243 results on '"Lawrenson, K"'
Search Results
2. Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk
- Author
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Amankwah, EK, Lin, HY, Tyrer, JP, Lawrenson, K, Dennis, J, Chornokur, G, Aben, KKH, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chen, Z, Chen, YA, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, du Bois, A, Despierre, E, Dicks, E, Doherty, JA, Dörk, T, Dürst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, BT, Karlan, BY, Jim, H, Kellar, M, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lim, BK, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, Mcguire, V, Mclaughlin, JR, Mcneish, I, Menon, U, Milne, RL, Modugno, F, Moysich, KB, Ness, RB, Nevanlinna, H, Eilber, U, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, and Weber, RP
- Subjects
Epidemiology ,Public Health and Health Services ,Genetics - Abstract
Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value
- Published
- 2015
3. Modelling neoplastic progression in epithelial ovarian cancer
- Author
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Lawrenson, K.
- Subjects
610 - Abstract
A national screening programme could significantly reduce mortality from epithelial ovarian cancer (EOC). The biological events that occur in the early stages of development of EOCs remain poorly understood, thus hindering the discovery of biomarkers of early disease. This thesis describes the development of a three-dimensional heterotypic genetic model of neoplastic transformation of normal ovarian surface epithelial (NOSE) cells. hTERT, C-MYC, KRAS and BRAF are genes that are commonly mutated or overexpressed in EOCs. Ectopic expression of hTERT increased in vitro lifespan of NOSE cells without inducing neoplastic transformation. Subsequent overexpression of CMYC +/- KRASG12V /BRAFV 600E in immortalised NOSE (IOSE) cells induced a significant increase in anchorage-independent growth and invasive ability. In in vitro assays and gene expression microarrays, phenotypic and molecular heterogeneity was associated with differential oncogene expression. Physiological and biological features of NOSE cells grown in 3D more closely resembled characteristics of NOSE cells in vivo than when grown by classical two-dimensional (2D) approaches. 3D models of oncogene-expressing clones revealed characteristics of malignant cells in vivo that could not be detected in 2D monolayer cultures. Gene expression microarrrays profiles of ~25,000 genes were generated to identify novel genes that are altered synergistically with the oncogenes that were introduced. A panel of genes has been identified that provides novel candidates for detecting ovarian carcinomas at the earliest, most treatable, stages of disease. Finally, a role for ageing fibroblasts in the initiation of EOC development was explored. In 2D and 3D in vitro co-culture assays, pre-senescent and senescent ovarian fibroblasts differentially affected proliferation, anchorage-independent growth, migration and invasion of IOSECMYC cell lines but not of IOSE cells. These data provide in vitro evidence that the ageing microenvironment can promote transformation of ovarian epithelial cells, and that this is conditional upon mutation in the OSE.
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- 2010
4. A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes
- Author
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Mortlock, S, Corona, R, Kho, PF, Pharoah, P, Seo, J-H, Freedman, ML, Gayther, SA, Siedhoff, MT, Rogers, PAW, Leuchter, R, Walsh, CS, Cass, I, Karlan, BY, Rimel, BJ, Montgomery, GW, Lawrenson, K, Kar, SP, Mortlock, S, Corona, R, Kho, PF, Pharoah, P, Seo, J-H, Freedman, ML, Gayther, SA, Siedhoff, MT, Rogers, PAW, Leuchter, R, Walsh, CS, Cass, I, Karlan, BY, Rimel, BJ, Montgomery, GW, Lawrenson, K, and Kar, SP
- Abstract
Endometriosis is associated with increased risk of epithelial ovarian cancers (EOCs). Using data from large endometriosis and EOC genome-wide association meta-analyses, we estimate the genetic correlation and evaluate the causal relationship between genetic liability to endometriosis and EOC histotypes, and identify shared susceptibility loci. We estimate a significant genetic correlation (rg) between endometriosis and clear cell (rg = 0.71), endometrioid (rg = 0.48), and high-grade serous (rg = 0.19) ovarian cancer, associations supported by Mendelian randomization analyses. Bivariate meta-analysis identified 28 loci associated with both endometriosis and EOC, including 19 with evidence for a shared underlying association signal. Differences in the shared risk suggest different underlying pathways may contribute to the relationship between endometriosis and the different histotypes. Functional annotation using transcriptomic and epigenomic profiles of relevant tissues/cells highlights several target genes. This comprehensive analysis reveals profound genetic overlap between endometriosis and EOC histotypes with valuable genomic targets for understanding the biological mechanisms linking the diseases.
- Published
- 2022
5. Correction: Polygenic risk modeling for prediction of epithelial ovarian cancer risk.
- Author
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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
6. Polygenic risk modeling for prediction of epithelial ovarian cancer risk
- Author
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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, Balmana, J, Bandera, E, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, N, 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, 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, Dork, T, du Bois, A, Durst, M, Eccles, DM, Eliassen, HA, Engel, C, Evans, GD, Fasching, PA, Flanagan, JM, Fortner, R, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, Group, OS, AOCSGroup, Hahnen, E, Haiman, CA, Hakansson, N, Hamann, U, Hansen, TVO, Harris, HR, Hartman, M, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Hopper, JL, Huang, R-Y, Huff, C, Hulick, PJ, Huntsman, DG, Imyanitov, EN, 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, Mai, PL, Manoukian, S, Marks, JR, KimMatsuno, R, 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, O, 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, Santamarina, 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, BethTerry, M, 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, 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, Balmana, J, Bandera, E, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, N, 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, 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, Dork, T, du Bois, A, Durst, M, Eccles, DM, Eliassen, HA, Engel, C, Evans, GD, Fasching, PA, Flanagan, JM, Fortner, R, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, Group, OS, AOCSGroup, Hahnen, E, Haiman, CA, Hakansson, N, Hamann, U, Hansen, TVO, Harris, HR, Hartman, M, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Hopper, JL, Huang, R-Y, Huff, C, Hulick, PJ, Huntsman, DG, Imyanitov, EN, 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, Mai, PL, Manoukian, S, Marks, JR, KimMatsuno, R, 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, O, 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, Santamarina, 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, BethTerry, M, 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, 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
- Abstract
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
7. Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci
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DeVries, A.A.F., Dennis, J., Tyrer, J.P., Peng, P.C., Coetzee, S.G., Reyes, A.L., Plummer, J.T., Davis, B.D., Chen, S.S., Dezem, F.S., Aben, K.K.H., Anton-Culver, H., Antonenkova, N.N., Beckmann, M.W., Beeghly-Fadiel, A., Berchuck, A., Bogdanova, N.V., Bogdanova-Markov, N., Brenton, J.D., Butzow, R., Campbell, I., Chang-Claude, J., Chenevix-Trench, G., Cook, L.S., Defazio, A., Doherty, J.A., Dörk, T., Eccles, D.M., Eliassen, A.H., Fasching, P.A., Fortner, R.T., Giles, G.G., Goode, E.L., Goodman, M.T., Gronwald, J., Håkansson, N., Hildebrandt, M.A., Huff, C., Huntsman, D.G., Jensen, A., Kar, S., Karlan, B.Y., Khusnutdinova, E.K., Kiemeney, L.A.L.M., Kjaer, S.K., Kupryjanczyk, J., Labrie, M., Lambrechts, D., Le, N.D., Lubiński, J., May, T., Menon, U., Milne, R.L., Modugno, F., Monteiro, Ana, Moysich, K.B., Odunsi, K., Olsson, H., Pearce, C.L., Pejovic, T., Ramus, S.J., Riboli, E., Riggan, M.J., Romieu, I., Sandler, D.P., Schildkraut, J.M., Setiawan, V.W., Sieh, W., Song, H., Sutphen, R., Terry, K.L., Thompson, P.J., Titus, L., Tworoger, S.S., Nieuwenhuysen, E. Van, Edwards, D.V., Webb, P.M., Wentzensen, N., Whittemore, A.S., Wolk, A., Wu, A.H., Ziogas, Argyrios, Freedman, M.L., Lawrenson, K., Pharoah, P.D., Easton, D.F., Gayther, S.A., Jones, M.R., DeVries, A.A.F., Dennis, J., Tyrer, J.P., Peng, P.C., Coetzee, S.G., Reyes, A.L., Plummer, J.T., Davis, B.D., Chen, S.S., Dezem, F.S., Aben, K.K.H., Anton-Culver, H., Antonenkova, N.N., Beckmann, M.W., Beeghly-Fadiel, A., Berchuck, A., Bogdanova, N.V., Bogdanova-Markov, N., Brenton, J.D., Butzow, R., Campbell, I., Chang-Claude, J., Chenevix-Trench, G., Cook, L.S., Defazio, A., Doherty, J.A., Dörk, T., Eccles, D.M., Eliassen, A.H., Fasching, P.A., Fortner, R.T., Giles, G.G., Goode, E.L., Goodman, M.T., Gronwald, J., Håkansson, N., Hildebrandt, M.A., Huff, C., Huntsman, D.G., Jensen, A., Kar, S., Karlan, B.Y., Khusnutdinova, E.K., Kiemeney, L.A.L.M., Kjaer, S.K., Kupryjanczyk, J., Labrie, M., Lambrechts, D., Le, N.D., Lubiński, J., May, T., Menon, U., Milne, R.L., Modugno, F., Monteiro, Ana, Moysich, K.B., Odunsi, K., Olsson, H., Pearce, C.L., Pejovic, T., Ramus, S.J., Riboli, E., Riggan, M.J., Romieu, I., Sandler, D.P., Schildkraut, J.M., Setiawan, V.W., Sieh, W., Song, H., Sutphen, R., Terry, K.L., Thompson, P.J., Titus, L., Tworoger, S.S., Nieuwenhuysen, E. Van, Edwards, D.V., Webb, P.M., Wentzensen, N., Whittemore, A.S., Wolk, A., Wu, A.H., Ziogas, Argyrios, Freedman, M.L., Lawrenson, K., Pharoah, P.D., Easton, D.F., Gayther, S.A., and Jones, M.R.
- Abstract
Item does not contain fulltext, BACKGROUND: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. METHODS: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. RESULTS: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CONCLUSIONS: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.
- Published
- 2022
8. Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci
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DeVries, AA, Dennis, J, Tyrer, JP, Peng, P-C, Coetzee, SG, Reyes, AL, Plummer, JT, Davis, BD, Chen, SS, Dezem, FS, Aben, KKH, Anton-Culver, H, Antonenkova, NN, Beckmann, MW, Beeghly-Fadiel, A, Berchuck, A, Bogdanova, N, Bogdanova-Markov, N, Brenton, JD, Butzow, R, Campbell, I, Chang-Claude, J, Chenevix-Trench, G, Cook, LS, DeFazio, A, Doherty, JA, Dork, T, Eccles, DM, Eliassen, AH, Fasching, PA, Fortner, RT, Giles, GG, Goode, EL, Goodman, MT, Gronwald, J, Hakansson, N, Hildebrandt, MAT, Huff, C, Huntsman, DG, Jensen, A, Kar, S, Karlan, BY, Khusnutdinova, EK, Kiemeney, LA, Kjaer, SK, Kupryjanczyk, J, Labrie, M, Lambrechts, D, Le, ND, Lubinski, J, May, T, Menon, U, Milne, RL, Modugno, F, Monteiro, AN, Moysich, KB, Odunsi, K, Olsson, H, Pearce, CL, Pejovic, T, Ramus, SJ, Riboli, E, Riggan, MJ, Romieu, I, Sandler, DP, Schildkraut, JM, Setiawan, VW, Sieh, W, Song, H, Sutphen, R, Terry, KL, Thompson, PJ, Titus, L, Tworoger, SS, Van Nieuwenhuysen, E, Edwards, DV, Webb, PM, Wentzensen, N, Whittemore, AS, Wolk, A, Wu, AH, Ziogas, A, Freedman, ML, Lawrenson, K, Pharoah, PDP, Easton, DF, Gayther, SA, Jones, MR, DeVries, AA, Dennis, J, Tyrer, JP, Peng, P-C, Coetzee, SG, Reyes, AL, Plummer, JT, Davis, BD, Chen, SS, Dezem, FS, Aben, KKH, Anton-Culver, H, Antonenkova, NN, Beckmann, MW, Beeghly-Fadiel, A, Berchuck, A, Bogdanova, N, Bogdanova-Markov, N, Brenton, JD, Butzow, R, Campbell, I, Chang-Claude, J, Chenevix-Trench, G, Cook, LS, DeFazio, A, Doherty, JA, Dork, T, Eccles, DM, Eliassen, AH, Fasching, PA, Fortner, RT, Giles, GG, Goode, EL, Goodman, MT, Gronwald, J, Hakansson, N, Hildebrandt, MAT, Huff, C, Huntsman, DG, Jensen, A, Kar, S, Karlan, BY, Khusnutdinova, EK, Kiemeney, LA, Kjaer, SK, Kupryjanczyk, J, Labrie, M, Lambrechts, D, Le, ND, Lubinski, J, May, T, Menon, U, Milne, RL, Modugno, F, Monteiro, AN, Moysich, KB, Odunsi, K, Olsson, H, Pearce, CL, Pejovic, T, Ramus, SJ, Riboli, E, Riggan, MJ, Romieu, I, Sandler, DP, Schildkraut, JM, Setiawan, VW, Sieh, W, Song, H, Sutphen, R, Terry, KL, Thompson, PJ, Titus, L, Tworoger, SS, Van Nieuwenhuysen, E, Edwards, DV, Webb, PM, Wentzensen, N, Whittemore, AS, Wolk, A, Wu, AH, Ziogas, A, Freedman, ML, Lawrenson, K, Pharoah, PDP, Easton, DF, Gayther, SA, and Jones, MR
- Abstract
BACKGROUND: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. METHODS: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. RESULTS: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CONCLUSIONS: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.
- Published
- 2022
9. COVID-19 testing in outbreak-free care homes: what are the public health benefits?
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Green, R., primary, Tulloch, J.S.P., additional, Tunnah, C., additional, Coffey, E., additional, Lawrenson, K., additional, Fox, A., additional, Mason, J., additional, Barnett, R., additional, Constantine, A., additional, Shepherd, W., additional, Ashton, M., additional, Beadsworth, M.B.J., additional, Vivancos, R., additional, Hall, I., additional, Walker, N., additional, and Ghebrehewet, S., additional
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- 2021
- Full Text
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10. Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer
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Kar, S.P., Considine, D.P.C., Tyrer, J.P., Plummer, J.T., Chen, S., Dezem, F.S., Barbeira, A.N., Rajagopal, P.S., Rosenow, W.T., Moreno, F., Bodelon, C., Chang-Claude, J., Chenevix-Trench, G., Defazio, A., Dörk, T., Ekici, A.B., Ewing, A., Fountzilas, G., Goode, E.L., Hartman, M, Heitz, F., Hillemanns, P., Høgdall, E., Høgdall, C.K., Huzarski, T., Jensen, A., Karlan, B.Y., Khusnutdinova, E., Kiemeney, L.A.L.M., Kjaer, S.K., Klapdor, R., Köbel, M., Li, J., Liebrich, C., May, T., Olsson, H., Permuth, J.B., Peterlongo, P., Radice, P., Ramus, S.J., Riggan, M.J., Risch, H.A., Saloustros, E., Simard, J., Szafron, L.M., Titus, L., Thompson, C.L., Vierkant, R.A., Winham, S.J., Zheng, W., Doherty, J.A., Berchuck, A., Lawrenson, K., Im, H.K., Manichaikul, A.W., Pharoah, P.D., Gayther, S.A., Schildkraut, J.M., Kar, S.P., Considine, D.P.C., Tyrer, J.P., Plummer, J.T., Chen, S., Dezem, F.S., Barbeira, A.N., Rajagopal, P.S., Rosenow, W.T., Moreno, F., Bodelon, C., Chang-Claude, J., Chenevix-Trench, G., Defazio, A., Dörk, T., Ekici, A.B., Ewing, A., Fountzilas, G., Goode, E.L., Hartman, M, Heitz, F., Hillemanns, P., Høgdall, E., Høgdall, C.K., Huzarski, T., Jensen, A., Karlan, B.Y., Khusnutdinova, E., Kiemeney, L.A.L.M., Kjaer, S.K., Klapdor, R., Köbel, M., Li, J., Liebrich, C., May, T., Olsson, H., Permuth, J.B., Peterlongo, P., Radice, P., Ramus, S.J., Riggan, M.J., Risch, H.A., Saloustros, E., Simard, J., Szafron, L.M., Titus, L., Thompson, C.L., Vierkant, R.A., Winham, S.J., Zheng, W., Doherty, J.A., Berchuck, A., Lawrenson, K., Im, H.K., Manichaikul, A.W., Pharoah, P.D., Gayther, S.A., and Schildkraut, J.M.
- Abstract
Contains fulltext : 237689.pdf (Publisher’s version ) (Open Access), Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.
- Published
- 2021
11. Characteristics of Suspected Endometriosis without Histologic Confirmation
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Krajisnik, A., primary, Medeiros, F., additional, Lawrenson, K., additional, Siedhoff, M.T., additional, Truong, M.D., additional, and Wright, K.N., additional
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- 2020
- Full Text
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12. In vitro three-dimensional modelling of human ovarian surface epithelial cells
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Lawrenson, K., Benjamin, E., Turmaine, M., Jacobs, I., Gayther, S., and Dafou, D.
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- 2009
- Full Text
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13. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer
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Phelan, CM, Kuchenbaecker, KB, Tyrer, JP, Kar, SP, Lawrenson, K, Winham, SJ, Dennis, J, Pirie, A, Riggan, MJ, Chornokur, G, Earp, MA, Lyra, PC, Lee, JM, Coetzee, S, Beesley, J, McGuffog, L, Soucy, P, Dicks, E, Lee, A, Barrowdale, D, Lecarpentier, J, Leslie, G, Aalfs, CM, Aben, KKH, Adams, M, Adlard, J, Andrulis, IL, Anton-Culver, H, Antonenkova, N, Aravantinos, G, Arnold, N, Arun, BK, Arver, B, Azzollini, J, Balmaña, J, Banerjee, SN, Barjhoux, L, Barkardottir, RB, Bean, Y, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Birrer, MJ, Bjorge, L, Black, A, Blankstein, K, Blok, MJ, Bodelon, C, Bogdanova, N, Bojesen, A, Bonanni, B, Borg, Å, Bradbury, AR, Brenton, JD, Brewer, C, Brinton, L, Broberg, P, Brooks-Wilson, A, Bruinsma, F, Brunet, J, Buecher, B, Butzow, R, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Cannioto, R, Carney, ME, Cescon, T, Chan, SB, Chang-Claude, J, Chanock, S, Chen, XQ, Chiew, YE, Chiquette, J, Chung, WK, Claes, KBM, Conner, T, Cook, LS, Cook, J, Cramer, DW, Cunningham, JM, and D'Aloisio, AA
- Subjects
endocrine system diseases ,female genital diseases and pregnancy complications - Abstract
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
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- 2017
14. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer
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Phelan, C.M., Kuchenbaecker, K.B., Tyrer, J.P., Kar, S.P., Lawrenson, K., Winham, S.J., Dennis, J., Pirie, A., Riggan, M.J., Chornokur, G., Earp, M.A., Lyra, P.C., Jr., Lee, J.M., Coetzee, S., Beesley, J., McGuffog, L., Soucy, P., Dicks, E., Lee, A., Barrowdale, D., Lecarpentier, J., Leslie, G., Aalfs, C.M., Aben, K.K.H., Adams, M., Adlard, J., Andrulis, I.L., Anton-Culver, H., Antonenkova, N., Aravantinos, G., Arnold, N., Arun, B.K., Arver, B., Azzollini, J., Balmana, J., Banerjee, S.N., Barjhoux, L., Barkardottir, R.B., Bean, Y., Beckmann, M.W., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Bernardini, M.Q., Birrer, M.J., Bjorge, L., Black, A., Blankstein, K., Blok, M.J., Bodelon, C., Bogdanova, N., Bojesen, A., Bonanni, B., Borg, A., Bradbury, A.R., Brenton, J.D., Brewer, C., Brinton, L., Broberg, P., Brooks-Wilson, A., Bruinsma, F., Brunet, J., Buecher, B., Butzow, R., Buys, S.S., Caldes, T., Caligo, M.A., Campbell, I., Cannioto, R., Carney, M.E., Cescon, T., Chan, S.B., Chang-Claude, J., Chanock, S., Chen, X.Q., Chiew, Y.E., Chiquette, J., Chung, W.K., Claes, K.B., Conner, T., Cook, L.S., Cook, J., Cramer, D.W, Cunningham, J.M., D'Aloisio, A.A., Daly, M.B., Damiola, F., Damirovna, S.D., Dansonka-Mieszkowska, A., Dao, F., Davidson, R., Defazio, A., Delnatte, C., Doheny, K.F., Diez, O., Ding, Y.C., Doherty, J.A., Domchek, S.M., Dorfling, C.M., Dork, T., Mensenkamp, A.R., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Altena, A.M. van, et al., Phelan, C.M., Kuchenbaecker, K.B., Tyrer, J.P., Kar, S.P., Lawrenson, K., Winham, S.J., Dennis, J., Pirie, A., Riggan, M.J., Chornokur, G., Earp, M.A., Lyra, P.C., Jr., Lee, J.M., Coetzee, S., Beesley, J., McGuffog, L., Soucy, P., Dicks, E., Lee, A., Barrowdale, D., Lecarpentier, J., Leslie, G., Aalfs, C.M., Aben, K.K.H., Adams, M., Adlard, J., Andrulis, I.L., Anton-Culver, H., Antonenkova, N., Aravantinos, G., Arnold, N., Arun, B.K., Arver, B., Azzollini, J., Balmana, J., Banerjee, S.N., Barjhoux, L., Barkardottir, R.B., Bean, Y., Beckmann, M.W., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Bernardini, M.Q., Birrer, M.J., Bjorge, L., Black, A., Blankstein, K., Blok, M.J., Bodelon, C., Bogdanova, N., Bojesen, A., Bonanni, B., Borg, A., Bradbury, A.R., Brenton, J.D., Brewer, C., Brinton, L., Broberg, P., Brooks-Wilson, A., Bruinsma, F., Brunet, J., Buecher, B., Butzow, R., Buys, S.S., Caldes, T., Caligo, M.A., Campbell, I., Cannioto, R., Carney, M.E., Cescon, T., Chan, S.B., Chang-Claude, J., Chanock, S., Chen, X.Q., Chiew, Y.E., Chiquette, J., Chung, W.K., Claes, K.B., Conner, T., Cook, L.S., Cook, J., Cramer, D.W, Cunningham, J.M., D'Aloisio, A.A., Daly, M.B., Damiola, F., Damirovna, S.D., Dansonka-Mieszkowska, A., Dao, F., Davidson, R., Defazio, A., Delnatte, C., Doheny, K.F., Diez, O., Ding, Y.C., Doherty, J.A., Domchek, S.M., Dorfling, C.M., Dork, T., Mensenkamp, A.R., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Altena, A.M. van, and et al.
- Abstract
Contains fulltext : 174141.pdf (publisher's version ) (Closed access), To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
- Published
- 2017
15. Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci
- Author
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Kar, S.P., Adler, E., Tyrer, J., Hazelett, D., Anton-Culver, H., Bandera, E.V., Beckmann, M.W., Berchuck, A., Bogdanova, N., Brinton, L., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Cook, L.S., Cramer, D.W, Cunningham, J.M., Dansonka-Mieszkowska, A., Doherty, J.A., Dork, T., Durst, M., Eccles, D., Fasching, P.A., Flanagan, J., Gentry-Maharaj, A., Glasspool, R., Goode, E.L., Goodman, M.T., Gronwald, J., Heitz, F., Hildebrandt, M.A.T., Hogdall, E., Hogdall, C.K., Huntsman, D.G., Jensen, A., Karlan, B.Y., Kelemen, L.E., Kiemeney, L.A.L.M., Kjaer, S.K., Kupryjanczyk, J., Lambrechts, D., Levine, D.A., Li, Q., Lissowska, J., Lu, K.H., Lubinski, J., Massuger, L.F.A.G., McGuire, V., McNeish, I., Menon, U., Modugno, F., Monteiro, A.N., Moysich, K.B., Ness, R.B., Nevanlinna, H., Paul, J., Pearce, C.L., Pejovic, T., Permuth, J.B., Phelan, C., Pike, M.C., Poole, E.M., Ramus, S.J., Risch, H.A., Rossing, M.A., Salvesen, H.B., Schildkraut, J.M., Sellers, T.A., Sherman, M., Siddiqui, N., Sieh, W., Song, H., Southey, M., Terry, K.L., Tworoger, S.S., Walsh, C., Wentzensen, N., Whittemore, A.S., Wu, A.H., Yang, H., Zheng, W., Ziogas, A., Freedman, M.L., Gayther, S.A., Pharoah, P.D., Lawrenson, K., Kar, S.P., Adler, E., Tyrer, J., Hazelett, D., Anton-Culver, H., Bandera, E.V., Beckmann, M.W., Berchuck, A., Bogdanova, N., Brinton, L., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Cook, L.S., Cramer, D.W, Cunningham, J.M., Dansonka-Mieszkowska, A., Doherty, J.A., Dork, T., Durst, M., Eccles, D., Fasching, P.A., Flanagan, J., Gentry-Maharaj, A., Glasspool, R., Goode, E.L., Goodman, M.T., Gronwald, J., Heitz, F., Hildebrandt, M.A.T., Hogdall, E., Hogdall, C.K., Huntsman, D.G., Jensen, A., Karlan, B.Y., Kelemen, L.E., Kiemeney, L.A.L.M., Kjaer, S.K., Kupryjanczyk, J., Lambrechts, D., Levine, D.A., Li, Q., Lissowska, J., Lu, K.H., Lubinski, J., Massuger, L.F.A.G., McGuire, V., McNeish, I., Menon, U., Modugno, F., Monteiro, A.N., Moysich, K.B., Ness, R.B., Nevanlinna, H., Paul, J., Pearce, C.L., Pejovic, T., Permuth, J.B., Phelan, C., Pike, M.C., Poole, E.M., Ramus, S.J., Risch, H.A., Rossing, M.A., Salvesen, H.B., Schildkraut, J.M., Sellers, T.A., Sherman, M., Siddiqui, N., Sieh, W., Song, H., Southey, M., Terry, K.L., Tworoger, S.S., Walsh, C., Wentzensen, N., Whittemore, A.S., Wu, A.H., Yang, H., Zheng, W., Ziogas, A., Freedman, M.L., Gayther, S.A., Pharoah, P.D., and Lawrenson, K.
- Abstract
Contains fulltext : 170527.pdf (publisher's version ) (Closed access), BACKGROUND: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. METHODS: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). RESULTS: The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10-5 (including six with P<5 x 10-8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. CONCLUSIONS: Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.
- Published
- 2017
16. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer
- Author
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Phelan, C. (Catherine), Kuchenbaecker, K.B. (Karoline), Tyrer, J.P. (Jonathan P.), Kar, S.P. (Siddhartha P.), Lawrenson, K. (Kate), Winham, S.J. (Stacey J.), Dennis, J. (Joe), Pirie, A. (Ailith), Riggan, M.J. (Marjorie J.), Chornokur, G. (Ganna), Earp, M.A. (Madalene A.), Lyra, P.C. (Paulo C.), Lee, J.M. (Janet M.), Coetzee, S. (Simon), Beesley, J. (Jonathan), McGuffog, L. (Lesley), Soucy, P. (Penny), Dicks, E. (Ed), Lee, A. (Andrew), Barrowdale, D. (Daniel), Lecarpentier, J. (Julie), Leslie, G. (Goska), Aalfs, C.M. (Cora), Aben, K.K.H. (Katja), Adams, M. (Marcia), Adlard, J.W. (Julian), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Antonenkova, N. (Natalia), Aravantinos, G. (Gerasimos), Arnold, N. (Norbert), Arun, B.K. (Banu), Arver, B. (Brita), Azzollini, J., Balmana, J. (Judith), Banerjee, S. (Susana), Barjhoux, L. (Laure), Barkardottir, R.B. (Rosa B.), Bean, Y. (Yukie), Beckmann, M.W. (Matthias), Beeghly-Fadiel, A. (Alicia), Benítez, J. (Javier), Bermisheva, M. (Marina), Bernardini, M.Q. (Marcus Q.), Birrer, M.J. (Michael J.), Bjorge, L. (Line), Black, A., Blankstein, K. (Kenneth), Blok, M.J. (Marinus), Bodelon, C. (Clara), Bogdanova, N. (Natalia), Bojesen, A. (Anders), Bonanni, B. (Bernardo), Borg, Å. (Åke), Bradbury, A.R. (Angela R.), Brenton, J.D. (James D.), Brewer, C. (Carole), Brinton, L.A. (Louise), Broberg, P. (Per), Brooks-Wilson, A. (Angela), Bruinsma, F. (Fiona), Brunet, J. (Joan), Buecher, B. (Bruno), Butzow, R. (Ralf), Buys, S.S. (Saundra), Caldes, T. (Trinidad), Caligo, M.A. (Maria A.), Campbell, I. (Ian), Cannioto, R. (Rikki), Carney, M.E. (Michael), Cescon, T. (Terence), Chan, S. (Salina), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen), Chen, X.Q. (Xiao Qing), Chiew, Y.-E. (Yoke-Eng), Chiquette, J. (Jocelyne), Chung, W. (Wendy), Claes, K. (Kathleen), Conner, T. (Thomas), Cook, L.S. (Linda S.), Cook, J. (Jackie), Cramer, D.W. (Daniel), Cunningham, J.M. (Julie), D'Aloisio, A.A. (Aimee A.), Daly, M.B. (Mary), Damiola, F. (Francesca), Damirovna, S.D. (Sakaeva Dina), Dansonka-Mieszkowska, A. (Agnieszka), Dao, F. (Fanny), Davidson, R. (Rosemarie), DeFazio, A. (Anna), Delnatte, C.D. (Capucine), Doheny, K.F. (Kimberly), Díez, O. (Orland), Ding, Y.C. (Yuan Chun), Doherty, J.A. (Jennifer), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Dossus, L. (Laure), Duran, M. (Mercedes), Dürst, M. (Matthias), Dworniczak, B. (Bernd), Eccles, D. (Diana), Edwards, T. (Todd), Eeles, R. (Rosalind), Eilber, U. (Ursula), Ejlertsen, B. (Bent), Ekici, A.B. (Arif), Ellis, S. (Steve), Elvira, M. (Mingajeva), Eng, K.H. (Kevin H.), Engel, C. (Christoph), Evans, D.G. (Gareth), Fasching, P.A. (Peter), Ferguson, S. (Sarah), Ferrer, S.F., Flanagan, J.M. (James), Fogarty, Z.C. (Zachary C.), Fortner, R.T. (Renée T.), Fostira, F. (Florentia), Foulkes, W.D. (William D.), Fountzilas, G. (George), Fridley, B.L. (Brooke), Friebel, M.O.W. (Mark ), Friedman, E. (Eitan), Frost, D. (Debra), Ganz, P.A. (Patricia), Garber, J. (Judy), García, M.J. (María J.), Garcia-Barberan, V. (Vanesa), Gehrig, P.A. (Paola A.), Gentry-Maharaj, A. (Aleksandra), Gerdes, A-M. (Anne-Marie), Giles, G.G. (Graham G.), Glasspool, R. (Rosalind), Glendon, G. (Gord), Godwin, A.K. (Andrew K.), Radice, P. (Paolo), Goranova, T. (Teodora), Gore, M. (Martin), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Gruber, S.B. (Stephen), Hahnen, E. (Eric), Haiman, C.A. (Christopher), Håkansson, N. (Niclas), Hamann, U. (Ute), Hansen, T.V.O. (Thomas V.O.), Harrington, P.A. (Patricia A.), Harris, H.R. (Holly), Hauke, J. (Jan), Hein, A. (Alexander), Henderson, A. (Alex), Hildebrandt, M.A.T. (Michelle A.T.), Hillemanns, P. (Peter), Hodgson, S. (Shirley), Høgdall, C.K. (Claus), Høgdall, E. (Estrid), Hogervorst, F.B.L. (Frans B. L.), Holland, H. (Helene), Hooning, M.J. (Maartje J.), Hosking, K. (Karen), Huang, R.-Y. (Ruea-Yea), Hulick, P.J. (Peter), Hung, J. (Jillian), Hunter, D.J. (David J.), Huntsman, D.G. (David G.), Huzarski, T. (Tomasz), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Iversen, E. (Erik), Izatt, L. (Louise), Izquierdo, A. (A.), Jakubowska, A. (Anna), James, P. (Paul), Janavicius, R. (Ramunas), Jernetz, M. (Mats), Jensen, A. (Allan), Jensen, U.B., John, E.M. (Esther), Johnatty, S.E. (Sharon), Jones, M.E. (Michael E.), Kannisto, P. (Päivi), Karlan, B.Y. (Beth), Karnezis, A. (Anthony), Kast, K. (Karin), Kennedy, C.J. (Catherine J.), Khusnutdinova, E.K. (Elza), Kiemeney, L.A.L.M. (Bart), Kiiski, J.I. (Johanna I.), Kim, S.-W. (Sung-Won), Kjaer, M. (Michael), Köbel, M. (Martin), Kopperud, R.K. (Reidun K.), Kruse, T.A. (Torben), Kupryjanczyk, J. (Jolanta), Kwong, A. (Ava), Laitman, Y. (Yael), Lambrechts, D. (Diether), Larrañaga, N. (Nerea), Larson, M.C. (Melissa), Lazaro, C. (Conxi), Le, N.D. (Nhu D.), Le Marchand, L. (Loic), Lee, J.W. (Jong Won), Lele, S.B. (Shashikant B.), Leminen, A. (Arto), Leroux, D. (Dominique), Lester, J. (Jenny), Lesueur, F. (Fabienne), Levine, D.A. (Douglas), Liang, D. (Dong), Liebrich, C. (Clemens), Lilyquist, J. (Jenna), Lipworth, L. (Loren), Lissowska, J. (Jolanta), Lu, K.H. (Karen), Lubinski, J. (Jan), Luccarini, C. (Craig), Lundvall, L. (Lene), Mai, P.L. (Phuong), Mendoza-Fandiño, G. (Gustavo), Manoukian, S. (Siranoush), Massuger, L.F. (Leon), May, T. (Taymaa), Mazoyer, S. (Sylvie), McAlpine, J.N. (Jessica N.), McGuire, V. (Valerie), McLaughlin, J. (John), McNeish, I. (Iain), Meijers-Heijboer, E.J. (Hanne), Meindl, A. (Alfons), Menon, U. (Usha), Mensenkamp, A.R. (Arjen R.), Merritt, M.A. (Melissa A.), Milne, R.L. (Roger), Mitchell, G. (Gillian), Modugno, F. (Francesmary), Moes-Sosnowska, J. (Joanna), Moffitt, M. (Melissa), Montagna, M. (Marco), Moysich, K.B. (Kirsten), Mulligan, A.M. (Anna Marie), Musinsky, J. (Jacob), Nathanson, K.L. (Katherine), Nedergaard, L. (Lotte), Ness, R.B. (Roberta), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Niederacher, D. (Dieter), Nussbaum, R. (Robert), Odunsi, K. (Kunle), Olah, E. (Edith), Olopade, O.I. (Olofunmilayo), Olsson, H. (Håkan), Olswold, C. (Curtis), O'Malley, D.M. (David M.), Ong, K.-R. (Kai-Ren), Onland-Moret, N.C. (Charlotte), Orr, N. (Nick), Orsulic, S. (Sandra), Osorio, A. (Ana), Palli, D. (Domenico), Papi, L. (Laura), Park-Simon, T.-W., Paul, J. (James), Pearce, C.L. (Celeste), Pedersen, I.S. (Inge Søkilde), Peeters, P.H.M., Peissel, B. (Bernard), Peixoto, A. (Ana), Pejovic, T. (Tanja), Pelttari, L.M. (Liisa M.), Permuth, J.B. (Jennifer B.), Peterlongo, P. (Paolo), Pezzani, L. (Lidia), Pfeiler, G. (Georg), Phillips, K.-A. (Kelly-Anne), Piedmonte, M. (Marion), Pike, M.C. (Malcolm), Piskorz, A.M. (Anna M.), Poblete, S.R. (Samantha R.), Pócza, T. (Tímea), Poole, E.M. (Elizabeth M.), Poppe, B. (Bruce), Porteous, M.E. (Mary), Prieur, F. (Fabienne), Prokofyeva, D. (Darya), Pugh, E. (Elizabeth), Pujana, M.A. (Miquel Angel), Pujol, P. (Pascal), Rantala, J. (Johanna), Rappaport-Fuerhauser, C. (Christine), Rennert, G. (Gad), Rhiem, K. (Kerstin), Rice, P. (Patricia), Richardson, A.L. (Andrea), Robson, M. (Mark), Rodriguez, G.C. (Gustavo), Rodríguez-Antona, C. (Cristina), Romm, J. (Jane), Rookus, M.A. (Matti), Rossing, M.A. (Mary Anne), Rothstein, J.H. (Joseph H.), Rudolph, A. (Anja), Runnebaum, I.B. (Ingo), Salvesen, H.B. (Helga), Sandler, D.P. (Dale P.), Schoemaker, M.J. (Minouk J.), Senter, L. (Leigha), Setiawan, V.W. (V. Wendy), Severi, G. (Gianluca), Sharma, P. (Priyanka), Shelford, T. (Tameka), Siddiqui, N. (Nadeem), Side, L. (Lucy), Sieh, W. (Weiva), Singer, C.F. (Christian), Sobol, H. (Hagay), Song, H. (Honglin), Southey, M.C. (Melissa), Spurdle, A.B. (Amanda), Stadler, Z. (Zsofia), Steinemann, D. (Doris), Stoppa-Lyonnet, D. (Dominique), Sucheston-Campbell, L.E. (Lara E.), Sukiennicki, G. (Grzegorz), Sutphen, R. (Rebecca), Sutter, C. (Christian), Swerdlow, A.J. (Anthony ), Szabo, C. (Csilla), Szafron, L. (Lukasz), Tan, Y.Y. (Yen Y.), Taylor, J.A. (Jack A.), Tea, M.-K., Teixeira, P.J., Teo, S.-H. (Soo-Hwang), Terry, K.L. (Kathryn L.), Thompson, P.J. (Pamela J.), Thomsen, L.C.V. (Liv Cecilie Vestrheim), Thull, D.L. (Darcy L.), Tihomirova, L. (Laima), Tinker, A.V. (Anna V.), Tischkowitz, M. (Marc), Tognazzo, S. (Silvia), Toland, A.E. (Amanda Ewart), Tone, A. (Alicia), Trabert, B. (Britton), Travis, S.P.L. (Simon), Trichopoulou, A. (Antonia), Tung, N. (Nadine), Tworoger, S. (Shelley), Van Altena, A.M. (Anne M.), Van Den Berg, D. (David), Van Der Hout, A.H. (Annemarie H.), Luijt, R.B. (Rob) van der, Van Heetvelde, M. (Mattias), Van Nieuwenhuysen, E. (Els), Rensburg, E.J. (Elizabeth) van, Vanderstichele, A. (Adriaan), Varon-Mateeva, R. (Raymonda), Vega, A. (Ana), Edwards, D.V. (Digna Velez), Vergote, I., Vierkant, R.A. (Robert), Vijai, J. (Joseph), Vratimos, A. (Athanassios), Walker, L.J. (Lisa), Walsh, C. (Christine), Wand, D. (Dorothea), Wang-Gohrke, S. (Shan), Wappenschmidt, B. (Barbara), Webb, P.M. (Penelope M.), Weinberg, C.R. (Clarice R.), Weitzel, J.N. (Jeffrey), Wentzensen, N. (N.), Whittemore, A.S. (Alice), Wijnen, J.T. (Juul), Wilkens, L.R. (Lynne), Wolk, K. (Kerstin), Woo, M. (Michelle), Wu, X. (Xifeng), Wu, A.H. (Anna), Yang, H.P. (Hannah), Yannoukakos, D. (Drakoulis), Ziogas, A. (Argyrios), Zorn, K.K. (Kristin K.), Narod, S.A. (Steven A.), Easton, D.F. (Douglas), Amos, W., Schildkraut, J.M. (Joellen), Ramus, S.J. (Susan), Ottini, L. (Laura), Goodman, M.T. (Marc), Park, S.K. (Sue K.), Kelemen, L.E. (Linda), Risch, H. (Harvey), Thomassen, M. (Mads), Offit, K. (Kenneth), Simard, J. (Jacques), Schmutzler, R.K. (Rita), Hazelett, D. (Dennis), Monteiro, A.N.A. (Alvaro N.), Couch, F.J. (Fergus), Berchuck, A. (Andrew), Chenevix-Trench, G. (Georgia), Goode, E.L. (Ellen), Sellers, T.F., Gayther, S.A. (Simon), Antoniou, A.C. (Antonis), Pharoah, P.D.P. (Paul), Phelan, C. (Catherine), Kuchenbaecker, K.B. (Karoline), Tyrer, J.P. (Jonathan P.), Kar, S.P. (Siddhartha P.), Lawrenson, K. (Kate), Winham, S.J. (Stacey J.), Dennis, J. (Joe), Pirie, A. (Ailith), Riggan, M.J. (Marjorie J.), Chornokur, G. (Ganna), Earp, M.A. (Madalene A.), Lyra, P.C. (Paulo C.), Lee, J.M. (Janet M.), Coetzee, S. (Simon), Beesley, J. (Jonathan), McGuffog, L. (Lesley), Soucy, P. (Penny), Dicks, E. (Ed), Lee, A. (Andrew), Barrowdale, D. (Daniel), Lecarpentier, J. (Julie), Leslie, G. (Goska), Aalfs, C.M. (Cora), Aben, K.K.H. (Katja), Adams, M. (Marcia), Adlard, J.W. (Julian), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Antonenkova, N. (Natalia), Aravantinos, G. (Gerasimos), Arnold, N. (Norbert), Arun, B.K. (Banu), Arver, B. (Brita), Azzollini, J., Balmana, J. (Judith), Banerjee, S. (Susana), Barjhoux, L. (Laure), Barkardottir, R.B. (Rosa B.), Bean, Y. (Yukie), Beckmann, M.W. (Matthias), Beeghly-Fadiel, A. (Alicia), Benítez, J. (Javier), Bermisheva, M. (Marina), Bernardini, M.Q. (Marcus Q.), Birrer, M.J. (Michael J.), Bjorge, L. (Line), Black, A., Blankstein, K. (Kenneth), Blok, M.J. (Marinus), Bodelon, C. (Clara), Bogdanova, N. (Natalia), Bojesen, A. (Anders), Bonanni, B. (Bernardo), Borg, Å. (Åke), Bradbury, A.R. (Angela R.), Brenton, J.D. (James D.), Brewer, C. (Carole), Brinton, L.A. (Louise), Broberg, P. (Per), Brooks-Wilson, A. (Angela), Bruinsma, F. (Fiona), Brunet, J. (Joan), Buecher, B. (Bruno), Butzow, R. (Ralf), Buys, S.S. (Saundra), Caldes, T. (Trinidad), Caligo, M.A. (Maria A.), Campbell, I. (Ian), Cannioto, R. (Rikki), Carney, M.E. (Michael), Cescon, T. (Terence), Chan, S. (Salina), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen), Chen, X.Q. (Xiao Qing), Chiew, Y.-E. (Yoke-Eng), Chiquette, J. (Jocelyne), Chung, W. (Wendy), Claes, K. (Kathleen), Conner, T. (Thomas), Cook, L.S. (Linda S.), Cook, J. (Jackie), Cramer, D.W. (Daniel), Cunningham, J.M. (Julie), D'Aloisio, A.A. (Aimee A.), Daly, M.B. (Mary), Damiola, F. (Francesca), Damirovna, S.D. (Sakaeva Dina), Dansonka-Mieszkowska, A. (Agnieszka), Dao, F. (Fanny), Davidson, R. (Rosemarie), DeFazio, A. (Anna), Delnatte, C.D. (Capucine), Doheny, K.F. (Kimberly), Díez, O. (Orland), Ding, Y.C. (Yuan Chun), Doherty, J.A. (Jennifer), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Dossus, L. (Laure), Duran, M. (Mercedes), Dürst, M. (Matthias), Dworniczak, B. (Bernd), Eccles, D. (Diana), Edwards, T. (Todd), Eeles, R. (Rosalind), Eilber, U. (Ursula), Ejlertsen, B. (Bent), Ekici, A.B. (Arif), Ellis, S. (Steve), Elvira, M. (Mingajeva), Eng, K.H. (Kevin H.), Engel, C. (Christoph), Evans, D.G. (Gareth), Fasching, P.A. (Peter), Ferguson, S. (Sarah), Ferrer, S.F., Flanagan, J.M. (James), Fogarty, Z.C. (Zachary C.), Fortner, R.T. (Renée T.), Fostira, F. (Florentia), Foulkes, W.D. (William D.), Fountzilas, G. (George), Fridley, B.L. (Brooke), Friebel, M.O.W. (Mark ), Friedman, E. (Eitan), Frost, D. (Debra), Ganz, P.A. (Patricia), Garber, J. (Judy), García, M.J. (María J.), Garcia-Barberan, V. (Vanesa), Gehrig, P.A. (Paola A.), Gentry-Maharaj, A. (Aleksandra), Gerdes, A-M. (Anne-Marie), Giles, G.G. (Graham G.), Glasspool, R. (Rosalind), Glendon, G. (Gord), Godwin, A.K. (Andrew K.), Radice, P. (Paolo), Goranova, T. (Teodora), Gore, M. (Martin), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Gruber, S.B. (Stephen), Hahnen, E. (Eric), Haiman, C.A. (Christopher), Håkansson, N. (Niclas), Hamann, U. (Ute), Hansen, T.V.O. (Thomas V.O.), Harrington, P.A. (Patricia A.), Harris, H.R. (Holly), Hauke, J. (Jan), Hein, A. (Alexander), Henderson, A. (Alex), Hildebrandt, M.A.T. (Michelle A.T.), Hillemanns, P. (Peter), Hodgson, S. (Shirley), Høgdall, C.K. (Claus), Høgdall, E. (Estrid), Hogervorst, F.B.L. (Frans B. L.), Holland, H. (Helene), Hooning, M.J. (Maartje J.), Hosking, K. (Karen), Huang, R.-Y. (Ruea-Yea), Hulick, P.J. (Peter), Hung, J. (Jillian), Hunter, D.J. (David J.), Huntsman, D.G. (David G.), Huzarski, T. (Tomasz), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Iversen, E. (Erik), Izatt, L. (Louise), Izquierdo, A. (A.), Jakubowska, A. (Anna), James, P. (Paul), Janavicius, R. (Ramunas), Jernetz, M. (Mats), Jensen, A. (Allan), Jensen, U.B., John, E.M. (Esther), Johnatty, S.E. (Sharon), Jones, M.E. (Michael E.), Kannisto, P. (Päivi), Karlan, B.Y. (Beth), Karnezis, A. (Anthony), Kast, K. (Karin), Kennedy, C.J. (Catherine J.), Khusnutdinova, E.K. (Elza), Kiemeney, L.A.L.M. (Bart), Kiiski, J.I. (Johanna I.), Kim, S.-W. (Sung-Won), Kjaer, M. (Michael), Köbel, M. (Martin), Kopperud, R.K. (Reidun K.), Kruse, T.A. (Torben), Kupryjanczyk, J. (Jolanta), Kwong, A. (Ava), Laitman, Y. (Yael), Lambrechts, D. (Diether), Larrañaga, N. (Nerea), Larson, M.C. (Melissa), Lazaro, C. (Conxi), Le, N.D. (Nhu D.), Le Marchand, L. (Loic), Lee, J.W. (Jong Won), Lele, S.B. (Shashikant B.), Leminen, A. (Arto), Leroux, D. (Dominique), Lester, J. (Jenny), Lesueur, F. (Fabienne), Levine, D.A. (Douglas), Liang, D. (Dong), Liebrich, C. (Clemens), Lilyquist, J. (Jenna), Lipworth, L. (Loren), Lissowska, J. (Jolanta), Lu, K.H. (Karen), Lubinski, J. (Jan), Luccarini, C. (Craig), Lundvall, L. (Lene), Mai, P.L. (Phuong), Mendoza-Fandiño, G. (Gustavo), Manoukian, S. (Siranoush), Massuger, L.F. (Leon), May, T. (Taymaa), Mazoyer, S. (Sylvie), McAlpine, J.N. (Jessica N.), McGuire, V. (Valerie), McLaughlin, J. (John), McNeish, I. (Iain), Meijers-Heijboer, E.J. (Hanne), Meindl, A. (Alfons), Menon, U. (Usha), Mensenkamp, A.R. (Arjen R.), Merritt, M.A. (Melissa A.), Milne, R.L. (Roger), Mitchell, G. (Gillian), Modugno, F. (Francesmary), Moes-Sosnowska, J. (Joanna), Moffitt, M. (Melissa), Montagna, M. (Marco), Moysich, K.B. (Kirsten), Mulligan, A.M. (Anna Marie), Musinsky, J. (Jacob), Nathanson, K.L. (Katherine), Nedergaard, L. (Lotte), Ness, R.B. (Roberta), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Niederacher, D. (Dieter), Nussbaum, R. (Robert), Odunsi, K. (Kunle), Olah, E. (Edith), Olopade, O.I. (Olofunmilayo), Olsson, H. (Håkan), Olswold, C. (Curtis), O'Malley, D.M. (David M.), Ong, K.-R. (Kai-Ren), Onland-Moret, N.C. (Charlotte), Orr, N. (Nick), Orsulic, S. (Sandra), Osorio, A. (Ana), Palli, D. (Domenico), Papi, L. (Laura), Park-Simon, T.-W., Paul, J. (James), Pearce, C.L. (Celeste), Pedersen, I.S. (Inge Søkilde), Peeters, P.H.M., Peissel, B. (Bernard), Peixoto, A. (Ana), Pejovic, T. (Tanja), Pelttari, L.M. (Liisa M.), Permuth, J.B. (Jennifer B.), Peterlongo, P. (Paolo), Pezzani, L. (Lidia), Pfeiler, G. (Georg), Phillips, K.-A. (Kelly-Anne), Piedmonte, M. (Marion), Pike, M.C. (Malcolm), Piskorz, A.M. (Anna M.), Poblete, S.R. (Samantha R.), Pócza, T. (Tímea), Poole, E.M. (Elizabeth M.), Poppe, B. (Bruce), Porteous, M.E. (Mary), Prieur, F. (Fabienne), Prokofyeva, D. (Darya), Pugh, E. (Elizabeth), Pujana, M.A. (Miquel Angel), Pujol, P. (Pascal), Rantala, J. (Johanna), Rappaport-Fuerhauser, C. (Christine), Rennert, G. (Gad), Rhiem, K. (Kerstin), Rice, P. (Patricia), Richardson, A.L. (Andrea), Robson, M. (Mark), Rodriguez, G.C. (Gustavo), Rodríguez-Antona, C. (Cristina), Romm, J. (Jane), Rookus, M.A. (Matti), Rossing, M.A. (Mary Anne), Rothstein, J.H. (Joseph H.), Rudolph, A. (Anja), Runnebaum, I.B. (Ingo), Salvesen, H.B. (Helga), Sandler, D.P. (Dale P.), Schoemaker, M.J. (Minouk J.), Senter, L. (Leigha), Setiawan, V.W. (V. Wendy), Severi, G. (Gianluca), Sharma, P. (Priyanka), Shelford, T. (Tameka), Siddiqui, N. (Nadeem), Side, L. (Lucy), Sieh, W. (Weiva), Singer, C.F. (Christian), Sobol, H. (Hagay), Song, H. (Honglin), Southey, M.C. (Melissa), Spurdle, A.B. (Amanda), Stadler, Z. (Zsofia), Steinemann, D. (Doris), Stoppa-Lyonnet, D. (Dominique), Sucheston-Campbell, L.E. (Lara E.), Sukiennicki, G. (Grzegorz), Sutphen, R. (Rebecca), Sutter, C. (Christian), Swerdlow, A.J. (Anthony ), Szabo, C. (Csilla), Szafron, L. (Lukasz), Tan, Y.Y. (Yen Y.), Taylor, J.A. (Jack A.), Tea, M.-K., Teixeira, P.J., Teo, S.-H. (Soo-Hwang), Terry, K.L. (Kathryn L.), Thompson, P.J. (Pamela J.), Thomsen, L.C.V. (Liv Cecilie Vestrheim), Thull, D.L. (Darcy L.), Tihomirova, L. (Laima), Tinker, A.V. (Anna V.), Tischkowitz, M. (Marc), Tognazzo, S. (Silvia), Toland, A.E. (Amanda Ewart), Tone, A. (Alicia), Trabert, B. (Britton), Travis, S.P.L. (Simon), Trichopoulou, A. (Antonia), Tung, N. (Nadine), Tworoger, S. (Shelley), Van Altena, A.M. (Anne M.), Van Den Berg, D. (David), Van Der Hout, A.H. (Annemarie H.), Luijt, R.B. (Rob) van der, Van Heetvelde, M. (Mattias), Van Nieuwenhuysen, E. (Els), Rensburg, E.J. (Elizabeth) van, Vanderstichele, A. (Adriaan), Varon-Mateeva, R. (Raymonda), Vega, A. (Ana), Edwards, D.V. (Digna Velez), Vergote, I., Vierkant, R.A. (Robert), Vijai, J. (Joseph), Vratimos, A. (Athanassios), Walker, L.J. (Lisa), Walsh, C. (Christine), Wand, D. (Dorothea), Wang-Gohrke, S. (Shan), Wappenschmidt, B. (Barbara), Webb, P.M. (Penelope M.), Weinberg, C.R. (Clarice R.), Weitzel, J.N. (Jeffrey), Wentzensen, N. (N.), Whittemore, A.S. (Alice), Wijnen, J.T. (Juul), Wilkens, L.R. (Lynne), Wolk, K. (Kerstin), Woo, M. (Michelle), Wu, X. (Xifeng), Wu, A.H. (Anna), Yang, H.P. (Hannah), Yannoukakos, D. (Drakoulis), Ziogas, A. (Argyrios), Zorn, K.K. (Kristin K.), Narod, S.A. (Steven A.), Easton, D.F. (Douglas), Amos, W., Schildkraut, J.M. (Joellen), Ramus, S.J. (Susan), Ottini, L. (Laura), Goodman, M.T. (Marc), Park, S.K. (Sue K.), Kelemen, L.E. (Linda), Risch, H. (Harvey), Thomassen, M. (Mads), Offit, K. (Kenneth), Simard, J. (Jacques), Schmutzler, R.K. (Rita), Hazelett, D. (Dennis), Monteiro, A.N.A. (Alvaro N.), Couch, F.J. (Fergus), Berchuck, A. (Andrew), Chenevix-Trench, G. (Georgia), Goode, E.L. (Ellen), Sellers, T.F., Gayther, S.A. (Simon), Antoniou, A.C. (Antonis), and Pharoah, P.D.P. (Paul)
- Abstract
To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
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- 2017
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17. Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci
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Kar, SP, Adler, E, Tyrer, J, Hazelett, D, Anton-Culver, H, Bandera, EV, Beckmann, MW, Berchuck, A, Bogdanova, N, Brinton, L, Butzow, R, Campbell, I, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Dansonka-Mieszkowska, A, Doherty, JA, Doerk, T, Duerst, M, Eccles, D, Fasching, PA, Flanagan, J, Gentry-Maharaj, A, Glasspool, R, Goode, EL, Goodman, MT, Gronwald, J, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Huntsman, DG, Jensen, A, Karlan, BY, Kelemen, LE, Kiemeney, LA, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Levine, DA, Li, Q, Lissowska, J, Lu, KH, Lubinski, J, Massuger, LFAG, McGuire, V, McNeish, I, Menon, U, Modugno, F, Monteiro, AN, Moysich, KB, Ness, RB, Nevanlinna, H, Paul, J, Pearce, CL, Pejovic, T, Permuth, JB, Phelan, C, Pike, MC, Poole, EM, Ramus, SJ, Risch, HA, Rossing, MA, Salvesen, HB, Schildkraut, JM, Sellers, TA, Sherman, M, Siddiqui, N, Sieh, W, Song, H, Southey, M, Terry, KL, Tworoger, SS, Walsh, C, Wentzensen, N, Whittemore, AS, Wu, AH, Yang, H, Zheng, W, Ziogas, A, Freedman, ML, Gayther, SA, Pharoah, PDP, Lawrenson, K, Kar, SP, Adler, E, Tyrer, J, Hazelett, D, Anton-Culver, H, Bandera, EV, Beckmann, MW, Berchuck, A, Bogdanova, N, Brinton, L, Butzow, R, Campbell, I, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Dansonka-Mieszkowska, A, Doherty, JA, Doerk, T, Duerst, M, Eccles, D, Fasching, PA, Flanagan, J, Gentry-Maharaj, A, Glasspool, R, Goode, EL, Goodman, MT, Gronwald, J, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Huntsman, DG, Jensen, A, Karlan, BY, Kelemen, LE, Kiemeney, LA, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Levine, DA, Li, Q, Lissowska, J, Lu, KH, Lubinski, J, Massuger, LFAG, McGuire, V, McNeish, I, Menon, U, Modugno, F, Monteiro, AN, Moysich, KB, Ness, RB, Nevanlinna, H, Paul, J, Pearce, CL, Pejovic, T, Permuth, JB, Phelan, C, Pike, MC, Poole, EM, Ramus, SJ, Risch, HA, Rossing, MA, Salvesen, HB, Schildkraut, JM, Sellers, TA, Sherman, M, Siddiqui, N, Sieh, W, Song, H, Southey, M, Terry, KL, Tworoger, SS, Walsh, C, Wentzensen, N, Whittemore, AS, Wu, AH, Yang, H, Zheng, W, Ziogas, A, Freedman, ML, Gayther, SA, Pharoah, PDP, and Lawrenson, K
- Abstract
BACKGROUND: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. METHODS: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). RESULTS: The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10-5 (including six with P<5 × 10-8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. CONCLUSIONS: Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.
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- 2017
18. Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia
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Gu, F, Zhang, H, Hyland, PL, Berndt, S, Gapstur, SM, Wheeler, W, Amos, CI, Bezieau, S, Bickeboller, H, Brenner, H, Brennan, P, Chang-Claude, J, Conti, DV, Doherty, JA, Gruber, SB, Harrison, TA, Hayes, RB, Hoffmeister, M, Houlston, RS, Hung, RJ, Jenkins, MA, Kraft, P, Lawrenson, K, Mckay, J, Markt, S, Mucci, L, Phelan, CM, Qu, C, Risch, A, Rossing, MA, Wichmann, H-E, Shi, J, Schernhammer, E, Yu, K, Landi, MT, Caporaso, NE, Gu, F, Zhang, H, Hyland, PL, Berndt, S, Gapstur, SM, Wheeler, W, Amos, CI, Bezieau, S, Bickeboller, H, Brenner, H, Brennan, P, Chang-Claude, J, Conti, DV, Doherty, JA, Gruber, SB, Harrison, TA, Hayes, RB, Hoffmeister, M, Houlston, RS, Hung, RJ, Jenkins, MA, Kraft, P, Lawrenson, K, Mckay, J, Markt, S, Mucci, L, Phelan, CM, Qu, C, Risch, A, Rossing, MA, Wichmann, H-E, Shi, J, Schernhammer, E, Yu, K, Landi, MT, and Caporaso, NE
- Abstract
Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (ppathway < 0.00625). The two most significant genes were NPAS2 (pgene = 0.0062) and AANAT (pgene = 0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (ppathway = 0.021); this association was not confirmed in GECCO (ppathway = 0.76) or the combined data (ppathway = 0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms.
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- 2017
19. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
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Lawrenson, K, Kar, S, McCue, K, Kuchenbaeker, K, Michailidou, K, Tyrer, J, Beesley, J, Ramus, SJ, Li, Q, Delgado, MK, Lee, JM, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arun, BK, Arver, B, Bandera, EV, Barile, M, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Benitez, J, Berchuck, A, Bisogna, M, Bjorge, L, Blomqvist, C, Blot, W, Bogdanova, N, Bojesen, A, Bojesen, SE, Bolla, MK, Bonanni, B, Børresen-Dale, AL, Brauch, H, Brennan, P, Brenner, H, Bruinsma, F, Brunet, J, Buhari, SA, Burwinkel, B, Butzow, R, Buys, SS, Cai, Q, Caldes, T, Campbell, I, Canniotto, R, Chang-Claude, J, Chiquette, J, Choi, JY, Claes, KBM, Cook, LS, Cox, A, Cramer, DW, Cross, SS, Cybulski, C, Czene, K, Daly, MB, Damiola, F, Dansonka-Mieszkowska, A, Darabi, H, Dennis, J, Devilee, P, Diez, O, Doherty, JA, Domchek, SM, Dorfling, CM, Dörk, T, Dumont, M, Ehrencrona, H, Ejlertsen, B, Ellis, S, Engel, C, Lee, E, Evans, DG, Fasching, PA, Feliubadalo, L, Figueroa, J, and Flesch-Janys, D
- Abstract
© 2016 The Author(s). A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P
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- 2016
20. Functional Mechanisms Underlying Pleiotropic Risk Alleles At The 19p13.1 Breast-Ovarian Cancer Susceptibility Locus
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Lawrenson, K. and Cox, A.
- Abstract
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we\ud analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation\ud carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous\ud OC (P ¼ 9.2 10 20), ER-negative BC (P ¼ 1.1 10 13), BRCA1-associated BC (P ¼ 7.7\ud 10 16) and triple negative BC (P-diff ¼ 2 10 5). Genotype-gene expression associations\ud are identified for candidate target genes ANKLE1 (P ¼ 2 10 3) and ABHD8 (Po2 10 3).\ud Chromosome conformation capture identifies interactions between four candidate SNPs and\ud ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8\ud promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative\ud enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional\ud effects for an ANKLE1 30\ud -UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13\ud regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms\ud underlying breast and ovarian cancer risk.\ud Correspond
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- 2016
21. Genome-wide meta-analyses of breast, ovarian, and prostate cancer association studies identify multiple new susceptibility loci shared by at least two cancer types
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Kar, SP, Beesley, J, Al Olama, AA, Michailidou, K, Tyrer, J, Kote-Jarai, ZA, Lawrenson, K, Lindstrom, S, Ramus, SJ, Thompson, DJ, Kibel, AS, Dansonka-Mieszkowska, A, Michael, A, Dieffenbach, AK, Gentry-Maharaj, A, Whittemore, AS, Wolk, A, Monteiro, A, Peixoto, A, Kierzek, A, Cox, A, Rudolph, A, Gonzalez-Neira, A, Wu, AH, Lindblom, A, Swerdlow, A, Ziogas, A, Ekici, AB, Burwinkel, B, Karlan, BY, Nordestgaard, BG, Blomqvist, C, Phelan, C, McLean, C, Pearce, CL, Vachon, C, Cybulski, C, Slavov, C, Stegmaier, C, Maier, C, Ambrosone, CB, Hogdall, CK, Teerlink, CC, Kang, D, Tessier, DC, Schaid, DJ, Stram, DO, Cramer, DW, Neal, DE, Eccles, D, Flesch-Janys, D, Velez Edwards, DR, Wokozorczyk, D, Levine, DA, Yannoukakos, D, Sawyer, EJ, Bandera, EV, Poole, EM, Goode, EL, Khusnutdinova, E, Hogdall, E, Song, F, Bruinsma, F, Heitz, F, Modugno, F, Hamdy, FC, Wiklund, F, Giles, GG, Olsson, H, Wildiers, H, and Ulmer, HU
- Abstract
© 2016 American Association for Cancer Research. Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/ BCL2L11; rs7937840/11q12/ INCENP; rs1469713/19p13/ GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/ SMC2; rs8037137/15q26/ RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/ NSUN4; rs9375701/6q23/ L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10−5 in the three-cancer meta-analysis. SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers.
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- 2016
22. Sphingosine kinase 1 is required for TGF-beta mediated fibroblast-to-myofibroblast differentiation in ovarian cancer
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Beach, JA, Aspuria, P-JP, Cheon, D-J, Lawrenson, K, Agadjanian, H, Walsh, CS, Karlan, BY, and Orsulic, S
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cancer-associated fibroblast (CAF) ,sphingosine kinase 1 (SPHK1) ,sphingosine-1-phosphate (S1P) ,microenvironment ,transforming growth factor-beta 1 (TGF-beta 1) - Published
- 2016
23. Genome-wide significant associations of common low penetrance single nucleotide polymorphisms with risk of mucinous ovarian carcinoma
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Berchuck, A., primary, Tyrer, J., additional, Kelemen, L., additional, Phelan, C., additional, Pearce, C.L., additional, Moysich, K., additional, Lawrenson, K., additional, Schildkraut, J.M., additional, Sellers, T., additional, Goode, E., additional, Gayther, S., additional, and Pharoah, P.D.P., additional
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- 2017
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24. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer
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Lawrenson, K, Li, Q, Kar, S, Seo, JH, Tyrer, J, Spindler, TJ, Lee, J, Chen, Y, Karst, A, Drapkin, R, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bandera, EV, Bean, Y, Beckmann, MW, Berchuck, A, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chenevix-Trench, G, Chen, A, Chen, Z, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, Du Bois, A, Dürst, M, Eccles, D, Easton, DT, Edwards, RP, Eilber, U, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goode, EL, Goodman, MT, Grownwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, E, Hogdall, C, Hosono, S, Iversen, ES, Jakubowska, A, James, P, Jensen, A, Ji, BT, Karlan, BY, Kjaer, SK, Kelemen, LE, Kellar, M, Kelley, JL, Kiemeney, LA, Krakstad, C, Kupryjanczyk, J, and Lambrechts, D
- Abstract
© 2015 Macmillan Publishers Limited. All rights reserved. Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10-5). For three cis-eQTL associations (P
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- 2015
25. Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci
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Coetzee, SG, Shen, HC, Hazelett, DJ, Lawrenson, K, Kuchenbaecker, K, Tyrer, J, Rhie, SK, Levanon, K, Karst, A, Drapkin, R, Ramus, SJ, Couch, FJ, Offit, K, Chenevix-Trench, G, Monteiro, ANA, Antoniou, A, Freedman, M, Coetzee, GA, Pharoah, PDP, Noushmehr, H, Gayther, SA, Anton-Culver, H, Antonenkova, N, Baker, H, Bandera, EV, Bean, Y, Beckmann, MW, Berchuck, A, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chen, A, Chen, Z, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, Bois, AD, Dürst, M, Eccles, D, Easton, DF, Edwards, RP, Eilber, U, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goode, EL, Goodman, MT, Grownwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, E, Hogdall, C, Hosono, S, Iversen, ES, Jakubowska, A, James, P, Jensen, A, Ji, BT, Karlan, BY, Kjaer, SK, Kelemen, LE, Kellar, M, Kelley, JL, Kiemeney, LA, Krakstad, C, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lele, S, Leminen, A, and Lester, J
- Abstract
© The Author 2015. Published by Oxford University Press. All rights reserved. Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most singlenucleotide polymorphisms (SNPs) associated with cancer risk lie in non-protein-coding regions, implicating regulatory DNA elements as functional targets of susceptibility variants. Here, we describe genome-wide annotation of regions of open chromatin and histone modification in fallopian tube and ovarian surface epithelial cells (FTSECs, OSECs), the debated cellular origins of high-grade serous ovarian cancers (HGSOCs) and in endometriosis epithelial cells (EECs), the likely precursor of clear cell ovarian carcinomas (CCOCs). The regulatory architecture of these cell types was compared with normal human mammary epithelial cells and LNCaP prostate cancer cells. We observed similar positional patterns of global enhancer signatures across the three different ovarian cancer precursor cell types, and evidence of tissue-specific regulatory signatures compared to nongynecological cell types. We found significant enrichment for risk-associated SNPs intersecting regulatory biofeatures at 17 known HGSOC susceptibility loci in FTSECs (P = 3.8 × 10-30), OSECs (P = 2.4 × 10-23) and HMECs (P = 6.7 × 10-15) but not for EECs (P = 0.45) or LNCaP cells (P = 0.88). Hierarchical clustering of risk SNPs conditioned on the six different cell types indicates FTSECs and OSECs are highly related (96% of samples using multi-scale bootstrapping) suggesting both cell types may be precursors of HGSOC. These data represent the first description of regulatory catalogues of normal precursor cells for different ovarian cancer subtypes, and provide unique insights into the tissue specific regulatory variation with respect to the likely functional targets of germline genetic susceptibility variants for ovarian cancer.
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- 2015
26. Common genetic variation in cellular transport genes and epithelial ovarian cancer (EOC) risk
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Chornokur, G, Lin, HY, Tyrer, JP, Lawrenson, K, Dennis, J, Amankwah, EK, Qu, X, Tsai, YY, Jim, HSL, Chen, Z, Chen, AY, Permuth-Wey, J, Aben, KKH, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Du Bois, A, Despierre, E, Dicks, E, Doherty, JA, Dörk, T, Dürst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harrington, P, Harter, P, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono, S, Jakubowska, A, Jensen, A, Ji, BT, Karlan, BY, Kelemen, LE, Kellar, M, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, and Lester, J
- Abstract
© 2015 Chornokur et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. Methods: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q-4). Conclusion: These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.
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- 2015
27. Genome-wide significant risk associations for mucinous ovarian carcinoma
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Kelemen, LE, Lawrenson, K, Tyrer, J, Li, Q, Lee, JM, Seo, JH, Phelan, CM, Beesley, J, Chen, X, Spindler, TJ, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bandera, EV, Bean, Y, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chen, YA, Chen, Z, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, Bois, AD, Dürst, M, Eccles, D, Easton, DT, Edwards, RP, Eilber, U, Ekici, AB, Engelholm, SA, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goode, EL, Goodman, MT, Grownwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, E, Hogdall, C, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, BT, Karlan, BY, Kellar, M, Kelley, JL, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, and Le, ND
- Abstract
© 2015 Nature America, Inc. All rights reserved. Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10-8), rs711830 at 2q31.1 (P = 7.5 × 10-12) and rs688187 at 19q13.2 (P = 6.8 × 10-13). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10-4, false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.
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- 2015
28. Network-based integration of GWAS and gene expression identifies a HOX-centric network associated with serous ovarian cancer risk
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Kar, SP, Tyrer, JP, Li, Q, Lawrenson, K, Aben, KKH, Anton-Culver, H, Antonenkova, N, Chenevix-Trench, G, Baker, H, Bandera, EV, Bean, YT, Beckmann, MW, Berchuck, A, Bisogna, M, Bjørge, L, Bogdanova, N, Brinton, L, Brooks-Wilson, A, Butzow, R, Campbell, I, Carty, K, Chang-Claude, J, Chen, YA, Chen, Z, Cook, LS, Cramer, D, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, Du Bois, A, Dürst, M, Eccles, D, Easton, DF, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goode, EL, Goodman, MT, Grownwald, J, Harrington, P, Harter, P, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, E, Hogdall, CK, Hosono, S, Iversen, ES, Jakubowska, A, Paul, J, Jensen, A, Ji, BT, Karlan, BY, Kjaer, SK, Kelemen, LE, Kellar, M, Kelley, J, Kiemeney, LA, Krakstad, C, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, and Liang, D
- Subjects
endocrine system diseases ,female genital diseases and pregnancy complications - Abstract
© 2015 American Association for Cancer Research. Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.
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- 2015
29. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types
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Kar, S.P., Beesley, J., Olama, A. Amin Al, Michailidou, K., Tyrer, J., Kote-Jarai, Z., Lawrenson, K., Lindstrom, S., Ramus, S.J., Thompson, D.J., Kibel, A.S., Dansonka-Mieszkowska, A., Michael, A., Dieffenbach, A.K., Gentry-Maharaj, A., Whittemore, A.S., Wolk, A., Monteiro, A., Peixoto, A., Kierzek, A., Cox, A, Rudolph, A., Gonzalez-Neira, A., Wu, A.H., Lindblom, A., Swerdlow, A., Ziogas, A., Ekici, A.B., Burwinkel, B., Karlan, B.Y., Nordestgaard, B.G., Blomqvist, C., Phelan, C., McLean, C., Pearce, C.L., Vachon, C., Cybulski, C., Slavov, C., Stegmaier, C., Maier, C., Ambrosone, C.B., Hogdall, C.K., Teerlink, C.C., Kang, D., Tessier, D.C., Schaid, D.J., Stram, D.O., Cramer, D.W, Neal, D.E., Eccles, D., Flesch-Janys, D., Edwards, D.R., Wokozorczyk, D., Levine, D.A., Yannoukakos, D., Sawyer, E.J., Bandera, E.V., Poole, E.M., Goode, E.L., Khusnutdinova, E., Hogdall, E., Song, F., Bruinsma, F., Heitz, F., Modugno, F., Hamdy, F.C., Wiklund, F., Giles, G.G., Olsson, H., Wildiers, H., Ulmer, H.U., Pandha, H., Risch, H.A., Darabi, H., Salvesen, H.B., Nevanlinna, H., Gronberg, H., Brenner, H., Brauch, H., Anton-Culver, H., Song, H., Lim, H.Y., McNeish, I., Campbell, I., Vergote, I., Gronwald, J., Lubinski, J., Stanford, J.L., Benitez, J., Doherty, J.A., Permuth, J.B., Chang-Claude, J., Donovan, J.L., Dennis, J., Schildkraut, J.M., Schleutker, J., Hopper, J.L., Kupryjanczyk, J., Park, J.Y., Figueroa, J., Kiemeney, L.A., Massuger, L.F.A.G., et al., Kar, S.P., Beesley, J., Olama, A. Amin Al, Michailidou, K., Tyrer, J., Kote-Jarai, Z., Lawrenson, K., Lindstrom, S., Ramus, S.J., Thompson, D.J., Kibel, A.S., Dansonka-Mieszkowska, A., Michael, A., Dieffenbach, A.K., Gentry-Maharaj, A., Whittemore, A.S., Wolk, A., Monteiro, A., Peixoto, A., Kierzek, A., Cox, A, Rudolph, A., Gonzalez-Neira, A., Wu, A.H., Lindblom, A., Swerdlow, A., Ziogas, A., Ekici, A.B., Burwinkel, B., Karlan, B.Y., Nordestgaard, B.G., Blomqvist, C., Phelan, C., McLean, C., Pearce, C.L., Vachon, C., Cybulski, C., Slavov, C., Stegmaier, C., Maier, C., Ambrosone, C.B., Hogdall, C.K., Teerlink, C.C., Kang, D., Tessier, D.C., Schaid, D.J., Stram, D.O., Cramer, D.W, Neal, D.E., Eccles, D., Flesch-Janys, D., Edwards, D.R., Wokozorczyk, D., Levine, D.A., Yannoukakos, D., Sawyer, E.J., Bandera, E.V., Poole, E.M., Goode, E.L., Khusnutdinova, E., Hogdall, E., Song, F., Bruinsma, F., Heitz, F., Modugno, F., Hamdy, F.C., Wiklund, F., Giles, G.G., Olsson, H., Wildiers, H., Ulmer, H.U., Pandha, H., Risch, H.A., Darabi, H., Salvesen, H.B., Nevanlinna, H., Gronberg, H., Brenner, H., Brauch, H., Anton-Culver, H., Song, H., Lim, H.Y., McNeish, I., Campbell, I., Vergote, I., Gronwald, J., Lubinski, J., Stanford, J.L., Benitez, J., Doherty, J.A., Permuth, J.B., Chang-Claude, J., Donovan, J.L., Dennis, J., Schildkraut, J.M., Schleutker, J., Hopper, J.L., Kupryjanczyk, J., Park, J.Y., Figueroa, J., Kiemeney, L.A., Massuger, L.F.A.G., and et al.
- Abstract
Contains fulltext : 172624.pdf (publisher's version ) (Closed access), Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis. SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. (c)2016 AACR.This article is highlighted in the In This Issue feature, p. 932.
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- 2016
30. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
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Lawrenson, K. (Kate), Kar, S. (Siddhartha), McCue, K. (Karen), Kuchenbaeker, K. (Karoline), Michailidou, K. (Kyriaki), Tyrer, J.P. (Jonathan), Beesley, J. (Jonathan), Ramus, S.J. (Susan), Li, Q. (Qiyuan), Delgado, M.K. (Melissa K.), Lee, J.M. (Janet M.), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Arun, B.K. (Banu), Arver, B. (Brita Wasteson), Bandera, E.V. (Elisa), Barile, M. (Monica), Barkardottir, R.B. (Rosa B.), Barrowdale, D. (Daniel), Beckmann, M.W. (Matthias), Benítez, J. (Javier), Berchuck, A. (Andrew), Bisogna, M. (Maria), Bjorge, L. (Line), Blomqvist, C. (Carl), Blot, W.J. (William), Bogdanova, N.V. (Natalia), Bojesen, A. (Anders), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet K.), Bonnani, B. (Bernardo), Borresen-Dale, A.-L. (Anne-Lise), Brauch, H. (Hiltrud), Brennan, P. (Paul), Brenner, H. (Hermann), Bruinsma, F. (Fiona), Brunet, J. (Joan), Buhari, S.A.B.S. (Shaik Ahmad Bin Syed), Burwinkel, B. (Barbara), Butzow, R. (Ralf), Buys, S.S. (Saundra), Cai, Q. (Qiuyin), Caldes, T. (Trinidad), Campbell, I. (Ian), Canniotto, R. (Rikki), Chang-Claude, J. (Jenny), Chiquette, J. (Jocelyne), Choi, J.-Y. (Ji-Yeob), Claes, K.B.M. (Kathleen B.M.), Cook, L.S. (Linda S.), Cox, A. (Angela), Cramer, D.W. (Daniel), Cross, S.S. (Simon), Cybulski, C. (Cezary), Czene, K. (Kamila), Daly, M.B. (Mary B.), Damiola, F. (Francesca), Dansonka-Mieszkowska, A. (Agnieszka), Darabi, H. (Hatef), Dennis, J. (Joe), Devilee, P. (Peter), Díez, O. (Orland), Doherty, J.A. (Jennifer A.), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Dumont, M. (Martine), Ehrencrona, H. (Hans), Ejlertsen, B. (Bent), Ellis, S.D. (Steve), Engel, C. (Christoph), Lee, E. (Eunjung), Evans, D.G. (D. Gareth), Fasching, P.A. (Peter), Feliubadaló, L. (L.), Figueroa, J.D. (Jonine), Flesch-Janys, D. (Dieter), Fletcher, O. (Olivia), Flyger, H. (Henrik), Foretova, L. (Lenka), Fostira, F. (Florentia), Foulkes, W.D. (William), Fridley, B.L. (Brooke), Friedman, E. (Eitan), Frost, D. (Debra), Gambino, G. (Gaetana), Ganz, P.A. (Patricia A.), Garber, J. (Judy), García-Closas, M. (Montserrat), Gentry-Maharaj, A. (Aleksandra), Ghoussaini, M. (Maya), Giles, G.G. (Graham), Glasspool, R. (Rosalind), Godwin, A.K. (Andrew K.), Goldberg, M.S. (Mark), Goldgar, D. (David), González-Neira, A. (Anna), Goode, E.L. (Ellen), Goodman, M.T. (Marc), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Guénel, P. (Pascal), Haiman, C.A. (Christopher A.), Hall, P. (Per), Hallberg, E. (Emily), Hamann, U. (Ute), Hansen, T.V.O. (Thomas), harrington, P. (Patricia), Hartman, J.M. (Joost), Hassan, N. (Norhashimah), Healey, S. (Sue), Heitz, P.U., Herzog, J. (Josef), Høgdall, E. (Estrid), Høgdall, C.K. (Claus), Hogervorst, F.B.L. (Frans), Hollestelle, A. (Antoinette), Hopper, J.L. (John), Hulick, P.J. (Peter), Huzarski, T. (Tomasz), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Ito, H. (Hidemi), Jakubowska, A. (Anna), Janavicius, R. (Ramunas), Jensen, A. (Allan), John, E.M. (Esther), Johnson, N. (Nichola), Kabisch, M. (Maria), Kang, D. (Daehee), Kapuscinski, M.K. (Miroslav K.), Karlan, B.Y. (Beth Y.), Khan, S. (Sofia), Kiemeney, L.A.L.M. (Bart), Kjaer, M. (Michael), Knight, J.A. (Julia), Konstantopoulou, I. (I.), Kosma, V-M. (Veli-Matti), Kristensen, V. (Vessela), Kupryjanczyk, J. (Jolanta), Kwong, A. (Ava), Hoya, M. (Miguel) de La, Laitman, Y. (Yael), Lambrechts, D. (Diether), Le, N.D. (Nhu D.), De Leeneer, K. (Kim), Lester, K.J. (Kathryn), Levine, D.A. (Douglas), Li, J. (Jingmei), Lindblom, A. (Annika), Long, J. (Jirong), Lophatananon, A. (Artitaya), Loud, J.T. (Jennifer), Lu, K.H. (Karen), Lubinski, J. (Jan), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Le Marchand, L. (Loic), Margolin, S. (Sara), Marme, F. (Frederick), Massuger, L.F. (Leon), Matsuo, K. (Keitaro), Mazoyer, S. (Sylvie), McGuffog, L. (Lesley), McLean, C.A. (Catriona Ann), McNeish, I. (Iain), Meindl, A. (Alfons), Menon, U. (Usha), Mensenkamp, A.R. (Arjen R.), Milne, R.L. (Roger), Montagna, M. (Marco), Moysich, K.B. (Kirsten), Muir, K.R. (K.), Mulligan, A.-M. (Anna-Marie), Nathanson, K.L. (Katherine), Ness, R.B. (Roberta), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Nord, S. (Silje), Nussbaum, R.L. (Robert L.), Odunsi, K. (Kunle), Offit, K. (Kenneth), Olah, E., Olopade, O.I. (Olufunmilayo I.), Olson, J.E. (Janet), Olswold, C. (Curtis), O'Malley, D.M. (David M.), Orlow, I. (Irene), Orr, N. (Nick), Osorio, A. (Ana), Park, S.K. (Sue Kyung), Pearce, C.L. (Celeste), Pejovic, T. (Tanja), Peterlongo, P. (Paolo), Pfeiler, G. (Georg), Phelan, C. (Catherine), Poole, E.M. (Elizabeth), Pykäs, K. (Katri), Radice, P. (Paolo), Rantala, J. (Johanna), Rashid, M.U. (Muhammad), Rennert, G. (Gad), Rhenius, V. (Valerie), Rhiem, K. (Kerstin), Risch, H. (Harvey), Rodriguez, G.C. (Gustavo), Rossing, M.A. (Mary Anne), Rudolph, A. (Anja), Salvesen, H.B. (Helga), Sangrajrang, S. (Suleeporn), Sawyer, E.J. (Elinor J.), Schildkraut, J.M. (Joellen), Schmidt, M.K. (Marjanka), Schmutzler, R.K. (Rita), Sellers, T.A. (Thomas A.), Seynaeve, C.M. (Caroline), Shah, M. (Mitul), Shen, C.-Y. (Chen-Yang), Shu, X.-O. (Xiao-Ou), Sieh, W. (Weiva), Singer, C.F. (Christian), Sinilnikova, O. (Olga), Slager, S. (Susan), Song, H. (Honglin), Soucy, P. (Penny), Southey, M.C. (Melissa), Stenmark-Askmalm, M. (Marie), Stoppa-Lyonnet, D. (Dominique), Sutter, C. (Christian), Swerdlow, A.J. (Anthony ), Tchatchou, S. (Sandrine), Teixeira, P.J., Teo, S.-H. (Soo-Hwang), Terry, K.L. (Kathryn), Terry, M.B. (Mary Beth), Thomassen, M. (Mads), Tibiletti, M.G. (Maria Grazia), Tihomirova, L. (Laima), Tognazzo, S. (Silvia), Toland, A.E. (Amanda), Tomlinson, I.P. (Ian), Torres, D. (Diana), Truong, T. (Thérèse), Tseng, C.-C. (Chiu-Chen), Tung, N. (Nadine), Tworoger, S.S. (Shelley S.), Vachon, C. (Celine), Van Den Ouweland, A.M.W. (Ans M.W.), Van Doorn, H.C. (Helena C.), Rensburg, E.J. (Elizabeth) van, Veer, L.J. (Laura) van 't, Vanderstichele, A. (Adriaan), Vergote, I. (Ignace), Vijai, J. (Joseph), Wang, Q. (Qin), Wang-Gohrke, S. (Shan), Weitzel, J.N. (Jeffrey), Wentzensen, N. (N.), Whittemore, A.S. (Alice), Wildiers, H. (Hans), Winqvist, R. (Robert), Wu, A.H. (Anna), Yannoukakos, D. (Drakoulis), Yoon, S.-Y. (Sook-Yee), Yu, J-C. (Jyh-Cherng), Zheng, W. (Wei), Zheng, Y. (Ying), Khanna, K.K. (Kum Kum), Simard, J. (Jacques), Monteiro, A.N.A. (Alvaro N.), French, J.D. (Juliet), Couch, F.J. (Fergus), Freedman, M. (Matthew), Easton, D.F. (Douglas F.), Dunning, A.M. (Alison), Pharoah, P.D.P. (Paul), Edwards, S.L. (Stacey), Chenevix-Trench, G. (Georgia), Antoniou, A.C. (Antonis), Gayther, S.A. (Simon), Bowtell, D. (David), DeFazio, A. (Anna), Webb, P. (Penny), Collonge-Rame, M.-A., Damette, A. (Alexandre), Barouk-Simonet, E. (Emmanuelle), Bonnet, F. (Françoise), Bubien, V. (Virginie), Sevenet, N. (Nicolas), Longy, M. (Michel), Berthet, P. (Pascaline), Vaur, D. (Dominique), Castera, L. (Laurent), Ferrer, S.F., Bignon, Y.-J. (Yves-Jean), Uhrhammer, N. (Nancy), Coron, F. (Fanny), Faivre, L. (Laurence), Baurand, A. (Amandine), Jacquot, C. (Caroline), Bertolone, G. (Geoffrey), Lizard, S. (Sarab), Leroux, D. (Dominique), Dreyfus, H. (Hélène), Rebischung, C. (Christine), Peysselon, M. (Magalie), Peyrat, J.-P., Fournier, J. (Joëlle), Révillion, F. (Françoise), Adenis, C. (Claude), Vénat-Bouvet, L. (Laurence), Léone, M. (Mélanie), Boutry-Kryza, N. (N.), Calender, A. (Alain), Giraud, S. (Sophie), Verny-Pierre, C. (Carole), Lasset, C. (Christine), Bonadona, V. (Valérie), Barjhoux, L. (Laure), Sobol, H. (Hagay), Bourdon, V. (Violaine), Noguchi, T. (Tetsuro), Remenieras, A. (Audrey), Coupier, I. (Isabelle), Pujol, P. (Pascal), Sokolowska, J. (Johanna), Bronner, M. (Myriam), Delnatte, C.D. (Capucine), Bézieau, S. (Stéphane), Mari, V. (Véronique), Gauthier-Villars, M. (Marion), Buecher, B. (Bruno), Rouleau, E. (Etienne), Golmard, L. (Lisa), Moncoutier, V. (Virginie), Belotti, M. (Muriel), Pauw, A. (Antoine) de, Elan, C. (Camille), Fourme, E. (Emmanuelle), Birot, A.-M. (Anne-Marie), Saule, C. (Claire), Laurent, M. (Maïté), Houdayer, C. (Claude), Lesueur, F. (Fabienne), Mebirouk, N. (Noura), Coulet, F. (Florence), Colas, C. (Chrystelle), Soubrier, F., Warcoin, M. (Mathilde), Prieur, F. (Fabienne), Lebrun, M. (Marine), Kientz, C. (Caroline), Muller, D.W. (Danièle), Fricker, J.P. (Jean Pierre), Toulas, C. (Christine), Guimbaud, R. (Rosine), Gladieff, L. (Laurence), Feillel, V. (Viviane), Mortemousque, I. (Isabelle), Bressac-de Paillerets, B. (Brigitte), Caron, O. (Olivier), Guillaud-Bataille, M. (Marine), Gregory, H. (Helen), Miedzybrodzka, Z. (Zosia), Morrison, P.J. (Patrick), Donaldson, A. (Alan), Rogers, M.T. (Mark), Kennedy, M.J. (John), Porteous, M.E. (Mary), Brady, A. (A.), Barwell, J. (Julian), Foo, C. (Claire), Lalloo, F. (Fiona), Side, L. (Lucy), Eason, J. (Jacqueline), Henderson, A. (Alex), Walker, L.J. (Lisa), Cook, J. (Jackie), Snape, K. (Katie), Murray, A. (Alexandra), McCann, E. (Emma), Rookus, M.A. (Matti), Leeuwen, F.E. (Flora) van, Kolk, L.E. (Lizet) van der, Russell, N.S. (Nicola), Lange, J.L. (J.) de, Wijnands, R., Collée, J.M. (Margriet), Hooning, M.J. (Maartje), Seynaeve, C., Deurzen, C.H.M. (Carolien) van, Obdeijn, A.I.M. (Inge-Marie), Asperen, C.J. (Christi) van, Tollenaar, R.A.E.M. (Rob), Cronenburg, T.C.T.E.F. van, Kets, C.M. (Marleen), Ausems, M.G.E.M. (Margreet), Pol, C. (Carmen) van der, Os, T.A.M. (Theo) van, Waisfisz, Q. (Quinten), Meijers-Heijboer, E.J. (Hanne), Gómez García, E.B. (Encarna), Oosterwijk, J.C. (Jan), Mourits, M.J. (Marjan), Bock, G.H. (Geertruida) de, Vasen, H. (Hans), Siesling, S., Verloop, J., Overbeek, L.I.H. (Lucy), Fox, S.B. (Stephen), Kirk, J. (Judy), Lindeman, G.J. (Geoffrey), Price, M. (Melanie), Lawrenson, K. (Kate), Kar, S. (Siddhartha), McCue, K. (Karen), Kuchenbaeker, K. (Karoline), Michailidou, K. (Kyriaki), Tyrer, J.P. (Jonathan), Beesley, J. (Jonathan), Ramus, S.J. (Susan), Li, Q. (Qiyuan), Delgado, M.K. (Melissa K.), Lee, J.M. (Janet M.), Aittomäki, K. (Kristiina), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Arun, B.K. (Banu), Arver, B. (Brita Wasteson), Bandera, E.V. (Elisa), Barile, M. (Monica), Barkardottir, R.B. (Rosa B.), Barrowdale, D. (Daniel), Beckmann, M.W. (Matthias), Benítez, J. (Javier), Berchuck, A. (Andrew), Bisogna, M. (Maria), Bjorge, L. (Line), Blomqvist, C. (Carl), Blot, W.J. (William), Bogdanova, N.V. (Natalia), Bojesen, A. (Anders), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet K.), Bonnani, B. (Bernardo), Borresen-Dale, A.-L. (Anne-Lise), Brauch, H. (Hiltrud), Brennan, P. (Paul), Brenner, H. (Hermann), Bruinsma, F. (Fiona), Brunet, J. (Joan), Buhari, S.A.B.S. (Shaik Ahmad Bin Syed), Burwinkel, B. (Barbara), Butzow, R. (Ralf), Buys, S.S. (Saundra), Cai, Q. (Qiuyin), Caldes, T. (Trinidad), Campbell, I. (Ian), Canniotto, R. (Rikki), Chang-Claude, J. (Jenny), Chiquette, J. (Jocelyne), Choi, J.-Y. (Ji-Yeob), Claes, K.B.M. (Kathleen B.M.), Cook, L.S. (Linda S.), Cox, A. (Angela), Cramer, D.W. (Daniel), Cross, S.S. (Simon), Cybulski, C. (Cezary), Czene, K. (Kamila), Daly, M.B. (Mary B.), Damiola, F. (Francesca), Dansonka-Mieszkowska, A. (Agnieszka), Darabi, H. (Hatef), Dennis, J. (Joe), Devilee, P. (Peter), Díez, O. (Orland), Doherty, J.A. (Jennifer A.), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Dumont, M. (Martine), Ehrencrona, H. (Hans), Ejlertsen, B. (Bent), Ellis, S.D. (Steve), Engel, C. (Christoph), Lee, E. (Eunjung), Evans, D.G. (D. Gareth), Fasching, P.A. (Peter), Feliubadaló, L. (L.), Figueroa, J.D. (Jonine), Flesch-Janys, D. (Dieter), Fletcher, O. (Olivia), Flyger, H. (Henrik), Foretova, L. (Lenka), Fostira, F. (Florentia), Foulkes, W.D. (William), Fridley, B.L. (Brooke), Friedman, E. (Eitan), Frost, D. (Debra), Gambino, G. (Gaetana), Ganz, P.A. (Patricia A.), Garber, J. (Judy), García-Closas, M. (Montserrat), Gentry-Maharaj, A. (Aleksandra), Ghoussaini, M. (Maya), Giles, G.G. (Graham), Glasspool, R. (Rosalind), Godwin, A.K. (Andrew K.), Goldberg, M.S. (Mark), Goldgar, D. (David), González-Neira, A. (Anna), Goode, E.L. (Ellen), Goodman, M.T. (Marc), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Guénel, P. (Pascal), Haiman, C.A. (Christopher A.), Hall, P. (Per), Hallberg, E. (Emily), Hamann, U. (Ute), Hansen, T.V.O. (Thomas), harrington, P. (Patricia), Hartman, J.M. (Joost), Hassan, N. (Norhashimah), Healey, S. (Sue), Heitz, P.U., Herzog, J. (Josef), Høgdall, E. (Estrid), Høgdall, C.K. (Claus), Hogervorst, F.B.L. (Frans), Hollestelle, A. (Antoinette), Hopper, J.L. (John), Hulick, P.J. (Peter), Huzarski, T. (Tomasz), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Ito, H. (Hidemi), Jakubowska, A. (Anna), Janavicius, R. (Ramunas), Jensen, A. (Allan), John, E.M. (Esther), Johnson, N. (Nichola), Kabisch, M. (Maria), Kang, D. (Daehee), Kapuscinski, M.K. (Miroslav K.), Karlan, B.Y. (Beth Y.), Khan, S. (Sofia), Kiemeney, L.A.L.M. (Bart), Kjaer, M. (Michael), Knight, J.A. (Julia), Konstantopoulou, I. (I.), Kosma, V-M. (Veli-Matti), Kristensen, V. (Vessela), Kupryjanczyk, J. (Jolanta), Kwong, A. (Ava), Hoya, M. (Miguel) de La, Laitman, Y. (Yael), Lambrechts, D. (Diether), Le, N.D. (Nhu D.), De Leeneer, K. (Kim), Lester, K.J. (Kathryn), Levine, D.A. (Douglas), Li, J. (Jingmei), Lindblom, A. (Annika), Long, J. (Jirong), Lophatananon, A. (Artitaya), Loud, J.T. (Jennifer), Lu, K.H. (Karen), Lubinski, J. (Jan), Mannermaa, A. (Arto), Manoukian, S. (Siranoush), Le Marchand, L. (Loic), Margolin, S. (Sara), Marme, F. (Frederick), Massuger, L.F. (Leon), Matsuo, K. (Keitaro), Mazoyer, S. (Sylvie), McGuffog, L. (Lesley), McLean, C.A. (Catriona Ann), McNeish, I. (Iain), Meindl, A. (Alfons), Menon, U. (Usha), Mensenkamp, A.R. (Arjen R.), Milne, R.L. (Roger), Montagna, M. (Marco), Moysich, K.B. (Kirsten), Muir, K.R. (K.), Mulligan, A.-M. (Anna-Marie), Nathanson, K.L. (Katherine), Ness, R.B. (Roberta), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Nord, S. (Silje), Nussbaum, R.L. (Robert L.), Odunsi, K. (Kunle), Offit, K. (Kenneth), Olah, E., Olopade, O.I. (Olufunmilayo I.), Olson, J.E. (Janet), Olswold, C. (Curtis), O'Malley, D.M. (David M.), Orlow, I. (Irene), Orr, N. (Nick), Osorio, A. (Ana), Park, S.K. (Sue Kyung), Pearce, C.L. (Celeste), Pejovic, T. (Tanja), Peterlongo, P. (Paolo), Pfeiler, G. (Georg), Phelan, C. (Catherine), Poole, E.M. (Elizabeth), Pykäs, K. (Katri), Radice, P. (Paolo), Rantala, J. (Johanna), Rashid, M.U. (Muhammad), Rennert, G. (Gad), Rhenius, V. (Valerie), Rhiem, K. (Kerstin), Risch, H. (Harvey), Rodriguez, G.C. (Gustavo), Rossing, M.A. (Mary Anne), Rudolph, A. (Anja), Salvesen, H.B. (Helga), Sangrajrang, S. (Suleeporn), Sawyer, E.J. (Elinor J.), Schildkraut, J.M. (Joellen), Schmidt, M.K. (Marjanka), Schmutzler, R.K. (Rita), Sellers, T.A. (Thomas A.), Seynaeve, C.M. (Caroline), Shah, M. (Mitul), Shen, C.-Y. (Chen-Yang), Shu, X.-O. (Xiao-Ou), Sieh, W. (Weiva), Singer, C.F. (Christian), Sinilnikova, O. (Olga), Slager, S. (Susan), Song, H. (Honglin), Soucy, P. (Penny), Southey, M.C. (Melissa), Stenmark-Askmalm, M. (Marie), Stoppa-Lyonnet, D. (Dominique), Sutter, C. (Christian), Swerdlow, A.J. (Anthony ), Tchatchou, S. (Sandrine), Teixeira, P.J., Teo, S.-H. (Soo-Hwang), Terry, K.L. (Kathryn), Terry, M.B. (Mary Beth), Thomassen, M. (Mads), Tibiletti, M.G. (Maria Grazia), Tihomirova, L. (Laima), Tognazzo, S. (Silvia), Toland, A.E. (Amanda), Tomlinson, I.P. (Ian), Torres, D. (Diana), Truong, T. (Thérèse), Tseng, C.-C. (Chiu-Chen), Tung, N. (Nadine), Tworoger, S.S. (Shelley S.), Vachon, C. (Celine), Van Den Ouweland, A.M.W. (Ans M.W.), Van Doorn, H.C. (Helena C.), Rensburg, E.J. (Elizabeth) van, Veer, L.J. (Laura) van 't, Vanderstichele, A. (Adriaan), Vergote, I. (Ignace), Vijai, J. (Joseph), Wang, Q. (Qin), Wang-Gohrke, S. (Shan), Weitzel, J.N. (Jeffrey), Wentzensen, N. (N.), Whittemore, A.S. (Alice), Wildiers, H. (Hans), Winqvist, R. (Robert), Wu, A.H. (Anna), Yannoukakos, D. (Drakoulis), Yoon, S.-Y. (Sook-Yee), Yu, J-C. (Jyh-Cherng), Zheng, W. (Wei), Zheng, Y. (Ying), Khanna, K.K. (Kum Kum), Simard, J. (Jacques), Monteiro, A.N.A. (Alvaro N.), French, J.D. (Juliet), Couch, F.J. (Fergus), Freedman, M. (Matthew), Easton, D.F. (Douglas F.), Dunning, A.M. (Alison), Pharoah, P.D.P. (Paul), Edwards, S.L. (Stacey), Chenevix-Trench, G. (Georgia), Antoniou, A.C. (Antonis), Gayther, S.A. (Simon), Bowtell, D. (David), DeFazio, A. (Anna), Webb, P. (Penny), Collonge-Rame, M.-A., Damette, A. (Alexandre), Barouk-Simonet, E. (Emmanuelle), Bonnet, F. (Françoise), Bubien, V. (Virginie), Sevenet, N. (Nicolas), Longy, M. (Michel), Berthet, P. (Pascaline), Vaur, D. (Dominique), Castera, L. (Laurent), Ferrer, S.F., Bignon, Y.-J. (Yves-Jean), Uhrhammer, N. (Nancy), Coron, F. (Fanny), Faivre, L. (Laurence), Baurand, A. (Amandine), Jacquot, C. (Caroline), Bertolone, G. (Geoffrey), Lizard, S. (Sarab), Leroux, D. (Dominique), Dreyfus, H. (Hélène), Rebischung, C. (Christine), Peysselon, M. (Magalie), Peyrat, J.-P., Fournier, J. (Joëlle), Révillion, F. (Françoise), Adenis, C. (Claude), Vénat-Bouvet, L. (Laurence), Léone, M. (Mélanie), Boutry-Kryza, N. (N.), Calender, A. (Alain), Giraud, S. (Sophie), Verny-Pierre, C. (Carole), Lasset, C. (Christine), Bonadona, V. (Valérie), Barjhoux, L. (Laure), Sobol, H. (Hagay), Bourdon, V. (Violaine), Noguchi, T. (Tetsuro), Remenieras, A. (Audrey), Coupier, I. (Isabelle), Pujol, P. (Pascal), Sokolowska, J. (Johanna), Bronner, M. (Myriam), Delnatte, C.D. (Capucine), Bézieau, S. (Stéphane), Mari, V. (Véronique), Gauthier-Villars, M. (Marion), Buecher, B. (Bruno), Rouleau, E. (Etienne), Golmard, L. (Lisa), Moncoutier, V. (Virginie), Belotti, M. (Muriel), Pauw, A. (Antoine) de, Elan, C. (Camille), Fourme, E. (Emmanuelle), Birot, A.-M. (Anne-Marie), Saule, C. (Claire), Laurent, M. (Maïté), Houdayer, C. (Claude), Lesueur, F. (Fabienne), Mebirouk, N. (Noura), Coulet, F. (Florence), Colas, C. (Chrystelle), Soubrier, F., Warcoin, M. (Mathilde), Prieur, F. (Fabienne), Lebrun, M. (Marine), Kientz, C. (Caroline), Muller, D.W. (Danièle), Fricker, J.P. (Jean Pierre), Toulas, C. (Christine), Guimbaud, R. (Rosine), Gladieff, L. (Laurence), Feillel, V. (Viviane), Mortemousque, I. (Isabelle), Bressac-de Paillerets, B. (Brigitte), Caron, O. (Olivier), Guillaud-Bataille, M. (Marine), Gregory, H. (Helen), Miedzybrodzka, Z. (Zosia), Morrison, P.J. (Patrick), Donaldson, A. (Alan), Rogers, M.T. (Mark), Kennedy, M.J. (John), Porteous, M.E. (Mary), Brady, A. (A.), Barwell, J. (Julian), Foo, C. (Claire), Lalloo, F. (Fiona), Side, L. (Lucy), Eason, J. (Jacqueline), Henderson, A. (Alex), Walker, L.J. (Lisa), Cook, J. (Jackie), Snape, K. (Katie), Murray, A. (Alexandra), McCann, E. (Emma), Rookus, M.A. (Matti), Leeuwen, F.E. (Flora) van, Kolk, L.E. (Lizet) van der, Russell, N.S. (Nicola), Lange, J.L. (J.) de, Wijnands, R., Collée, J.M. (Margriet), Hooning, M.J. (Maartje), Seynaeve, C., Deurzen, C.H.M. (Carolien) van, Obdeijn, A.I.M. (Inge-Marie), Asperen, C.J. (Christi) van, Tollenaar, R.A.E.M. (Rob), Cronenburg, T.C.T.E.F. van, Kets, C.M. (Marleen), Ausems, M.G.E.M. (Margreet), Pol, C. (Carmen) van der, Os, T.A.M. (Theo) van, Waisfisz, Q. (Quinten), Meijers-Heijboer, E.J. (Hanne), Gómez García, E.B. (Encarna), Oosterwijk, J.C. (Jan), Mourits, M.J. (Marjan), Bock, G.H. (Geertruida) de, Vasen, H. (Hans), Siesling, S., Verloop, J., Overbeek, L.I.H. (Lucy), Fox, S.B. (Stephen), Kirk, J. (Judy), Lindeman, G.J. (Geoffrey), and Price, M. (Melanie)
- Abstract
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
- Published
- 2016
- Full Text
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31. Targeting Src in endometriosis-associated ovarian cancer
- Author
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Manek, R, primary, Pakzamir, E, additional, Mhawech-Fauceglia, P, additional, Pejovic, T, additional, Sowter, H, additional, Gayther, S A, additional, and Lawrenson, K, additional
- Published
- 2016
- Full Text
- View/download PDF
32. Strategic cotargeting in epithelial ovarian cancer: FOXM1
- Author
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Garcia, J., primary, Lawrenson, K., additional, Mhawech-Fauceglia, P., additional, Roman, L.D., additional, and Gayther, S.A., additional
- Published
- 2016
- Full Text
- View/download PDF
33. Genome-wide significant risk associations for mucinous ovarian carcinoma
- Author
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Kelemen, L.E., Lawrenson, K., Tyrer, J., Li, Q., Lee, J.M., Seo, J.H., Phelan, C.M., Beesley, J., Chen, X., Spindler, T.J., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Baker, H., Bandera, E.V., Bean, Y., Beckmann, M.W., Bisogna, M., Bjorge, T., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Bruinsma, F., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Chen, Y.A., Chen, Z.H., Cook, L.S., Cramer, D.W, Cunningham, J.M., Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Dicks, E., Doherty, J.A., Kiemeney, L.A., Altena, A.M. van, et al., Kelemen, L.E., Lawrenson, K., Tyrer, J., Li, Q., Lee, J.M., Seo, J.H., Phelan, C.M., Beesley, J., Chen, X., Spindler, T.J., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Baker, H., Bandera, E.V., Bean, Y., Beckmann, M.W., Bisogna, M., Bjorge, T., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Bruinsma, F., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Chen, Y.A., Chen, Z.H., Cook, L.S., Cramer, D.W, Cunningham, J.M., Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Dicks, E., Doherty, J.A., Kiemeney, L.A., Altena, A.M. van, and et al.
- Abstract
Item does not contain fulltext
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- 2015
34. Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci
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Coetzee, S.G., Shen, H.C., Hazelett, D.J., Lawrenson, K., Kuchenbaecker, K., Tyrer, J., Rhie, S.K., Levanon, K., Karst, A., Drapkin, R., Ramus, S.J., Couch, F.J., Offit, K., Chenevix-Trench, G., Monteiro, A.N., Antoniou, A., Freedman, M., Coetzee, G.A., Pharoah, P.D., Noushmehr, H., Gayther, S.A., Kiemeney, B., Massuger, L.F.A.G., et al., Coetzee, S.G., Shen, H.C., Hazelett, D.J., Lawrenson, K., Kuchenbaecker, K., Tyrer, J., Rhie, S.K., Levanon, K., Karst, A., Drapkin, R., Ramus, S.J., Couch, F.J., Offit, K., Chenevix-Trench, G., Monteiro, A.N., Antoniou, A., Freedman, M., Coetzee, G.A., Pharoah, P.D., Noushmehr, H., Gayther, S.A., Kiemeney, B., Massuger, L.F.A.G., and et al.
- Abstract
Contains fulltext : 154725.pdf (publisher's version ) (Closed access), Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most single-nucleotide polymorphisms (SNPs) associated with cancer risk lie in non-protein-coding regions, implicating regulatory DNA elements as functional targets of susceptibility variants. Here, we describe genome-wide annotation of regions of open chromatin and histone modification in fallopian tube and ovarian surface epithelial cells (FTSECs, OSECs), the debated cellular origins of high-grade serous ovarian cancers (HGSOCs) and in endometriosis epithelial cells (EECs), the likely precursor of clear cell ovarian carcinomas (CCOCs). The regulatory architecture of these cell types was compared with normal human mammary epithelial cells and LNCaP prostate cancer cells. We observed similar positional patterns of global enhancer signatures across the three different ovarian cancer precursor cell types, and evidence of tissue-specific regulatory signatures compared to non-gynecological cell types. We found significant enrichment for risk-associated SNPs intersecting regulatory biofeatures at 17 known HGSOC susceptibility loci in FTSECs (P = 3.8 x 10(-30)), OSECs (P = 2.4 x 10(-23)) and HMECs (P = 6.7 x 10(-15)) but not for EECs (P = 0.45) or LNCaP cells (P = 0.88). Hierarchical clustering of risk SNPs conditioned on the six different cell types indicates FTSECs and OSECs are highly related (96% of samples using multi-scale bootstrapping) suggesting both cell types may be precursors of HGSOC. These data represent the first description of regulatory catalogues of normal precursor cells for different ovarian cancer subtypes, and provide unique insights into the tissue specific regulatory variation with respect to the likely functional targets of germline genetic susceptibility variants for ovarian cancer.
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- 2015
35. Identification of six new susceptibility loci for invasive epithelial ovarian cancer
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Kuchenbaecker, K.B., Ramus, S.J., Tyrer, J., Lee, A., Shen, H.C., Beesley, J., Lawrenson, K., McGuffog, L., Healey, S., Lee, J.M., Spindler, T.J., Lin, Y.G., Pejovic, T., Bean, Y., Li, Q., Coetzee, S., Hazelett, D., Miron, A., Southey, M., Terry, M.B., Goldgar, D.E., Buys, S.S., Janavicius, R., Dorfling, C.M., Rensburg, E.J. van, Neuhausen, S.L., Ding, Y.C., Hansen, T.V., Jonson, L., Gerdes, A.M., Ejlertsen, B., Barrowdale, D., Dennis, J., Benitez, J., Osorio, A., Garcia, M.J., Komenaka, I., Weitzel, J.N., Ganschow, P., Peterlongo, P., Bernard, L., Viel, A., Bonanni, B., Peissel, B., Manoukian, S., Radice, P., Papi, L., Ottini, L., Fostira, F., Konstantopoulou, I., Garber, J., Frost, D., Perkins, J., Platte, R., Ellis, S., Embrace, ., Godwin, A.K., Schmutzler, R.K., Meindl, A., Engel, C., Sutter, C., Sinilnikova, O.M., Damiola, F., Mazoyer, S., Stoppa-Lyonnet, D., Claes, K., Leeneer, K. De, Kirk, J., Rodriguez, G.C., Piedmonte, M., O'Malley, D.M., Hoya, M. de la, Caldes, T., Aittomaki, K., Nevanlinna, H., Collee, J.M., Rookus, M.A., Oosterwijk, J.C, Tihomirova, L., Tung, N., Hamann, U., Isaccs, C., Tischkowitz, M., Imyanitov, E.N., Caligo, M.A., Campbell, I.G., Hogervorst, F.B., Olah, E., Diez, O., Blanco, I., Brunet, J., Lazaro, C., Pujana, M.A., Jakubowska, A., Gronwald, J., Lubinski, J., Sukiennicki, G., Massuger, L.F.A.G., Altena, A.M. van, Aben, K.K.H., Kiemeney, B., Mensenkamp, A.R., Kets, M., Hoogerbrugge, N., Ligtenberg, M.J.L., et al., Kuchenbaecker, K.B., Ramus, S.J., Tyrer, J., Lee, A., Shen, H.C., Beesley, J., Lawrenson, K., McGuffog, L., Healey, S., Lee, J.M., Spindler, T.J., Lin, Y.G., Pejovic, T., Bean, Y., Li, Q., Coetzee, S., Hazelett, D., Miron, A., Southey, M., Terry, M.B., Goldgar, D.E., Buys, S.S., Janavicius, R., Dorfling, C.M., Rensburg, E.J. van, Neuhausen, S.L., Ding, Y.C., Hansen, T.V., Jonson, L., Gerdes, A.M., Ejlertsen, B., Barrowdale, D., Dennis, J., Benitez, J., Osorio, A., Garcia, M.J., Komenaka, I., Weitzel, J.N., Ganschow, P., Peterlongo, P., Bernard, L., Viel, A., Bonanni, B., Peissel, B., Manoukian, S., Radice, P., Papi, L., Ottini, L., Fostira, F., Konstantopoulou, I., Garber, J., Frost, D., Perkins, J., Platte, R., Ellis, S., Embrace, ., Godwin, A.K., Schmutzler, R.K., Meindl, A., Engel, C., Sutter, C., Sinilnikova, O.M., Damiola, F., Mazoyer, S., Stoppa-Lyonnet, D., Claes, K., Leeneer, K. De, Kirk, J., Rodriguez, G.C., Piedmonte, M., O'Malley, D.M., Hoya, M. de la, Caldes, T., Aittomaki, K., Nevanlinna, H., Collee, J.M., Rookus, M.A., Oosterwijk, J.C, Tihomirova, L., Tung, N., Hamann, U., Isaccs, C., Tischkowitz, M., Imyanitov, E.N., Caligo, M.A., Campbell, I.G., Hogervorst, F.B., Olah, E., Diez, O., Blanco, I., Brunet, J., Lazaro, C., Pujana, M.A., Jakubowska, A., Gronwald, J., Lubinski, J., Sukiennicki, G., Massuger, L.F.A.G., Altena, A.M. van, Aben, K.K.H., Kiemeney, B., Mensenkamp, A.R., Kets, M., Hoogerbrugge, N., Ligtenberg, M.J.L., and et al.
- Abstract
Contains fulltext : 153049.pdf (publisher's version ) (Closed access), Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 x 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
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- 2015
36. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer
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Lawrenson, K., Li, Q., Kar, S., Seo, J.H., Tyrer, J., Spindler, T.J., Lee, J. van der, Chen, Y, Karst, A., Drapkin, R., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Baker, H., Bandera, E.V., Bean, Y., Beckmann, M.W., Berchuck, A., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Bruinsma, F., Butzow, R., Campbell, I.G., Carty, K., Chang-Claude, J., Chenevix-Trench, G., Chen, A, Chen, Z., Cook, L.S., Cramer, D.W, Cunningham, J.M., Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Dicks, E., Doherty, J.A., Dork, T., Bois, A. du, Durst, M., Eccles, D., Easton, D.T., Edwards, R.P., Eilber, U., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Goode, E.L., Goodman, M.T., Grownwald, J., Harrington, P., Harter, P., Hasmad, H.N., Hein, A., Heitz, F., Hildebrandt, M.A., Hillemanns, P., Hogdall, E., Hogdall, C., Hosono, S., Iversen, E.S., Jakubowska, A., James, P., Jensen, A., Ji, B.T., Karlan, B.Y., Kjaer, S. Kruger, Kelemen, L.E., Kellar, M., Kelley, J.L., Kiemeney, L.A., Krakstad, C., 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., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F., Matsuo, K., McGuire, V., McLaughlin, J.R., Nevanlinna, H., McNeish, I., Menon, U., Modugno, F., et al., Lawrenson, K., Li, Q., Kar, S., Seo, J.H., Tyrer, J., Spindler, T.J., Lee, J. van der, Chen, Y, Karst, A., Drapkin, R., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Baker, H., Bandera, E.V., Bean, Y., Beckmann, M.W., Berchuck, A., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Bruinsma, F., Butzow, R., Campbell, I.G., Carty, K., Chang-Claude, J., Chenevix-Trench, G., Chen, A, Chen, Z., Cook, L.S., Cramer, D.W, Cunningham, J.M., Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Dicks, E., Doherty, J.A., Dork, T., Bois, A. du, Durst, M., Eccles, D., Easton, D.T., Edwards, R.P., Eilber, U., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Goode, E.L., Goodman, M.T., Grownwald, J., Harrington, P., Harter, P., Hasmad, H.N., Hein, A., Heitz, F., Hildebrandt, M.A., Hillemanns, P., Hogdall, E., Hogdall, C., Hosono, S., Iversen, E.S., Jakubowska, A., James, P., Jensen, A., Ji, B.T., Karlan, B.Y., Kjaer, S. Kruger, Kelemen, L.E., Kellar, M., Kelley, J.L., Kiemeney, L.A., Krakstad, C., 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., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F., Matsuo, K., McGuire, V., McLaughlin, J.R., Nevanlinna, H., McNeish, I., Menon, U., Modugno, F., and et al.
- Abstract
Contains fulltext : 154767.pdf (publisher's version ) (Open Access), Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P=10(-5)). For three cis-eQTL associations (P<1.4 x 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 x 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.
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- 2015
37. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk
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Chornokur, G., Lin, H.Y., Tyrer, J.P., Lawrenson, K., Dennis, J., Amankwah, E.K., Qu, X., Tsai, Y.Y., Jim, H.S., Chen, Z., Chen, A.Y., Permuth-Wey, J., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Bruinsma, F., Bandera, E.V., Bean, Y.T., Beckmann, M.W., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Bunker, C.H., Butzow, R., Campbell, I.G., Carty, K., Chang-Claude, J., Cook, L.S., Cramer, D.W, Cunningham, J.M., Cybulski, C., Dansonka-Mieszkowska, A., Bois, A. du, Despierre, E., Dicks, E., Doherty, J.A., Dork, T., Durst, M., Easton, D.F., Eccles, D.M., Edwards, R.P., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Goodman, M.T., Gronwald, J., Harrington, P., Harter, P., Hein, A., Heitz, F., Hildebrandt, M.A.T., Hillemanns, P., Hogdall, C.K., Hogdall, E., Hosono, S., Jakubowska, A., Jensen, A., Ji, B.T., Karlan, B.Y., Kelemen, L.E., Kellar, M., Kiemeney, L.A.L.M., Krakstad, C., Kjaer, S.K., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, A.W., Lele, S., Leminen, A., Lester, J., Levine, D.A., Liang, D., Lim, B.K., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F.A.G., Matsuo, K., McGuire, V., McLaughlin, J.R., McNeish, I., Menon, U., Milne, R.L., Modugno, F., Moysich, K.B., Ness, R.B., Nevanlinna, H., Eilber, U., Odunsi, K., Olson, S.H., Orlow, I., et al., Chornokur, G., Lin, H.Y., Tyrer, J.P., Lawrenson, K., Dennis, J., Amankwah, E.K., Qu, X., Tsai, Y.Y., Jim, H.S., Chen, Z., Chen, A.Y., Permuth-Wey, J., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Bruinsma, F., Bandera, E.V., Bean, Y.T., Beckmann, M.W., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Bunker, C.H., Butzow, R., Campbell, I.G., Carty, K., Chang-Claude, J., Cook, L.S., Cramer, D.W, Cunningham, J.M., Cybulski, C., Dansonka-Mieszkowska, A., Bois, A. du, Despierre, E., Dicks, E., Doherty, J.A., Dork, T., Durst, M., Easton, D.F., Eccles, D.M., Edwards, R.P., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Goodman, M.T., Gronwald, J., Harrington, P., Harter, P., Hein, A., Heitz, F., Hildebrandt, M.A.T., Hillemanns, P., Hogdall, C.K., Hogdall, E., Hosono, S., Jakubowska, A., Jensen, A., Ji, B.T., Karlan, B.Y., Kelemen, L.E., Kellar, M., Kiemeney, L.A.L.M., Krakstad, C., Kjaer, S.K., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, A.W., Lele, S., Leminen, A., Lester, J., Levine, D.A., Liang, D., Lim, B.K., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F.A.G., Matsuo, K., McGuire, V., McLaughlin, J.R., McNeish, I., Menon, U., Milne, R.L., Modugno, F., Moysich, K.B., Ness, R.B., Nevanlinna, H., Eilber, U., Odunsi, K., Olson, S.H., and Orlow, I., et al.
- Abstract
Contains fulltext : 154822.PDF (publisher's version ) (Open Access), BACKGROUND: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. METHODS: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons. RESULTS: The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). CONCLUSION: These results, generated on a large cohort of women, revealed associatio
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- 2015
38. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer
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Lawrenson, K., Iversen, E.S., Tyrer, J., Weber, R.P., Concannon, P., Hazelett, D.J., Li, Q., Marks, J.R., Berchuck, A., Lee, J.M., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Bandera, E.V., 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., Chang-Claude, J., Chenevix-Trench, G., Chen, A, Chen, Z., Cook, L.S., Cramer, D.W, Cunningham, J.M., Cybulski, C., Plisiecka-Halasa, J., Dennis, J., Dicks, E., Doherty, J.A., Dork, T., Bois, A. du, Eccles, D., Easton, D.T., Edwards, R.P., Eilber, U., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Goode, E.L., Goodman, M.T., Gronwald, J., Harter, P., Hasmad, H.N., Hein, A., Heitz, F., Hildebrandt, M.A.T., Hillemanns, P., Hogdall, E., Hogdall, C., Hosono, S., Jakubowska, A., Paul, J., Jensen, A., Karlan, B.Y., Kjaer, S.K., Kelemen, L.E., Kellar, M., Kelley, J.L., Kiemeney, L.A., Krakstad, C., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, A.W., Cannioto, R., Leminen, A., Lester, J., Levine, D.A., Liang, D., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F., Matsuo, K., McGuire, V., McLaughlin, J.R., Nevanlinna, H., McNeish, I., Menon, U., Modugno, F., Moysich, K.B., Narod, S.A., Nedergaard, L., Ness, R.B., Azmi, M.A. Noor, Odunsi, K., Olson, S.H., Lawrenson, K., Iversen, E.S., Tyrer, J., Weber, R.P., Concannon, P., Hazelett, D.J., Li, Q., Marks, J.R., Berchuck, A., Lee, J.M., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Bandera, E.V., 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., Chang-Claude, J., Chenevix-Trench, G., Chen, A, Chen, Z., Cook, L.S., Cramer, D.W, Cunningham, J.M., Cybulski, C., Plisiecka-Halasa, J., Dennis, J., Dicks, E., Doherty, J.A., Dork, T., Bois, A. du, Eccles, D., Easton, D.T., Edwards, R.P., Eilber, U., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Goode, E.L., Goodman, M.T., Gronwald, J., Harter, P., Hasmad, H.N., Hein, A., Heitz, F., Hildebrandt, M.A.T., Hillemanns, P., Hogdall, E., Hogdall, C., Hosono, S., Jakubowska, A., Paul, J., Jensen, A., Karlan, B.Y., Kjaer, S.K., Kelemen, L.E., Kellar, M., Kelley, J.L., Kiemeney, L.A., Krakstad, C., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, A.W., Cannioto, R., Leminen, A., Lester, J., Levine, D.A., Liang, D., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F., Matsuo, K., McGuire, V., McLaughlin, J.R., Nevanlinna, H., McNeish, I., Menon, U., Modugno, F., Moysich, K.B., Narod, S.A., Nedergaard, L., Ness, R.B., Azmi, M.A. Noor, Odunsi, K., and Olson, S.H.
- Abstract
Contains fulltext : 152042.pdf (publisher's version ) (Closed access), Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P = 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1x10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72x10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70x10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.
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- 2015
39. Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk
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Kar, S.P., Tyrer, J.P., Li, Q., Lawrenson, K., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Chenevix-Trench, G., Baker, H., Bandera, E.V., Bean, Y.T., Beckmann, M.W., Berchuck, A., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L., Brooks-Wilson, A., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Chen, Y.A., Chen, Z., Cook, L.S., Cramer, D., Cunningham, J.M., Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Dicks, E., Doherty, J.A., Dork, T., Bois, A. du, Durst, M., Eccles, D., Easton, D.F., Edwards, R.P., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Goode, E.L., Goodman, M.T., Grownwald, J., Harrington, P., Harter, P., Hein, A., Heitz, F., Hildebrandt, M.A.T., Hillemanns, P., Hogdall, E., Hogdall, C.K., Hosono, S., Iversen, E.S., Jakubowska, A., Paul, J., Jensen, A., Ji, B.T., Karlan, B.Y., Kjaer, S.K., Kelemen, L.E., Kellar, M., Kelley, J., Kiemeney, L.A.L.M., Krakstad, C., 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., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F., Matsuo, K., McGuire, V., McLaughlin, J.R., McNeish, I.A., Menon, U., Modugno, F., Moysich, K.B., Narod, S.A., Nedergaard, L., Ness, R.B., Nevanlinna, H., Odunsi, K., Olson, S.H., Orlow, I., Orsulic, S., Weber, R.P., Kar, S.P., Tyrer, J.P., Li, Q., Lawrenson, K., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Chenevix-Trench, G., Baker, H., Bandera, E.V., Bean, Y.T., Beckmann, M.W., Berchuck, A., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L., Brooks-Wilson, A., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Chen, Y.A., Chen, Z., Cook, L.S., Cramer, D., Cunningham, J.M., Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Dicks, E., Doherty, J.A., Dork, T., Bois, A. du, Durst, M., Eccles, D., Easton, D.F., Edwards, R.P., Ekici, A.B., Fasching, P.A., Fridley, B.L., Gao, Y.T., Gentry-Maharaj, A., Giles, G.G., Glasspool, R., Goode, E.L., Goodman, M.T., Grownwald, J., Harrington, P., Harter, P., Hein, A., Heitz, F., Hildebrandt, M.A.T., Hillemanns, P., Hogdall, E., Hogdall, C.K., Hosono, S., Iversen, E.S., Jakubowska, A., Paul, J., Jensen, A., Ji, B.T., Karlan, B.Y., Kjaer, S.K., Kelemen, L.E., Kellar, M., Kelley, J., Kiemeney, L.A.L.M., Krakstad, C., 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., Lu, K., Lubinski, J., Lundvall, L., Massuger, L.F., Matsuo, K., McGuire, V., McLaughlin, J.R., McNeish, I.A., Menon, U., Modugno, F., Moysich, K.B., Narod, S.A., Nedergaard, L., Ness, R.B., Nevanlinna, H., Odunsi, K., Olson, S.H., Orlow, I., Orsulic, S., and Weber, R.P.
- Abstract
Contains fulltext : 153484.pdf (publisher's version ) (Closed access), BACKGROUND: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. METHODS: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). RESULTS: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. CONCLUSION: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. IMPACT: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574-84. (c)2015 AACR.
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- 2015
40. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk
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Agoulnik, IU, Chornokur, G, Lin, H-Y, Tyrer, JP, Lawrenson, K, Dennis, J, Amankwah, EK, Qu, X, Tsai, Y-Y, Jim, HSL, Chen, Z, Chen, AY, Permuth-Wey, J, Aben, KKH, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, du Bois, A, Despierre, E, Dicks, E, Doherty, JA, Dork, T, Durst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harrington, P, Harter, P, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono, S, Jakubowska, A, Jensen, A, Ji, B-T, Karlan, BY, Kelemen, LE, Kellar, M, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lim, BK, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Milne, RL, Modugno, F, Moysich, KB, Ness, RB, Nevanlinna, H, Eilber, U, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Weber, RP, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM, Pike, MC, Poole, EM, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schernhammer, E, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Spiewankiewicz, B, Sucheston, L, Teo, S-H, Terry, KL, Thompson, PJ, Thomsen, L, Tangen, IL, Tworoger, SS, van Altena, AM, Vierkant, RA, Vergote, I, Walsh, CS, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, Y-L, Yang, H, Zheng, W, Ziogas, A, Hasmad, HN, Berchuck, A, Iversen, ES, Schildkraut, JM, Ramus, SJ, Goode, EL, Monteiro, ANA, Gayther, SA, Narod, SA, Pharoah, PP, Sellers, TA, Phelan, CM, Agoulnik, IU, Chornokur, G, Lin, H-Y, Tyrer, JP, Lawrenson, K, Dennis, J, Amankwah, EK, Qu, X, Tsai, Y-Y, Jim, HSL, Chen, Z, Chen, AY, Permuth-Wey, J, Aben, KKH, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, du Bois, A, Despierre, E, Dicks, E, Doherty, JA, Dork, T, Durst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harrington, P, Harter, P, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono, S, Jakubowska, A, Jensen, A, Ji, B-T, Karlan, BY, Kelemen, LE, Kellar, M, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lim, BK, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Milne, RL, Modugno, F, Moysich, KB, Ness, RB, Nevanlinna, H, Eilber, U, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Weber, RP, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM, Pike, MC, Poole, EM, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schernhammer, E, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Spiewankiewicz, B, Sucheston, L, Teo, S-H, Terry, KL, Thompson, PJ, Thomsen, L, Tangen, IL, Tworoger, SS, van Altena, AM, Vierkant, RA, Vergote, I, Walsh, CS, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, Y-L, Yang, H, Zheng, W, Ziogas, A, Hasmad, HN, Berchuck, A, Iversen, ES, Schildkraut, JM, Ramus, SJ, Goode, EL, Monteiro, ANA, Gayther, SA, Narod, SA, Pharoah, PP, Sellers, TA, and Phelan, CM
- Abstract
BACKGROUND: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. METHODS: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons. RESULTS: The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). CONCLUSION: These results, generated on a large cohort of women, revealed associatio
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- 2015
41. Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC).
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Jim, HSL, Lin, H-Y, Tyrer, JP, Lawrenson, K, Dennis, J, Chornokur, G, Chen, Z, Chen, AY, Permuth-Wey, J, Aben, KK, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, du Bois, A, Despierre, E, Sieh, W, Doherty, JA, Dörk, T, Dürst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, B-T, Karlan, BY, Kellar, M, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Vierkant, RA, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lim, BK, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Milne, RL, Modugno, F, Thomsen, L, Moysich, KB, Ness, RB, Nevanlinna, H, Eilber, U, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Palmieri Weber, R, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM, Pike, MC, Poole, EM, Schernhammer, E, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Song, H, Southey, MC, Spiewankiewicz, B, Sucheston-Campbell, L, Teo, S-H, Terry, KL, Thompson, PJ, Tangen, IL, Tworoger, SS, van Altena, AM, Vergote, I, Walsh, CS, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, Y-L, Yang, H, Zheng, W, Ziogas, A, Amankwah, E, Berchuck, A, Georgia Chenevix-Trench on behalf of the AOCS management group 95,96, Schildkraut, JM, Kelemen, LE, Ramus, SJ, Monteiro, ANA, Goode, EL, Narod, SA, Gayther, SA, Pharoah, PDP, Sellers, TA, Phelan, CM, Jim, HSL, Lin, H-Y, Tyrer, JP, Lawrenson, K, Dennis, J, Chornokur, G, Chen, Z, Chen, AY, Permuth-Wey, J, Aben, KK, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, du Bois, A, Despierre, E, Sieh, W, Doherty, JA, Dörk, T, Dürst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, B-T, Karlan, BY, Kellar, M, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Vierkant, RA, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lim, BK, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Milne, RL, Modugno, F, Thomsen, L, Moysich, KB, Ness, RB, Nevanlinna, H, Eilber, U, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Palmieri Weber, R, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM, Pike, MC, Poole, EM, Schernhammer, E, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Song, H, Southey, MC, Spiewankiewicz, B, Sucheston-Campbell, L, Teo, S-H, Terry, KL, Thompson, PJ, Tangen, IL, Tworoger, SS, van Altena, AM, Vergote, I, Walsh, CS, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, Y-L, Yang, H, Zheng, W, Ziogas, A, Amankwah, E, Berchuck, A, Georgia Chenevix-Trench on behalf of the AOCS management group 95,96, Schildkraut, JM, Kelemen, LE, Ramus, SJ, Monteiro, ANA, Goode, EL, Narod, SA, Gayther, SA, Pharoah, PDP, Sellers, TA, and Phelan, CM
- Abstract
Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10-4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.
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- 2015
42. Identification of six new susceptibility loci for invasive epithelial ovarian cancer
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Kuchenbaecker, KB, Ramus, SJ, Tyrer, J, Lee, A, Shen, HC, Beesley, J, Lawrenson, K, McGuffog, L, Healey, S, Lee, JM, Spindler, TJ, Lin, YG, Pejovic, T, Bean, Y, Li, Q, Coetzee, S, Hazelett, D, Miron, A, Southey, M, Terry, MB, Goldgar, DE, Buys, SS, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Hansen, TVO, Jonson, L, Gerdes, A-M, Ejlertsen, B, Barrowdale, D, Dennis, J, Benitez, J, Osorio, A, Garcia, MJ, Komenaka, I, Weitzel, JN, Ganschow, P, Peterlongo, P, Bernard, L, Viel, A, Bonanni, B, Peissel, B, Manoukian, S, Radice, P, Papi, L, Ottini, L, Fostira, F, Konstantopoulou, I, Garber, J, Frost, D, Perkins, J, Platte, R, Ellis, S, Godwin, AK, Schmutzler, RK, Meindl, A, Engel, C, Sutter, C, Sinilnikova, OM, Damiola, F, Mazoyer, S, Stoppa-Lyonnet, D, Claes, K, De Leeneer, K, Kirk, J, Rodriguez, GC, Piedmonte, M, O'Malley, DM, de la Hoya, M, Caldes, T, Aittomaeki, K, Nevanlinna, H, Collee, JM, Rookus, MA, Oosterwijk, JC, Tihomirova, L, Tung, N, Hamann, U, Isaccs, C, Tischkowitz, M, Imyanitov, EN, Caligo, MA, Campbell, IG, Hogervorst, FBL, Olah, E, Diez, O, Blanco, I, Brunet, J, Lazaroso, C, Angel Pujana, M, Jakubowska, A, Gronwald, J, Lubinski, J, Sukiennicki, G, Barkardottir, RB, Plante, M, Simard, J, Soucy, P, Montagna, M, Tognazzo, S, Teixeira, MR, Pankratz, VS, Wang, X, Lindor, N, Szabo, CI, Kauff, N, Vijai, J, Aghajanian, CA, Pfeiler, G, Berger, A, Singer, CF, Tea, M-K, Phelan, CM, Greene, MH, Mai, PL, Rennert, G, Mulligan, AM, Tchatchou, S, Andrulis, IL, Glendon, G, Toland, AE, Jensen, UB, Kruse, TA, Thomassen, M, Bojesen, A, Zidan, J, Friedman, E, Laitman, Y, Soller, M, Liljegren, A, Arver, B, Einbeigi, Z, Stenmark-Askmalm, M, Olopade, OI, Nussbaum, RL, Rebbeck, TR, Nathanson, KL, Domchek, SM, Lu, KH, Karlan, BY, Walsh, C, Lester, J, Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambrechts, S, Dicks, E, Doherty, JA, Wicklund, KG, Rossing, MA, Rudolph, A, Chang-Claude, J, Wang-Gohrke, S, Eilber, U, Moysich, KB, Odunsi, K, Sucheston, L, Lele, S, Wilkens, LR, Goodman, MT, Thompson, PJ, Shvetsov, YB, Runnebaum, IB, Duerst, M, Hillemanns, P, Doerk, T, Antonenkova, N, Bogdanova, N, Leminen, A, Pelttari, LM, Butzow, R, Modugno, F, Kelley, JL, Edwards, RP, Ness, RB, du Bois, A, Heitz, F, Schwaab, I, Harter, P, Matsuo, K, Hosono, S, Orsulic, S, Jensen, A, Kjaer, SK, Hogdall, E, Hasmad, HN, Azmi, MAN, Teo, S-H, Woo, Y-L, Fridley, BL, Goode, EL, Cunningham, JM, Vierkant, RA, Bruinsma, F, Giles, GG, Liang, D, Hildebrandt, MAT, Wu, X, Levine, DA, Bisogna, M, Berchuck, A, Iversen, ES, Schildkraut, JM, Concannon, P, Weber, RP, Cramer, DW, Terry, KL, Poole, EM, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Krakstad, C, Salvesen, HB, Tangen, IL, Bjorge, L, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Kellar, M, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Cybulski, C, Yang, H, Lissowska, J, Brinton, LA, Wentzensen, N, Hogdall, C, Lundvall, L, Nedergaard, L, Baker, H, Song, H, Eccles, D, McNeish, I, Paul, J, Carty, K, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Ji, B-T, Zheng, W, Shu, X-O, Gao, Y-T, Rosen, B, Risch, HA, McLaughlin, JR, Narod, SA, Monteiro, AN, Chen, A, Lin, H-Y, Permuth-Wey, J, Sellers, TA, Tsai, Y-Y, Chen, Z, Ziogas, A, Anton-Culver, H, Gentry-Maharaj, A, Menon, U, Harrington, P, Lee, AW, Wu, AH, Pearce, CL, Coetzee, G, Pike, MC, Dansonka-Mieszkowska, A, Timorek, A, Rzepecka, IK, Kupryjanczyk, J, Freedman, M, Noushmehr, H, Easton, DF, Offit, K, Couch, FJ, Gayther, S, Pharoah, PP, Antoniou, AC, Chenevix-Trench, G, Kuchenbaecker, KB, Ramus, SJ, Tyrer, J, Lee, A, Shen, HC, Beesley, J, Lawrenson, K, McGuffog, L, Healey, S, Lee, JM, Spindler, TJ, Lin, YG, Pejovic, T, Bean, Y, Li, Q, Coetzee, S, Hazelett, D, Miron, A, Southey, M, Terry, MB, Goldgar, DE, Buys, SS, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Hansen, TVO, Jonson, L, Gerdes, A-M, Ejlertsen, B, Barrowdale, D, Dennis, J, Benitez, J, Osorio, A, Garcia, MJ, Komenaka, I, Weitzel, JN, Ganschow, P, Peterlongo, P, Bernard, L, Viel, A, Bonanni, B, Peissel, B, Manoukian, S, Radice, P, Papi, L, Ottini, L, Fostira, F, Konstantopoulou, I, Garber, J, Frost, D, Perkins, J, Platte, R, Ellis, S, Godwin, AK, Schmutzler, RK, Meindl, A, Engel, C, Sutter, C, Sinilnikova, OM, Damiola, F, Mazoyer, S, Stoppa-Lyonnet, D, Claes, K, De Leeneer, K, Kirk, J, Rodriguez, GC, Piedmonte, M, O'Malley, DM, de la Hoya, M, Caldes, T, Aittomaeki, K, Nevanlinna, H, Collee, JM, Rookus, MA, Oosterwijk, JC, Tihomirova, L, Tung, N, Hamann, U, Isaccs, C, Tischkowitz, M, Imyanitov, EN, Caligo, MA, Campbell, IG, Hogervorst, FBL, Olah, E, Diez, O, Blanco, I, Brunet, J, Lazaroso, C, Angel Pujana, M, Jakubowska, A, Gronwald, J, Lubinski, J, Sukiennicki, G, Barkardottir, RB, Plante, M, Simard, J, Soucy, P, Montagna, M, Tognazzo, S, Teixeira, MR, Pankratz, VS, Wang, X, Lindor, N, Szabo, CI, Kauff, N, Vijai, J, Aghajanian, CA, Pfeiler, G, Berger, A, Singer, CF, Tea, M-K, Phelan, CM, Greene, MH, Mai, PL, Rennert, G, Mulligan, AM, Tchatchou, S, Andrulis, IL, Glendon, G, Toland, AE, Jensen, UB, Kruse, TA, Thomassen, M, Bojesen, A, Zidan, J, Friedman, E, Laitman, Y, Soller, M, Liljegren, A, Arver, B, Einbeigi, Z, Stenmark-Askmalm, M, Olopade, OI, Nussbaum, RL, Rebbeck, TR, Nathanson, KL, Domchek, SM, Lu, KH, Karlan, BY, Walsh, C, Lester, J, Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambrechts, S, Dicks, E, Doherty, JA, Wicklund, KG, Rossing, MA, Rudolph, A, Chang-Claude, J, Wang-Gohrke, S, Eilber, U, Moysich, KB, Odunsi, K, Sucheston, L, Lele, S, Wilkens, LR, Goodman, MT, Thompson, PJ, Shvetsov, YB, Runnebaum, IB, Duerst, M, Hillemanns, P, Doerk, T, Antonenkova, N, Bogdanova, N, Leminen, A, Pelttari, LM, Butzow, R, Modugno, F, Kelley, JL, Edwards, RP, Ness, RB, du Bois, A, Heitz, F, Schwaab, I, Harter, P, Matsuo, K, Hosono, S, Orsulic, S, Jensen, A, Kjaer, SK, Hogdall, E, Hasmad, HN, Azmi, MAN, Teo, S-H, Woo, Y-L, Fridley, BL, Goode, EL, Cunningham, JM, Vierkant, RA, Bruinsma, F, Giles, GG, Liang, D, Hildebrandt, MAT, Wu, X, Levine, DA, Bisogna, M, Berchuck, A, Iversen, ES, Schildkraut, JM, Concannon, P, Weber, RP, Cramer, DW, Terry, KL, Poole, EM, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Krakstad, C, Salvesen, HB, Tangen, IL, Bjorge, L, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Kellar, M, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Cybulski, C, Yang, H, Lissowska, J, Brinton, LA, Wentzensen, N, Hogdall, C, Lundvall, L, Nedergaard, L, Baker, H, Song, H, Eccles, D, McNeish, I, Paul, J, Carty, K, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Ji, B-T, Zheng, W, Shu, X-O, Gao, Y-T, Rosen, B, Risch, HA, McLaughlin, JR, Narod, SA, Monteiro, AN, Chen, A, Lin, H-Y, Permuth-Wey, J, Sellers, TA, Tsai, Y-Y, Chen, Z, Ziogas, A, Anton-Culver, H, Gentry-Maharaj, A, Menon, U, Harrington, P, Lee, AW, Wu, AH, Pearce, CL, Coetzee, G, Pike, MC, Dansonka-Mieszkowska, A, Timorek, A, Rzepecka, IK, Kupryjanczyk, J, Freedman, M, Noushmehr, H, Easton, DF, Offit, K, Couch, FJ, Gayther, S, Pharoah, PP, Antoniou, AC, and Chenevix-Trench, G
- Abstract
Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
- Published
- 2015
43. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31
- Author
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Permuth-Wey, J, Lawrenson, K, Shen, HC, Velkova, A, Tyrer, JP, Chen, Z, Lin, HY, Ann Chen, Y, Tsai, YY, Qu, X, Ramus, SJ, Karevan, R, Lee, J, Lee, N, Larson, MC, Aben, KK, Anton-Culver, H, Antonenkova, N, Antoniou, AC, Armasu, SM, Bacot, F, Baglietto, L, Bandera, EV, Barnholtz-Sloan, J, Beckmann, MW, Birrer, MJ, Bloom, G, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Brown, R, Butzow, R, Cai, Q, Campbell, I, Chang-Claude, J, Chanock, S, Chenevix-Trench, G, Cheng, JQ, Cicek, MS, Coetzee, GA, Cook, LS, Couch, FJ, Cramer, DW, Cunningham, JM, Dansonka-Mieszkowska, A, Despierre, E, Doherty, JA, Dörk, T, Du Bois, A, Dürst, M, Easton, DF, Eccles, D, Edwards, R, Ekici, AB, Fasching, PA, Fenstermacher, DA, Flanagan, JM, Garcia-Closas, M, Gentry-Maharaj, A, Giles, GG, Glasspool, RM, Gonzalez-Bosquet, J, Goodman, MT, Gore, M, Górski, B, Gronwald, J, Hall, P, Halle, MK, Harter, P, Heitz, F, Hillemanns, P, Hoatlin, M, Høgdall, CK, Høgdall, E, Hosono, S, Jakubowska, A, Jensen, A, Jim, H, Kalli, KR, Karlan, BY, Kaye, SB, Kelemen, LE, Kiemeney, LA, Kikkawa, F, and Konecny, GE
- Subjects
endocrine system diseases ,female genital diseases and pregnancy complications - Abstract
Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3′ untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10-8) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10-10). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes. © 2013 Macmillan Publishers Limited. All rights reserved.
- Published
- 2013
44. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer
- Author
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Pharoah, PDP, Tsai, YY, Ramus, SJ, Phelan, CM, Goode, EL, Lawrenson, K, Buckley, M, Fridley, BL, Tyrer, JP, Shen, H, Weber, R, Karevan, R, Larson, MC, Song, H, Tessier, DC, Bacot, F, Vincent, D, Cunningham, JM, Dennis, J, Dicks, E, Aben, KK, Anton-Culver, H, Antonenkova, N, Armasu, SM, Baglietto, L, Bandera, EV, Beckmann, MW, Birrer, MJ, Bloom, G, Bogdanova, N, Brenton, JD, Brinton, LA, Brooks-Wilson, A, Brown, R, Butzow, R, Campbell, I, Carney, ME, Carvalho, RS, Chang-Claude, J, Chen, YA, Chen, Z, Chow, WH, Cicek, MS, Coetzee, G, Cook, LS, Cramer, DW, Cybulski, C, Dansonka-Mieszkowska, A, Despierre, E, Doherty, JA, Dörk, T, Du Bois, A, Dürst, M, Eccles, D, Edwards, R, Ekici, AB, Fasching, PA, Fenstermacher, D, Flanagan, J, Gao, YT, Garcia-Closas, M, Gentry-Maharaj, A, Giles, G, Gjyshi, A, Gore, M, Gronwald, J, Guo, Q, Halle, MK, Harter, P, Hein, A, Heitz, F, Hillemanns, P, Hoatlin, M, Høgdall, E, Høgdall, CK, Hosono, S, Jakubowska, A, Jensen, A, Kalli, KR, and Karlan, BY
- Subjects
endocrine system diseases - Abstract
Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10-9) and 10p12 (rs1243180, P = 1.8 × 10-8) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10-10). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.
- Published
- 2013
45. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer
- Author
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Bojesen, S.E., Pooley, K.A., Johnatty, S.E., Beesley, J., Michailidou, K., Tyrer, J.P., Edwards, S.L., Pickett, H.A., Shen, H.C., Smart, C.E., Hillman, K.M., Mai, P.L., Lawrenson, K., Stutz, M.D., Lu, Y., Karevan, R., Woods, N., Johnston, R.L., French, J.D., Chen, X., Weischer, M., Nielsen, S.F., Maranian, M.J., Ghoussaini, M., Ahmed, S., Baynes, C., Bolla, M.K., Wang, Q., Dennis, J., McGuffog, L., Barrowdale, D., Lee, A., Healey, S., Lush, M., Tessier, D.C., Vincent, D., Bacot, F., Vergote, I., Lambrechts, S., Despierre, E., Risch, H.A., Gonzalez-Neira, A., Rossing, M.A., Pita, G., Doherty, J.A., Alvarez, N., Larson, M.C., Fridley, B.L., Schoof, N., Chang-Claude, J., Cicek, M.S., Peto, J., Kalli, K.R., Broeks, A., Armasu, S.M., Schmidt, M.K., Braaf, L.M., Winterhoff, B., Nevanlinna, H., Konecny, G.E., Lambrechts, D., Rogmann, L., Guenel, P., Teoman, A., Milne, R.L., Garcia, J.J., Cox, A, Shridhar, V., Burwinkel, B., Marme, F., Hein, R., Sawyer, E.J., Haiman, C.A., Wang-Gohrke, S., Andrulis, I.L., Moysich, K.B., Hopper, J.L., Odunsi, K., Lindblom, A., Giles, G.G., Brenner, H., Simard, J., Lurie, G., Fasching, P.A., Carney, M.E., Radice, P., Wilkens, L.R., Swerdlow, A., Goodman, M.T., Kiemeney, L.A.L.M., Aben, K.K.H., Altena, A.M. van, Massuger, L.F.A.G., Mensenkamp, A.R., et al., Bojesen, S.E., Pooley, K.A., Johnatty, S.E., Beesley, J., Michailidou, K., Tyrer, J.P., Edwards, S.L., Pickett, H.A., Shen, H.C., Smart, C.E., Hillman, K.M., Mai, P.L., Lawrenson, K., Stutz, M.D., Lu, Y., Karevan, R., Woods, N., Johnston, R.L., French, J.D., Chen, X., Weischer, M., Nielsen, S.F., Maranian, M.J., Ghoussaini, M., Ahmed, S., Baynes, C., Bolla, M.K., Wang, Q., Dennis, J., McGuffog, L., Barrowdale, D., Lee, A., Healey, S., Lush, M., Tessier, D.C., Vincent, D., Bacot, F., Vergote, I., Lambrechts, S., Despierre, E., Risch, H.A., Gonzalez-Neira, A., Rossing, M.A., Pita, G., Doherty, J.A., Alvarez, N., Larson, M.C., Fridley, B.L., Schoof, N., Chang-Claude, J., Cicek, M.S., Peto, J., Kalli, K.R., Broeks, A., Armasu, S.M., Schmidt, M.K., Braaf, L.M., Winterhoff, B., Nevanlinna, H., Konecny, G.E., Lambrechts, D., Rogmann, L., Guenel, P., Teoman, A., Milne, R.L., Garcia, J.J., Cox, A, Shridhar, V., Burwinkel, B., Marme, F., Hein, R., Sawyer, E.J., Haiman, C.A., Wang-Gohrke, S., Andrulis, I.L., Moysich, K.B., Hopper, J.L., Odunsi, K., Lindblom, A., Giles, G.G., Brenner, H., Simard, J., Lurie, G., Fasching, P.A., Carney, M.E., Radice, P., Wilkens, L.R., Swerdlow, A., Goodman, M.T., Kiemeney, L.A.L.M., Aben, K.K.H., Altena, A.M. van, Massuger, L.F.A.G., Mensenkamp, A.R., and et al.
- Abstract
Contains fulltext : 118827.pdf (publisher's version ) (Closed access), TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed approximately 480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10(-14)) breast and invasive ovarian (P = 1.3 x 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
- Published
- 2013
46. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer
- Author
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Shen, H., Fridley, B.L., Song, H., Lawrenson, K., Cunningham, J.M., Ramus, S.J., Cicek, M.S., Tyrer, J., Stram, D., Larson, M.C., Kobel, M., Ziogas, A., Zheng, W., Yang, H.P., Wu, A.H., Wozniak, E.L., Ling Woo, Y., Winterhoff, B., Wik, E., Whittemore, A.S., Wentzensen, N., Palmieri Weber, R., Vitonis, A.F., Vincent, D., Vierkant, R.A., Vergote, I., Berg, D.P.G. van den, Altena, A.M. van, Tworoger, S.S., Thompson, P.J., Tessier, D.C., Terry, K.L., Teo, S.H., Templeman, C., Stram, D.O., Southey, M.C., Sieh, W., Siddiqui, N., Shvetsov, Y.B., Shu, X.O., Shridhar, V., Wang-Gohrke, S., Severi, G., Schwaab, I., Salvesen, H.B., Rzepecka, I.K., Runnebaum, I.B., Rossing, M.A., Rodriguez-Rodriguez, L., Risch, H.A., Renner, S.P., Poole, E.M., Pike, M.C., Phelan, C.M., Pelttari, L.M., Pejovic, T., Paul, J., Orlow, I., Zawiah Omar, S., Olson, S.H., Odunsi, K., Nickels, S., Nevanlinna, H., Ness, R.B., Narod, S.A., Nakanishi, T., Moysich, K.B., Monteiro, A.N., Moes-Sosnowska, J., Modugno, F., Menon, U., McLaughlin, J.R., McGuire, V., Matsuo, K., Mat Adenan, N.A., Massuger, L.F.A.G., Lurie, G., Lundvall, L., Lubinski, J., Lissowska, J., Levine, D.A., Leminen, A., Lee, A.W., Le, N.D., Lambrechts, S., Lambrechts, D., Kupryjanczyk, J., Krakstad, C., Konecny, G.E., Kruger Kjaer, S., Kiemeney, L.A.L.M., Kelemen, L.E., Keeney, G.L., Karlan, B.Y., Karevan, R., Kalli, K.R., Kajiyama, H., Ji, B.T., Jensen, A., Jakubowska, A., Iversen, E., Hosono, S., Hogdall, C.K., Hogdall, E., Hoatlin, M., Hillemans, P., Heitz, F., Hein, R., Harter, P., Halle, M.K., Hall, P., Gronwald, J., Gore, M., Goodman, M.T., Giles, G.G., Gentry-Maharaj, A., Garcia-Closas, M., Flanagan, J.M., Fasching, P.A., Ekici, A.B., Edwards, R., Eccles, D., Easton, D.F., Durst, M., Bois, A. du, Dork, T., Doherty, J.A., Despierre, E., Dansonka-Mieszkowska, A., Cybulski, C., Cramer, D.W, Cook, L.S., Chen, X., Charbonneau, B., Chang-Claude, J., Campbell, I., Butzow, R., Bunker, C.H., Brueggmann, D., Brown, R., Brooks-Wilson, A., Brinton, L.A., Bogdanova, N., Block, M.S., Benjamin, E., Beesley, J., Beckmann, M.W., Bandera, E.V., Baglietto, L., Bacot, F., Armasu, S.M., Antonenkova, N., Anton-Culver, H., Aben, K.K.H., Liang, D., et al., Shen, H., Fridley, B.L., Song, H., Lawrenson, K., Cunningham, J.M., Ramus, S.J., Cicek, M.S., Tyrer, J., Stram, D., Larson, M.C., Kobel, M., Ziogas, A., Zheng, W., Yang, H.P., Wu, A.H., Wozniak, E.L., Ling Woo, Y., Winterhoff, B., Wik, E., Whittemore, A.S., Wentzensen, N., Palmieri Weber, R., Vitonis, A.F., Vincent, D., Vierkant, R.A., Vergote, I., Berg, D.P.G. van den, Altena, A.M. van, Tworoger, S.S., Thompson, P.J., Tessier, D.C., Terry, K.L., Teo, S.H., Templeman, C., Stram, D.O., Southey, M.C., Sieh, W., Siddiqui, N., Shvetsov, Y.B., Shu, X.O., Shridhar, V., Wang-Gohrke, S., Severi, G., Schwaab, I., Salvesen, H.B., Rzepecka, I.K., Runnebaum, I.B., Rossing, M.A., Rodriguez-Rodriguez, L., Risch, H.A., Renner, S.P., Poole, E.M., Pike, M.C., Phelan, C.M., Pelttari, L.M., Pejovic, T., Paul, J., Orlow, I., Zawiah Omar, S., Olson, S.H., Odunsi, K., Nickels, S., Nevanlinna, H., Ness, R.B., Narod, S.A., Nakanishi, T., Moysich, K.B., Monteiro, A.N., Moes-Sosnowska, J., Modugno, F., Menon, U., McLaughlin, J.R., McGuire, V., Matsuo, K., Mat Adenan, N.A., Massuger, L.F.A.G., Lurie, G., Lundvall, L., Lubinski, J., Lissowska, J., Levine, D.A., Leminen, A., Lee, A.W., Le, N.D., Lambrechts, S., Lambrechts, D., Kupryjanczyk, J., Krakstad, C., Konecny, G.E., Kruger Kjaer, S., Kiemeney, L.A.L.M., Kelemen, L.E., Keeney, G.L., Karlan, B.Y., Karevan, R., Kalli, K.R., Kajiyama, H., Ji, B.T., Jensen, A., Jakubowska, A., Iversen, E., Hosono, S., Hogdall, C.K., Hogdall, E., Hoatlin, M., Hillemans, P., Heitz, F., Hein, R., Harter, P., Halle, M.K., Hall, P., Gronwald, J., Gore, M., Goodman, M.T., Giles, G.G., Gentry-Maharaj, A., Garcia-Closas, M., Flanagan, J.M., Fasching, P.A., Ekici, A.B., Edwards, R., Eccles, D., Easton, D.F., Durst, M., Bois, A. du, Dork, T., Doherty, J.A., Despierre, E., Dansonka-Mieszkowska, A., Cybulski, C., Cramer, D.W, Cook, L.S., Chen, X., Charbonneau, B., Chang-Claude, J., Campbell, I., Butzow, R., Bunker, C.H., Brueggmann, D., Brown, R., Brooks-Wilson, A., Brinton, L.A., Bogdanova, N., Block, M.S., Benjamin, E., Beesley, J., Beckmann, M.W., Bandera, E.V., Baglietto, L., Bacot, F., Armasu, S.M., Antonenkova, N., Anton-Culver, H., Aben, K.K.H., Liang, D., and et al.
- Abstract
Contains fulltext : 118378.pdf (publisher's version ) (Open Access), HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 x 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 x 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.
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- 2013
47. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31
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Permuth-Wey, J., Lawrenson, K., Shen, H.C., Velkova, A., Tyrer, J.P., Chen, Z., Lin, H.Y., Ann Chen, Y., Tsai, Y.Y., Qu, X., Ramus, S.J., Karevan, R., Lee, J. van der, Lee, N., Larson, M.C., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Antoniou, A.C., Armasu, S.M., Bacot, F., Baglietto, L., Bandera, E.V., Barnholtz-Sloan, J., Beckmann, M.W., Birrer, M.J., Bloom, G., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Brown, R., Butzow, R., Cai, Q., Campbell, I., Chang-Claude, J., Chanock, S., Chenevix-Trench, G., Cheng, J.Q., Cicek, M.S., Coetzee, G.A., Cook, L.S., Couch, F.J., Cramer, D.W, Cunningham, J.M., Dansonka-Mieszkowska, A., Despierre, E., Doherty, J.A., Dork, T., Bois, A. du, Durst, M., Easton, D.F., Eccles, D., Edwards, R., Ekici, A.B., Fasching, P.A., Fenstermacher, D.A., Flanagan, J.M., Garcia-Closas, M., Gentry-Maharaj, A., Giles, G.G., Glasspool, R.M., Gonzalez-Bosquet, J., Goodman, M.T., Gore, M., Gorski, B., Gronwald, J., Hall, P., Halle, M.K., Harter, P., Heitz, F., Hillemanns, P., Hoatlin, M., Hogdall, C.K., Hogdall, E., Hosono, S., Jakubowska, A., Jensen, A., Jim, H., Kalli, K.R., Karlan, B.Y., Kaye, S.B., Kelemen, L.E., Kiemeney, L.A.L.M., Kikkawa, F., Konecny, G.E., Krakstad, C., Kruger Kjaer, S., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Lancaster, J.M., Le, N.D., Leminen, A., Levine, D.A., Liang, D., Kiong Lim, B., Lin, J., Massuger, L.F.A.G., Altena, A.M. van, et al., Permuth-Wey, J., Lawrenson, K., Shen, H.C., Velkova, A., Tyrer, J.P., Chen, Z., Lin, H.Y., Ann Chen, Y., Tsai, Y.Y., Qu, X., Ramus, S.J., Karevan, R., Lee, J. van der, Lee, N., Larson, M.C., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Antoniou, A.C., Armasu, S.M., Bacot, F., Baglietto, L., Bandera, E.V., Barnholtz-Sloan, J., Beckmann, M.W., Birrer, M.J., Bloom, G., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., Brown, R., Butzow, R., Cai, Q., Campbell, I., Chang-Claude, J., Chanock, S., Chenevix-Trench, G., Cheng, J.Q., Cicek, M.S., Coetzee, G.A., Cook, L.S., Couch, F.J., Cramer, D.W, Cunningham, J.M., Dansonka-Mieszkowska, A., Despierre, E., Doherty, J.A., Dork, T., Bois, A. du, Durst, M., Easton, D.F., Eccles, D., Edwards, R., Ekici, A.B., Fasching, P.A., Fenstermacher, D.A., Flanagan, J.M., Garcia-Closas, M., Gentry-Maharaj, A., Giles, G.G., Glasspool, R.M., Gonzalez-Bosquet, J., Goodman, M.T., Gore, M., Gorski, B., Gronwald, J., Hall, P., Halle, M.K., Harter, P., Heitz, F., Hillemanns, P., Hoatlin, M., Hogdall, C.K., Hogdall, E., Hosono, S., Jakubowska, A., Jensen, A., Jim, H., Kalli, K.R., Karlan, B.Y., Kaye, S.B., Kelemen, L.E., Kiemeney, L.A.L.M., Kikkawa, F., Konecny, G.E., Krakstad, C., Kruger Kjaer, S., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Lancaster, J.M., Le, N.D., Leminen, A., Levine, D.A., Liang, D., Kiong Lim, B., Lin, J., Massuger, L.F.A.G., Altena, A.M. van, and et al.
- Abstract
Contains fulltext : 118576.pdf (publisher's version ) (Open Access), Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.
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- 2013
48. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer
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Pharoah, P.D., Tsai, Y.Y., Ramus, S.J., Phelan, C.M., Goode, E.L., Lawrenson, K., Buckley, M., Fridley, B.L., Tyrer, J.P., Shen, H., Weber, R., Karevan, R., Larson, M.C., Song, H., Tessier, D.C., Bacot, F., Vincent, D., Cunningham, J.M., Dennis, J., Dicks, E., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Armasu, S.M., Baglietto, L., Bandera, E.V., Beckmann, M.W., Birrer, M.J., Bloom, G., Bogdanova, N., Brenton, J.D., Brinton, L.A., Brooks-Wilson, A., Brown, R., Butzow, R., Campbell, I., Carney, M.E., Carvalho, R.S., Chang-Claude, J., Chen, Y.A., Chen, Z., Chow, W.H., Cicek, M.S., Coetzee, G., Cook, L.S., Cramer, D.W, Cybulski, C., Dansonka-Mieszkowska, A., Despierre, E., Doherty, J.A., Dork, T., Bois, A. du, Durst, M., Eccles, D., Edwards, R., Ekici, A.B., Fasching, P.A., Fenstermacher, D., Flanagan, J., Gao, Y.T., Garcia-Closas, M., Gentry-Maharaj, A., Giles, G., Gjyshi, A., Gore, M., Gronwald, J., Guo, Q., Halle, M.K., Harter, P., Hein, A., Heitz, F., Hillemanns, P., Hoatlin, M., Hogdall, E., Hogdall, C.K., Hosono, S., Jakubowska, A., Jensen, A., Kalli, K.R., Karlan, B.Y., Kelemen, L.E., Kiemeney, L.A.L.M., Kjaer, S.K., Konecny, G.E., Krakstad, C., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, N., Lee, J. van der, Leminen, A., Lim, B.K., Lissowska, J., Lubinski, J., Lundvall, L., Lurie, G., Massuger, L.F.A.G., Altena, A.M. van, Pharoah, P.D., Tsai, Y.Y., Ramus, S.J., Phelan, C.M., Goode, E.L., Lawrenson, K., Buckley, M., Fridley, B.L., Tyrer, J.P., Shen, H., Weber, R., Karevan, R., Larson, M.C., Song, H., Tessier, D.C., Bacot, F., Vincent, D., Cunningham, J.M., Dennis, J., Dicks, E., Aben, K.K.H., Anton-Culver, H., Antonenkova, N., Armasu, S.M., Baglietto, L., Bandera, E.V., Beckmann, M.W., Birrer, M.J., Bloom, G., Bogdanova, N., Brenton, J.D., Brinton, L.A., Brooks-Wilson, A., Brown, R., Butzow, R., Campbell, I., Carney, M.E., Carvalho, R.S., Chang-Claude, J., Chen, Y.A., Chen, Z., Chow, W.H., Cicek, M.S., Coetzee, G., Cook, L.S., Cramer, D.W, Cybulski, C., Dansonka-Mieszkowska, A., Despierre, E., Doherty, J.A., Dork, T., Bois, A. du, Durst, M., Eccles, D., Edwards, R., Ekici, A.B., Fasching, P.A., Fenstermacher, D., Flanagan, J., Gao, Y.T., Garcia-Closas, M., Gentry-Maharaj, A., Giles, G., Gjyshi, A., Gore, M., Gronwald, J., Guo, Q., Halle, M.K., Harter, P., Hein, A., Heitz, F., Hillemanns, P., Hoatlin, M., Hogdall, E., Hogdall, C.K., Hosono, S., Jakubowska, A., Jensen, A., Kalli, K.R., Karlan, B.Y., Kelemen, L.E., Kiemeney, L.A.L.M., Kjaer, S.K., Konecny, G.E., Krakstad, C., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N.D., Lee, N., Lee, J. van der, Leminen, A., Lim, B.K., Lissowska, J., Lubinski, J., Lundvall, L., Lurie, G., Massuger, L.F.A.G., and Altena, A.M. van
- Abstract
Contains fulltext : 118459.pdf (publisher's version ) (Closed access), Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 x 10(-9)) and 10p12 (rs1243180, P = 1.8 x 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 x 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.
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- 2013
49. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer
- Author
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Shen, H, Fridley, BL, Song, H, Lawrenson, K, Cunningham, JM, Ramus, SJ, Cicek, MS, Tyrer, J, Stram, D, Larson, MC, Koebel, M, Ziogas, A, Zheng, W, Yang, HP, Wu, AH, Wozniak, EL, Woo, YL, Winterhoff, B, Wik, E, Whittemore, AS, Wentzensen, N, Weber, RP, Vitonis, AF, Vincent, D, Vierkant, RA, Vergote, I, Van Den Berg, D, Van Altena, AM, Tworoger, SS, Thompson, PJ, Tessier, DC, Terry, KL, Teo, S-H, Templeman, C, Stram, DO, Southey, MC, Sieh, W, Siddiqui, N, Shvetsov, YB, Shu, X-O, Shridhar, V, Wang-Gohrke, S, Severi, G, Schwaab, I, Salvesen, HB, Rzepecka, IK, Runnebaum, IB, Rossing, MA, Rodriguez-Rodriguez, L, Risch, HA, Renner, SP, Poole, EM, Pike, MC, Phelan, CM, Pelttari, LM, Pejovic, T, Paul, J, Orlow, I, Omar, SZ, Olson, SH, Odunsi, K, Nickels, S, Nevanlinna, H, Ness, RB, Narod, SA, Nakanishi, T, Moysich, KB, Monteiro, ANA, Moes-Sosnowska, J, Modugno, F, Menon, U, McLaughlin, JR, McGuire, V, Matsuo, K, Adenan, NAM, Massuger, LFAG, Lurie, G, Lundvall, L, Lubinski, J, Lissowska, J, Levine, DA, Leminen, A, Lee, AW, Le, ND, Lambrechts, S, Lambrechts, D, Kupryjanczyk, J, Krakstad, C, Konecny, GE, Kjaer, SK, Kiemeney, LA, Kelemen, LE, Keeney, GL, Karlan, BY, Karevan, R, Kalli, KR, Kajiyama, H, Ji, B-T, Jensen, A, Jakubowska, A, Iversen, E, Hosono, S, Hogdall, CK, Hogdall, E, Hoatlin, M, Hillemanns, P, Heitz, F, Hein, R, Harter, P, Halle, MK, Hall, P, Gronwald, J, Gore, M, Goodman, MT, Giles, GG, Gentry-Maharaj, A, Garcia-Closas, M, Flanagan, JM, Fasching, PA, Ekici, AB, Edwards, R, Eccles, D, Easton, DF, Duerst, M, du Bois, A, Doerk, T, Doherty, JA, Despierre, E, Dansonka-Mieszkowska, A, Cybulski, C, Cramer, DW, Cook, LS, Chen, X, Charbonneau, B, Chang-Claude, J, Campbell, I, Butzow, R, Bunker, CH, Brueggmann, D, Brown, R, Brooks-Wilson, A, Brinton, LA, Bogdanova, N, Block, MS, Benjamin, E, Beesley, J, Beckmann, MW, Bandera, EV, Baglietto, L, Bacot, F, Armasu, SM, Antonenkova, N, Anton-Culver, H, Aben, KK, Liang, D, Wu, X, Lu, K, Hildebrandt, MAT, Schildkraut, JM, Sellers, TA, Huntsman, D, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Pharoah, PDP, Laird, PW, Goode, EL, Pearce, CL, Shen, H, Fridley, BL, Song, H, Lawrenson, K, Cunningham, JM, Ramus, SJ, Cicek, MS, Tyrer, J, Stram, D, Larson, MC, Koebel, M, Ziogas, A, Zheng, W, Yang, HP, Wu, AH, Wozniak, EL, Woo, YL, Winterhoff, B, Wik, E, Whittemore, AS, Wentzensen, N, Weber, RP, Vitonis, AF, Vincent, D, Vierkant, RA, Vergote, I, Van Den Berg, D, Van Altena, AM, Tworoger, SS, Thompson, PJ, Tessier, DC, Terry, KL, Teo, S-H, Templeman, C, Stram, DO, Southey, MC, Sieh, W, Siddiqui, N, Shvetsov, YB, Shu, X-O, Shridhar, V, Wang-Gohrke, S, Severi, G, Schwaab, I, Salvesen, HB, Rzepecka, IK, Runnebaum, IB, Rossing, MA, Rodriguez-Rodriguez, L, Risch, HA, Renner, SP, Poole, EM, Pike, MC, Phelan, CM, Pelttari, LM, Pejovic, T, Paul, J, Orlow, I, Omar, SZ, Olson, SH, Odunsi, K, Nickels, S, Nevanlinna, H, Ness, RB, Narod, SA, Nakanishi, T, Moysich, KB, Monteiro, ANA, Moes-Sosnowska, J, Modugno, F, Menon, U, McLaughlin, JR, McGuire, V, Matsuo, K, Adenan, NAM, Massuger, LFAG, Lurie, G, Lundvall, L, Lubinski, J, Lissowska, J, Levine, DA, Leminen, A, Lee, AW, Le, ND, Lambrechts, S, Lambrechts, D, Kupryjanczyk, J, Krakstad, C, Konecny, GE, Kjaer, SK, Kiemeney, LA, Kelemen, LE, Keeney, GL, Karlan, BY, Karevan, R, Kalli, KR, Kajiyama, H, Ji, B-T, Jensen, A, Jakubowska, A, Iversen, E, Hosono, S, Hogdall, CK, Hogdall, E, Hoatlin, M, Hillemanns, P, Heitz, F, Hein, R, Harter, P, Halle, MK, Hall, P, Gronwald, J, Gore, M, Goodman, MT, Giles, GG, Gentry-Maharaj, A, Garcia-Closas, M, Flanagan, JM, Fasching, PA, Ekici, AB, Edwards, R, Eccles, D, Easton, DF, Duerst, M, du Bois, A, Doerk, T, Doherty, JA, Despierre, E, Dansonka-Mieszkowska, A, Cybulski, C, Cramer, DW, Cook, LS, Chen, X, Charbonneau, B, Chang-Claude, J, Campbell, I, Butzow, R, Bunker, CH, Brueggmann, D, Brown, R, Brooks-Wilson, A, Brinton, LA, Bogdanova, N, Block, MS, Benjamin, E, Beesley, J, Beckmann, MW, Bandera, EV, Baglietto, L, Bacot, F, Armasu, SM, Antonenkova, N, Anton-Culver, H, Aben, KK, Liang, D, Wu, X, Lu, K, Hildebrandt, MAT, Schildkraut, JM, Sellers, TA, Huntsman, D, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Pharoah, PDP, Laird, PW, Goode, EL, and Pearce, CL
- Abstract
HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.
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- 2013
50. A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24.
- Author
-
Goode, E.L., Chenevix-Trench, G., Song, H., Ramus, S.J., Notaridou, M., Lawrenson, K., Widschwendter, M., Vierkant, R.A., Larson, M.C., Kjaer, S.K., Birrer, M.J., Berchuck, A., Schildkraut, J., Tomlinson, I.P., Kiemeney, L.A.L.M., Cook, L.S., Gronwald, J., Garcia-Closas, M., Gore, M.E., Campbell, I., Whittemore, A.S., Sutphen, R., Phelan, C.M., Anton-Culver, H., Pearce, C.L., Lambrechts, D., Rossing, M.A., Chang-Claude, J., Moysich, K.B., Goodman, M.T., Dork, T., Nevanlinna, H., Ness, R.B., Rafnar, T., Hogdall, E., Fridley, B.L., Cunningham, J.M., Sieh, W., McGuire, V., Godwin, A.K., Cramer, D.W, Hernandez, D., Levine, D., Lu, K., Iversen, E.S., Palmieri, R.T., Houlston, R.S., Altena, A.M. van, Aben, K.K.H., Massuger, L.F.A.G., Brooks-Wilson, A., Kelemen, L.E., Le, N.D., Jakubowska, A., Lubinski, J., Medrek, K., Stafford, A., Easton, D.F., Tyrer, J.P., Bolton, K.L., Harrington, P., Eccles, D., Chen, A., Molina, A.N., Davila, B.N., Arango, H., Tsai, Y.Y., Chen, Z., Risch, H.A., McLaughlin, J., Narod, S., Ziogas, A., Brewster, W., Gentry-Maharaj, A., Menon, U., Wu, A.H., Stram, D.O., Pike, M.C., Beesley, J., Webb, P.M., Chen, X., Ekici, A.B., Thiel, F.C., Beckmann, M.W., Yang, H., Wentzensen, N., Lissowska, J., Fasching, P.A., Despierre, E., Amant, F., Vergote, I., Doherty, J., Hein, R., Wang-Gohrke, S., Lurie, G., Carney, M.E., Thompson, P., Goode, E.L., Chenevix-Trench, G., Song, H., Ramus, S.J., Notaridou, M., Lawrenson, K., Widschwendter, M., Vierkant, R.A., Larson, M.C., Kjaer, S.K., Birrer, M.J., Berchuck, A., Schildkraut, J., Tomlinson, I.P., Kiemeney, L.A.L.M., Cook, L.S., Gronwald, J., Garcia-Closas, M., Gore, M.E., Campbell, I., Whittemore, A.S., Sutphen, R., Phelan, C.M., Anton-Culver, H., Pearce, C.L., Lambrechts, D., Rossing, M.A., Chang-Claude, J., Moysich, K.B., Goodman, M.T., Dork, T., Nevanlinna, H., Ness, R.B., Rafnar, T., Hogdall, E., Fridley, B.L., Cunningham, J.M., Sieh, W., McGuire, V., Godwin, A.K., Cramer, D.W, Hernandez, D., Levine, D., Lu, K., Iversen, E.S., Palmieri, R.T., Houlston, R.S., Altena, A.M. van, Aben, K.K.H., Massuger, L.F.A.G., Brooks-Wilson, A., Kelemen, L.E., Le, N.D., Jakubowska, A., Lubinski, J., Medrek, K., Stafford, A., Easton, D.F., Tyrer, J.P., Bolton, K.L., Harrington, P., Eccles, D., Chen, A., Molina, A.N., Davila, B.N., Arango, H., Tsai, Y.Y., Chen, Z., Risch, H.A., McLaughlin, J., Narod, S., Ziogas, A., Brewster, W., Gentry-Maharaj, A., Menon, U., Wu, A.H., Stram, D.O., Pike, M.C., Beesley, J., Webb, P.M., Chen, X., Ekici, A.B., Thiel, F.C., Beckmann, M.W., Yang, H., Wentzensen, N., Lissowska, J., Fasching, P.A., Despierre, E., Amant, F., Vergote, I., Doherty, J., Hein, R., Wang-Gohrke, S., Lurie, G., Carney, M.E., and Thompson, P.
- Abstract
Contains fulltext : 89180.pdf (publisher's version ) (Closed access)
- Published
- 2010
Catalog
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