed-effect, (2) random-effect, (3) one-sided subset (ASSET) and (4) two-sided subset (ASSET) models. The subset analysis were conducted assuming either the same direction of effects across cancers (one-sided ASSET) or allowed for opposite direction of effects across cancers (two-sided ASSET). In all analyses, we used tetrachoric correlations to account for sample overlap across cancer sites. In total, we tested 10,223,013 variants for association. We considered regions with a p-value We identified eight novel regions that reached genome-wide significance. Of those eight regions, two were identified from fixed-effects meta-analysis, three from random effects meta-analysis, one from the two-sided subset analysis, and two regions (15.q15.3 and 21q22.3) were identified at p Citation Format: Sara Lindström, Siddhartha Kar, Lu Wang, Constance Turman, James MacDonald, Theo Bammler, BCAC, OCAC, PRACTICAL, Jeroen Huyghe, Stephanie Schmit, Tracy A. O'Mara, Deborah J. Thompson, Puya Gharahkhani, Stuart MacGregor, Paul Brennan, Richard S. Houlston, Beatrice S. Melin, Christopher I. Amos, James McKay, Mark M. Iles, Matthew H. Law, Alison Klein, Laufey Amundadottir, Bogdan Pasaniuc, Paul Pharoah, Rayjean J. Hung, Peter Kraft. Cross-cancer GWAS meta-analysis of more than 370,000 cases and 530,000 controls identifies multiple novel cancer risk regions [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1194.
- Published
- 2020
15. Circulating vitamin D concentration and risk of seven cancers: Mendelian randomisation study
- Author
-
Dimitrakopoulou, Vasiliki I., Tsilidis, Konstantinos K., Haycock, Philip C ., Dimou, Niki L, Al-Dabhani, Kawthar, Martin, Richard M., Lewis, Sarah J ., Gunter, Marc J., Mondul, Alison, Shui, Irene M., Theodoratou, Evropi, Nimptsch, Katharina, Lindström, Sara, Albanes, Demetrius, Kühn, Tilman, Key, Timothy J ., Travis, Ruth C ., Vimaleswaran, Karani Santhanakrishnan, Kraft, Peter, Pierce, Brandon L., Schildkraut, Joellen M., The GECCO Consortium, The PRACTICAL Consortium, and The GAME-ON Network (CORECT, DRIVE, ELLIPSE, FOCI-OCAC, TRICL-ILCCO)
- Abstract
Objective To determine if circulating concentrations of vitamin D are causally associated with risk of cancer.Design Mendelian randomisation study.Setting Large genetic epidemiology networks (the Genetic Associations and Mechanisms in Oncology (GAME-ON), the Genetic and Epidemiology of Colorectal Cancer Consortium (GECCO), and the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortiums, and the MR-Base platform).Participants 70 563 cases of cancer (22 898 prostate cancer, 15 748 breast cancer, 12 537 lung cancer, 11 488 colorectal cancer, 4369 ovarian cancer, 1896 pancreatic cancer, and 1627 neuroblastoma) and 84 418 controls.Exposures Four single nucleotide polymorphisms (rs2282679, rs10741657, rs12785878 and rs6013897) associated with vitamin D were used to define a multi-polymorphism score for circulating 25-hydroxyvitamin D (25(OH)D) concentrations.Main outcomes measures The primary outcomes were the risk of incident colorectal, breast, prostate, ovarian, lung, and pancreatic cancer and neuroblastoma, which was evaluated with an inverse variance weighted average of the associations with specific polymorphisms and a likelihood based approach. Secondary outcomes based on cancer subtypes by sex, anatomic location, stage, and histology were also examined.Results There was little evidence that the multi-polymorphism score of 25(OH)D was associated with risk of any of the seven cancers or their subtypes. Specifically, the odds ratios per 25 nmol/L increase in genetically determined 25(OH)D concentrations were 0.92 (95% confidence interval 0.76 to 1.10) for colorectal cancer, 1.05 (0.89 to 1.24) for breast cancer, 0.89 (0.77 to 1.02) for prostate cancer, and 1.03 (0.87 to 1.23) for lung cancer. The results were consistent with the two different analytical approaches, and the study was powered to detect relative effect sizes of moderate magnitude (for example, 1.20-1.50 per 25 nmol/L decrease in 25(OH)D for most primary cancer outcomes. The Mendelian randomisation assumptions did not seem to be violated.Conclusions There is little evidence for a linear causal association between circulating vitamin D concentration and risk of various types of cancer, though the existence of causal clinically relevant effects of low magnitude cannot be ruled out. These results, in combination with previous literature, provide evidence that population-wide screening for vitamin D deficiency and subsequent widespread vitamin D supplementation should not currently be recommended as a strategy for primary cancer prevention.
- Published
- 2017
16. Circulating vitamin D concentration and risk of seven cancers: a Mendelian randomization study
- Author
-
Dimitrakopoulou, VI, Tsilidis, KK, Haycock, PC, Dimou, NL, Al-Dabhani, K, Martin, RM, Lewis, SJ, Gunter, MJ, Mondul, A, Shui, IM, Theodoratou, E, Nimptsch, K, Lindström, S, Albanes, D, Kühn, T, Key, TJ, Travis, RC, Vimaleswaran, KS, GECCO Consortium, PRACTICAL Consortium, GAME-ON Network (CORECT, DRIVE, ELLIPSE, FOCI-OCAC, TRICL-ILCCO), Kraft, P, Pierce, BL, and Schildkraut, JM
- Subjects
Male ,25-HYDROXYVITAMIN D ,Lung Neoplasms ,SUSCEPTIBILITY LOCI ,Breast Neoplasms ,GENOTYPE IMPUTATION ,Polymorphism, Single Nucleotide ,Risk Assessment ,COLORECTAL-CANCER ,1117 Public Health and Health Services ,Neuroblastoma ,Medicine, General & Internal ,General & Internal Medicine ,Neoplasms ,BREAST-CANCER ,Humans ,PRACTICAL Consortium ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,Vitamin D ,METAANALYSIS ,GECCO Consortium ,Ovarian Neoplasms ,Science & Technology ,Incidence ,GENETIC-VARIATION ,Genetic Variation ,Prostatic Neoplasms ,1103 Clinical Sciences ,Mendelian Randomization Analysis ,Vitamin D Deficiency ,PREVENTION ,PROSTATE-CANCER ,Pancreatic Neoplasms ,Case-Control Studies ,Female ,GAME-ON Network (CORECT, DRIVE, ELLIPSE, FOCI-OCAC, TRICL-ILCCO) ,Colorectal Neoplasms ,Life Sciences & Biomedicine ,Genome-Wide Association Study - Abstract
Objective To determine if circulating concentrations of vitamin D are causally associated with risk of cancer. Design Mendelian randomisation study. Setting Large genetic epidemiology networks (the Genetic Associations and Mechanisms in Oncology (GAME-ON), the Genetic and Epidemiology of Colorectal Cancer Consortium (GECCO), and the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortiums, and the MR-Base platform). Participants 70 563 cases of cancer (22 898 prostate cancer, 15 748 breast cancer, 12 537 lung cancer, 11 488 colorectal cancer, 4369 ovarian cancer, 1896 pancreatic cancer, and 1627 neuroblastoma) and 84 418 controls. Exposures Four single nucleotide polymorphisms (rs2282679, rs10741657, rs12785878 and rs6013897) associated with vitamin D were used to define a multi-polymorphism score for circulating 25-hydroxyvitamin D (25(OH)D) concentrations. Main outcomes measures The primary outcomes were the risk of incident colorectal, breast, prostate, ovarian, lung, and pancreatic cancer and neuroblastoma, which was evaluated with an inverse variance weighted average of the associations with specific polymorphisms and a likelihood based approach. Secondary outcomes based on cancer subtypes by sex, anatomic location, stage, and histology were also examined. Results There was little evidence that the multi-polymorphism score of 25(OH)D was associated with risk of any of the seven cancers or their subtypes. Specifically, the odds ratios per 25 nmol/L increase in genetically determined 25(OH)D concentrations were 0.92 (95% confidence interval 0.76 to 1.10) for colorectal cancer, 1.05 (0.89 to 1.24) for breast cancer, 0.89 (0.77 to 1.02) for prostate cancer, and 1.03 (0.87 to 1.23) for lung cancer. The results were consistent with the two different analytical approaches, and the study was powered to detect relative effect sizes of moderate magnitude (for example, 1.20-1.50 per 25 nmol/L decrease in 25(OH)D for most primary cancer outcomes. The Mendelian randomisation assumptions did not seem to be violated. Conclusions There is little evidence for a linear causal association between circulating vitamin D concentration and risk of various types of cancer, though the existence of causal clinically relevant effects of low magnitude cannot be ruled out. These results, in combination with previous literature, provide evidence that population-wide screening for vitamin D deficiency and subsequent widespread vitamin D supplementation should not currently be recommended as a strategy for primary cancer prevention.
- Published
- 2017
17. Cross-cancer genome-wide analysis of lung, ovary, breast, prostate and colorectal cancer reveals novel pleiotropic associations
- Author
-
Fehringer, Gordon, Kraft, Peter, Pharoah, Paul D, Eeles, Rosalind A, Chatterjee, Nilanjan, Schumacher, Fredrick R, Schildkraut, Joellen M, Lindstrom, Sara, Brennan, Paul, Bickeboller, Heike, Houlston, Richard S, Landi, Maria Teresa, Caporaso, Neil, Risch, Angela, Al Olama, Ali Amin, Berndt, Sonja I, Giovannucci, Edward L, Gronberg, Henrik, Kote-Jarai, Zsofia, Ma, Jing, Muir, Kenneth, Stampfer, Meir J, Stevens, Victoria L, Wiklund, Fredrik, Willett, Walter C, Goode, Ellen L, Permuth, Jennifer B, Risch, Harvey A, Reid, Brett M, Bezieau, Stephane, Brenner, Hermann, Chan, Andrew T, Chang-Claude, Jenny, Hudson, Thomas J, Kocarnik, Jonathan K, Newcomb, Polly A, Schoen, Robert E, Slattery, Martha L, White, Emily, Adank, Muriel A, Ahsan, Habibul, Aittomaki, Kristiina, Baglietto, Laura, Blomquist, Carl, Canzian, Federico, Czene, Kamila, dos-Santos-Silva, Isabel, Eliassen, A Heather, Figueroa, Jonine D, Flesch-Janys, Dieter, Fletcher, Olivia, Garcia-Closas, Montserrat, Gaudet, Mia M, Johnson, Nichola, Hall, Per, Hazra, Aditi, Hein, Rebecca, Hofman, Albert, Hopper, John L, Irwanto, Astrid, Johansson, Mattias, Kaaks, Rudolf, Kibriya, Muhammad G, Lichtner, Peter, Liu, Jianjun, Lund, Eiliv, Makalic, Enes, Meindl, Alfons, Muller-Myhsok, Bertram, Muranen, Taru A, Nevanlinna, Heli, Peeters, Petra H, Peto, Julian, Prentice, Ross L, Rahman, Nazneen, Sanchez, Maria Jose, Schmidt, Daniel F, Schmutzler, Rita K, Southey, Melissa C, Tamimi, Rulla, Travis, Ruth C, Turnbull, Clare, Uitterlinden, Andre G, Wang, Zhaoming, Whittemore, Alice S, Yang, Xiaohong R, Zheng, Wei, Buchanan, Daniel D, Casey, Graham, Conti, David V, Edlund, Christopher K, Gallinger, Steven, Haile, Robert W, Jenkins, Mark, Le Marchand, Loic, Li, Li, Lindor, Noralene M, Schmit, Stephanie L, Thibodeau, Stephen N, Woods, Michael O, Rafnar, Thorunn, Gudmundsson, Julius, Stacey, Simon N, Stefansson, Kari, Sulem, Patrick, Chen, Y Ann, Tyrer, Jonathan P, Christiani, David C, Wei, Yongyue, Shen, Hongbing, Hu, Zhibin, Shu, Xiao-Ou, Shiraishi, Kouya, Takahashi, Atsushi, Bosse, Yohan, Obeidat, Ma'en, Nickle, David, Timens, Wim, Freedman, Matthew L, Li, Qiyuan, Seminara, Daniela, Chanock, Stephen J, Gong, Jian, Peters, Ulrike, Gruber, Stephen B, Amos, Christopher I, Sellers, Thomas A, Easton, Douglas F, Hunter, David J, Haiman, Christopher A, Henderson, Brian E, Hung, Rayjean J, OCAC, Consortium, PRACTICAL, Res, Hereditary Breast Ovarian Canc, Transdisciplinary, Colorectal, Canc, African Amer Breast, Canc, African Ancestry Prostate, Medical Oncology, Epidemiology, Internal Medicine, Surgery, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Groningen Research Institute for Asthma and COPD (GRIAC)
- Subjects
0301 basic medicine ,Oncology ,Male ,medicine.medical_specialty ,Cancer Research ,Lung Neoplasms ,SUSCEPTIBILITY LOCI ,Genotype ,IDENTIFIES 2 ,Colorectal cancer ,Locus (genetics) ,Genome-wide association study ,Breast Neoplasms ,Article ,03 medical and health sciences ,Prostate cancer ,AFRICAN ANCESTRY ,Breast cancer ,SDG 3 - Good Health and Well-being ,Internal medicine ,medicine ,Journal Article ,AGGRESSIVE PROSTATE ,Humans ,GENETIC POLYMORPHISMS ,Lung cancer ,METAANALYSIS ,Ovarian Neoplasms ,business.industry ,COMMON VARIANTS ,Prostatic Neoplasms ,CELL CARCINOMA ,medicine.disease ,RISK LOCI ,3. Good health ,030104 developmental biology ,Expression quantitative trait loci ,Adenocarcinoma ,Female ,business ,Colorectal Neoplasms ,GASTRIC-CANCER ,Genome-Wide Association Study - Abstract
Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103–14. ©2016 AACR.
- Published
- 2016
18. Abstract 230: Joint genome-wide association study of endometrial cancer and ovarian cancer identifies a novel genetic risk region at 14q23.3
- Author
-
Paul L. Auer, Douglas F. Easton, Ellen L. Goode, Emma Tham, Daniel D. Buchanan, Peter A. Fasching, Dylan M. Glubb, Diether Lambrechts, Thilo Dörk, Graham G. Giles, Per Hall, Immaculata De Vivo, Bcac, Roger L. Milne, Ocac, John R. B. Perry, Ecac, Tracy A. O'Mara, Rodney J. Scott, Jone Trovik, Amanda B. Spurdle, Ian Tomlinson, and Deborah J. Thompson
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Endometrial cancer ,Internal medicine ,medicine ,Genome-wide association study ,Genetic risk ,Ovarian cancer ,medicine.disease ,business - Abstract
Ovarian cancer is the most lethal gynecologic malignancy and the sixth most common cause of death from all cancer in women, with an estimated 140,000 deaths per year worldwide. Endometrial cancer (cancer of the uterine lining) is the most commonly diagnosed gynecologic cancer, ranking sixth in incident cancer in women. Ovarian and endometrial cancer share many epidemiologic, histopathologic, and tumor genetic characteristics. Meta-analyses of genome-wide association study (GWAS) datasets across etiologically related diseases have successfully been used to increase statistical power and identify novel genetic risk regions. We hypothesised that joint meta-analysis of ovarian and endometrial cancer GWAS datasets would identify novel genetic loci for both cancers. Following quality control, summary statistics for >11 million genetic variants were available from the largest genome-wide association studies performed by the Ovarian Cancer Association Consortium (OCAC, Phelan et al., Nature Genetics 2017) and the Endometrial Cancer Association Consortium (ECAC, unpublished). A total of 35,312 cancer cases from all histologic subtypes (22,406 ovarian and 12,906 endometrial cancer cases) and 149,920 controls were included in the analysis. Summary statistics were combined using an inverse-variance, fixed-effects model in METAL and identified ten loci at genome-wide significance (P < 5 x 10-8), of which one locus at 14q23.3 (rs4072776 combined OR 0.94; 95% CI 0.92-0.96; P = 8.0 x 10-9) had not been previously associated with the risk of either cancer. Integration with chromatin conformation data (RNAPolII HiChIP) from the Ishikawa endometrial cancer cell line suggests interaction between the risk signal and the promoter of FUT8. FUT8 encodes a fucosyltransferase and its expression has been implicated in breast, stomach, and melanoma and lung cancer. Interestingly, FUT8 is a downstream target regulated by the loss of PAX2 and mutated p53, which is the earliest known molecular aberration in the progression of the fallopian tissue epithelial to serous ovarian cancer. Further functional evaluation of the 14q23.3 risk region is required to determine the regulatory effect of genetic risk variants on FUT8. Future meta-analyses of datasets, stratifying results by histologic subtypes, will be undertaken. Citation Format: Tracy A. O'Mara, Dylan M. Glubb, Daniel D. Buchanan, Diether Lambrechts, Per Hall, Emma Tham, Jone Trovik, Ellen L. Goode, Peter Fasching, Thilo Dörk, Rodney J. Scott, Paul L. Auer, Roger L. Milne, Graham G. Giles, John Perry, Immaculata de Vivo, Ian Tomlinson, Douglas F. Easton, Deborah J. Thompson, Amanda B. Spurdle, E2C2, BCAC, OCAC, ECAC. Joint genome-wide association study of endometrial cancer and ovarian cancer identifies a novel genetic risk region at 14q23.3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 230.
- Published
- 2018
19. Abstract 2783: Common functional mechanisms underlying pleiotropy at the 19p13.1 breast and ovarian cancer cusceptibility locus
- Author
-
Jonathan Beesley, Georgia Chenevix-Trench, Stacey L. Edwards, Paul D.P. Pharoah, Douglas F. Easton, Karoline Kuckenbaeker, Jacques Simard, Siddhartha Kar, Alvaro N.A. Monteiro, Simon A. Gayther, Kate Lawrenson, Susan J. Ramus, Jonathan Tyrer, Bcac Ocac, Qiyuan Li, Kyriaki Michailidou, Alison M. Dunning, Fergus J. Couch, Cimba, Antonis C. Antoniou, and Matthew L. Freedman
- Subjects
Genetics ,Cancer Research ,education.field_of_study ,Population ,Genome-wide association study ,Locus (genetics) ,Single-nucleotide polymorphism ,Biology ,medicine.disease ,Breast cancer ,Oncology ,Genotype ,Expression quantitative trait loci ,medicine ,Cancer research ,education ,Ovarian cancer - Abstract
Genome-wide association studies (GWAS) have identified several susceptibility regions that confer risk of two or more cancers. A region at 19p13 is associated with both breast and ovarian cancer risk in the general population as well as in BRCA1/BRCA2 mutation carriers. Using the iCOGs custom genotyping array, we analyzed 438 SNPs in this region in 7,435 ER-negative breast cancer cases and 42,599 controls from BCAC, and 15,347 ovarian cancer cases and 30,845 controls from OCAC and 15,252 BRCA1 mutation carriers. We identified two significant peaks of association. Peak 1, consisting of 13 highly correlated SNPs (r2>0.95), spans a 19.4kb region harboring the BABAM1, ANKLE1 and ABHD8 genes. Peak 1 SNPs are associated with serous ovarian cancer (top hit rs4808075, P = 9.2×10-20), ER-negative breast cancer (rs61494113, P = 1.1×10-13) and breast cancer in BRCA1 mutation carriers (rs61494113, P = 7.7×10-16). Peak 2 spans over 100kb and contains 7 SNPs associated with breast cancer in BRCA1 mutation carriers only (rs4464206, P = 8.9×10-8). Multiple assays were used to establish the putative functional roles of risk SNPs and candidate susceptibility genes in this region. Expression quantitative trait locus (eQTL) analyses identified significant genotype-gene expression correlations between genotype at the Peak 1 SNP rs480816 and ABHD8 expression in ovarian tumors (P = 3.0×10-5) and normal breast tissues (P = 2.8×10-3). The Peak 2 SNP, rs7246243, was significantly associated with BABAM1 expression (P = 5×10-3) in normal breast tissue only. Overexpression of BABAM1 in normal ovarian and breast cells did not modulate neoplastic phenotypes, whereas overexpression of ABHD8 induced a significant reduction in migration in both cell types in vitro. Differentially expressed genes in ABHD8 models, identified by RNAseq, were associated with cellular movement (P Citation Format: Kate Lawrenson, Siddhartha Kar, Karoline Kuckenbaeker, Stacey Edwards, Qiyuan Li, Jonathan Tyrer, Jonathan Beesley, Kyriaki Michailidou, Susan Ramus, Alison Dunning, Fergus Couch, Alvaro Monteiro, Jacques Simard, Matthew Freedman, Douglas Easton, Georgia Chenevix-Trench, Paul Pharoah, Antonis Antoniou, Simon Gayther, OCAC, BCAC and CIMBA. Common functional mechanisms underlying pleiotropy at the 19p13.1 breast and ovarian cancer cusceptibility locus. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2783. doi:10.1158/1538-7445.AM2015-2783
- Published
- 2015
20. Identification of novel epithelial ovarian cancer loci in women of African ancestry
- Author
-
Manichaikul, Ani, Peres, Lauren C, Wang, Xin-Qun, Barnard, Mollie E, Chyn, Deanna, Sheng, Xin, Du, Zhaohui, Tyrer, Jonathan, Dennis, Joseph, Schwartz, Ann G, Cote, Michele L, Peters, Edward, Moorman, Patricia G, Bondy, Melissa, Barnholtz-Sloan, Jill S, Terry, Paul, Alberg, Anthony J, Bandera, Elisa V, Funkhouser, Ellen, Wu, Anna H, Pearce, Celeste Leigh, Pike, Malcom, Setiawan, Veronica Wendy, Haiman, Christopher A, African American Breast Cancer Consortium (AABC), African Ancestry Prostate Cancer Consortium (AAPC), Palmer, Julie R, LeMarchand, Loic, Wilkens, Lynne R, Berchuck, Andrew, Doherty, Jennifer A, Modugno, Francesmary, Ness, Roberta, Moysich, Kirsten, Karlan, Beth Y, Whittemore, Alice S, McGuire, Valerie, Sieh, Weiva, Lawrenson, Kate, Gayther, Simon, Sellers, Thomas A, Pharoah, Paul, Schildkraut, Joellen M, and African American Cancer Epidemiology Study (AACES) And The Ovarian Cancer Association Consortium (OCAC)
- Subjects
Follistatin ,endocrine system diseases ,eQTLs ,Aldo-Keto Reductase Family 1 Member C3 ,Black People ,Breast Neoplasms ,Carcinoma, Ovarian Epithelial ,Polymorphism, Single Nucleotide ,female genital diseases and pregnancy complications ,United States ,White People ,3. Good health ,Neoplasm Proteins ,Black or African American ,ovarian cancer ,African ancestry ,Antigens, Neoplasm ,gene expression ,Humans ,Female ,Genetic Predisposition to Disease ,genome wide association study ,Genome-Wide Association Study - Abstract
Women of African ancestry have lower incidence of epithelial ovarian cancer (EOC) yet worse survival compared to women of European ancestry. We conducted a genome-wide association study in African ancestry women with 755 EOC cases, including 537 high-grade serous ovarian carcinomas (HGSOC) and 1,235 controls. We identified four novel loci with suggestive evidence of association with EOC (p < 1 × 10-6 ), including rs4525119 (intronic to AKR1C3), rs7643459 (intronic to LOC101927394), rs4286604 (12 kb 3' of UGT2A2) and rs142091544 (5 kb 5' of WWC1). For HGSOC, we identified six loci with suggestive evidence of association including rs37792 (132 kb 5' of follistatin [FST]), rs57403204 (81 kb 3' of MAGEC1), rs79079890 (LOC105376360 intronic), rs66459581 (5 kb 5' of PRPSAP1), rs116046250 (GABRG3 intronic) and rs192876988 (32 kb 3' of GK2). Among the identified variants, two are near genes known to regulate hormones and diseases of the ovary (AKR1C3 and FST), and two are linked to cancer (AKR1C3 and MAGEC1). In follow-up studies of the 10 identified variants, the GK2 region SNP, rs192876988, showed an inverse association with EOC in European ancestry women (p = 0.002), increased risk of ER positive breast cancer in African ancestry women (p = 0.027) and decreased expression of GK2 in HGSOC tissue from African ancestry women (p = 0.004). A European ancestry-derived polygenic risk score showed positive associations with EOC and HGSOC in women of African ancestry suggesting shared genetic architecture. Our investigation presents evidence of variants for EOC shared among European and African ancestry women and identifies novel EOC risk loci in women of African ancestry.
21. Polygenic risk modeling for prediction of epithelial ovarian cancer risk
- Author
-
Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana. Grupo de investigación Instituto de Genética Humana, Torres-López, Diana María, Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones. Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V., Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia V., Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, EMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Chun Ding, Yuan, Doherty, Jennifer A., Domchek, Susan M., Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana M., Eliassen, Heather A., Engel, Christoph, Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, Renée T., Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, OPAL Study Group, AOCS Group, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Høgdall, Estrid, Høgdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., KConFab Investigators, HEBON Investigators, Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th., John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Lubiński, Jan, Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., Matsuno, Rayna Kim, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Ngeow Yuen, Yie Joanne, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo I., Olson, Sara H., Olsson, Håkan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Sokilde Pedersen, Inge, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamariña, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., Terry, Mary Beth, The OCAC Consortium, The CIMBA Consortium, Thomassen, Mads, Thompson, Pamela J., Vestrheim Thomsen, Liv Cecilie, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Van Nieuwenhuysen, Els, van Rensburg, Elizabeth J., Vega, Ana, Velez Edwards, Digna, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., Pharoah, Paul D. P., Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana. Grupo de investigación Instituto de Genética Humana, Torres-López, Diana María, Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones. Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V., Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia V., Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, EMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Chun Ding, Yuan, Doherty, Jennifer A., Domchek, Susan M., Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana M., Eliassen, Heather A., Engel, Christoph, Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, Renée T., Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, OPAL Study Group, AOCS Group, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Høgdall, Estrid, Høgdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., KConFab Investigators, HEBON Investigators, Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th., John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Lubiński, Jan, Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., Matsuno, Rayna Kim, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Ngeow Yuen, Yie Joanne, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo I., Olson, Sara H., Olsson, Håkan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Sokilde Pedersen, Inge, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamariña, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., Terry, Mary Beth, The OCAC Consortium, The CIMBA Consortium, Thomassen, Mads, Thompson, Pamela J., Vestrheim Thomsen, Liv Cecilie, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Van Nieuwenhuysen, Els, van Rensburg, Elizabeth J., Vega, Ana, Velez Edwards, Digna, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., and Pharoah, Paul D. P.
22. Effects of diet on skin sensitization by nickel, poison ivy, and sesquiterpene lactones.
- Author
-
An N, Pourzal S, Luccioli S, and Vukmanović S
- Subjects
- Dermatitis, Allergic Contact etiology, Diet, Humans, Skin drug effects, Toxicodendron immunology, Dermatitis, Allergic Contact immunology, Lactones toxicity, Nickel toxicity, Plant Extracts toxicity, Sesquiterpenes toxicity, Skin immunology, Toxicodendron toxicity
- Abstract
Skin contact or exposure to sensitizers often occurs as a consequence of occupational exposures (e.g. poison ivy in forestry), wearing jewelry (e.g. nickel), or use of cosmetics (e.g. fragrances). However, many of the known skin sensitizers or their chemical variants are also consumed orally through foods or other sources. Since oral exposure to antigenic substances can lead to tolerance, consumption of sensitizers may impact the development and potency of skin sensitization, especially if the sensitizer is consumed early in life, prior to the first skin contact. To address this issue, we have reviewed human clinical and epidemiological literature relevant to this subject and evaluated whether early oral exposures to relevant sensitizers, or their chemical variants, are associated with reduced prevalence of skin sensitization to three main allergic sensitizers - nickel, urushiols of poison ivy, and sesquiterpene lactones of chrysanthemum and other plants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)
- Published
- 2020
- Full Text
- View/download PDF
23. Skin sensitizers in cosmetics and beyond: potential multiple mechanisms of action and importance of T-cell assays for in vitro screening.
- Author
-
Vukmanović S and Sadrieh N
- Subjects
- Computer Simulation, Consumer Product Safety, Dermatitis, Allergic Contact, Humans, In Vitro Techniques, Skin, T-Lymphocytes, Allergens analysis, Biological Assay, Cosmetics analysis
- Abstract
Allergic contact dermatitis (ACD) is a delayed-type hypersensitivity (DTH) reaction induced by repeated contact with sensitizers. The ability of a chemical to act as a sensitizer has most frequently been tested in animals. As the use of animals for these purposes is gradually and globally being phased out, there is a need for reliable in vitro surrogate assays. Currently proposed in vitro assays are designed to test four key events of the adverse outcome pathway (AOP) involving covalent modification of self-proteins by sensitizers (haptenation) and presentation of new antigens (hapten/carrier complexes) to the immune system. There appears to be imperfect alignment of in vitro assays with clinical and/or animal data, suggesting possibly additional mechanisms of ACD development. Indeed, studies on allergies to small drugs, small chemical-induced HLA-peptide exchange for vaccination purposes and cosmetic ingredient-induced exposure of autoantigens suggest a possibility of DTH response promotion by hapten/carrier-independent mechanisms. Therefore, there is a need for additional appropriate in vitro assays, in order to achieve maximal concordance between clinical and/or animal data and in vitro assays. In this paper, we will review evidence supporting the idea of diverse mechanisms of ACD development. We will also discuss the impact of these multiple mechanisms, on the AOP and on the in vitro assays that should be used for allergen detection. We will propose alloreactivity-like reactions, aided by computer modeling and biochemical tests of compound-HLA binding, as additional tools for better prediction of DTH reactions, resulting from exposure to ingredients in cosmetic products. The combination of the proposed tests, along with the existing assays, should further enhance animal-free assessment of sensitizing potential of individual chemicals.
- Published
- 2017
- Full Text
- View/download PDF
24. PPM1D Mosaic Truncating Variants in Ovarian Cancer Cases May Be Treatment-Related Somatic Mutations.
- Author
-
Pharoah PDP, Song H, Dicks E, Intermaggio MP, Harrington P, Baynes C, Alsop K, Bogdanova N, Cicek MS, Cunningham JM, Fridley BL, Gentry-Maharaj A, Hillemanns P, Lele S, Lester J, McGuire V, Moysich KB, Poblete S, Sieh W, Sucheston-Campbell L, Widschwendter M, Whittemore AS, Dörk T, Menon U, Odunsi K, Goode EL, Karlan BY, Bowtell DD, Gayther SA, and Ramus SJ
- Subjects
- Adult, Aged, Antineoplastic Agents therapeutic use, Case-Control Studies, Female, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Middle Aged, Polymerase Chain Reaction, Protein Phosphatase 2C, Gene Frequency, Mosaicism, Mutation, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics, Phosphoprotein Phosphatases genetics
- Abstract
Mosaic truncating mutations in the protein phosphatase, Mg(2+)/Mn(2+)-dependent, 1D (PPM1D) gene have recently been reported with a statistically significantly greater frequency in lymphocyte DNA from ovarian cancer case patients compared with unaffected control patients. Using massively parallel sequencing (MPS) we identified truncating PPM1D mutations in 12 of 3236 epithelial ovarian cancer (EOC) case patients (0.37%) but in only one of 3431 unaffected control patients (0.03%) (P = .001). All statistical tests were two-sided. A combination of Sanger sequencing, pyrosequencing, and MPS data suggested that 12 of the 13 mutations were mosaic. All mutations were identified in post-chemotherapy treatment blood samples from case patients (n = 1827) (average 1234 days post-treatment in carriers) rather than from cases collected pretreatment (less than 14 days after diagnosis, n = 1384) (P = .002). These data suggest that PPM1D variants in EOC cases are primarily somatic mosaic mutations caused by treatment and are not associated with germline predisposition to EOC., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2016
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.