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1. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants.

Author: Gesta P., Mulligan A.M., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Niederacher D., Nielsen F.C., Nikitina-Zake L., Nogues C., Olah E., Olopade O.I., Ong K.-R., O'Shaughnessy-Kirwan A., Osorio A., Ott C.-E., Papi L., Park S.K., Parsons M.T., Pedersen I.S., Peissel B., Peixoto A., Peterlongo P., Pfeiler G., Phillips K.-A., Prajzendanc K., Pujana M.A., Radice P., Ramser J., Ramus S.J., Rantala J., Rennert G., Risch H.A., Robson M., Ronlund K., Salani R., Schuster H., Senter L., Shah P.D., Sharma P., Side L.E., Singer C.F., Slavin T.P., Soucy P., Southey M.C., Spurdle A.B., Steinemann D., Steinsnyder Z., Stoppa-Lyonnet D., Sutter C., Tan Y.Y., Teixeira M.R., Teo S.H., Thull D.L., Tischkowitz M., Tognazzo S., Toland A.E., Trainer A.H., Tung N., van Engelen K., van Rensburg E.J., Vega A., Vierstraete J., Wagner G., Walker L., Wang-Gohrke S., Wappenschmidt B., Weitzel J.N., Yadav S., Yang X., Yannoukakos D., Zimbalatti D., Offit K., Thomassen M., Couch F.J., Schmutzler R.K., Simard J., Easton D.F., Antoniou A.C., GEMO Study Collaborators, EMBRACE Collaborators, kConFab Investigators, HEBON Investigators, GENEPSO Investigators, Barnes D.R., Rookus M.A., McGuffog L., Leslie G., Mooij T.M., Dennis J., Mavaddat N., Aittomaki K., Andrulis I.L., Arnold N., Arun B.K., Azzollini J., Balmana J., Barkardottir R.B., Benitez J., Bialkowska K., Blanco A.M., Blok M.J., Bonanni B., Boonen S.E., Borg A., Bozsik A., Bradbury A.R., Brunet J., Buys S.S., Caldes T., Caligo M.A., Campbell I., Christensen L.L., Chung W.K., Claes K.B.M., Berthet P., Colas C., Adlard J., Ahmed M., Antoniou A., Barrowdale D., Brennan P., Brewer C., Easton D., Evans D.G., Side L., Collonge-Rame M.-A., Cook J., Daly M.B., Davidson R., de la Hoya M., de Putter R., Delnatte C., Diez O., Ding Y.C., Domchek S.M., Dorfling C.M., Dumont M., Eeles R., Ejlertsen B., Engel C., Faivre L., Foretova L., Fostira F., Friedlander M., Friedman E., Frost D., Ganz P.A., Garber J., Gehrig A., Gerdes A.-M., Giraud S., Glendon G., Godwin A.K., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Gschwantler-Kaulich D., Hahnen E., Hamann U., Hanson H., Hentschel J., Hogervorst F.B.L., Hooning M.J., Horvath J., Hu C., Hulick P.J., Imyanitov E.N., Chenevix-Trench G., Spurdle A., Blok M., Devilee P., Hogervorst F., Hooning M., Mensenkamp A., Meijers-Heijboer H., Rookus M., Engelen K., Andrieu N., Isaacs C., Izatt L., Izquierdo A., Jakubowska A., James P.A., Janavicius R., John E.M., Joseph V., Karlan B.Y., Kast K., Koudijs M., Kruse T.A., Kwong A., Laitman Y., Lasset C., Lazaro C., Lester J., Lesueur F., Liljegren A., Loud J.T., Lubinski J., Mai P.L., Manoukian S., Mari V., Mebirouk N., Meijers-Heijboer H.E.J., Meindl A., Mensenkamp A.R., Miller A., Montagna M., Mouret-Fourme E., Mukherjee S., Gesta P., Mulligan A.M., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Niederacher D., Nielsen F.C., Nikitina-Zake L., Nogues C., Olah E., Olopade O.I., Ong K.-R., O'Shaughnessy-Kirwan A., Osorio A., Ott C.-E., Papi L., Park S.K., Parsons M.T., Pedersen I.S., Peissel B., Peixoto A., Peterlongo P., Pfeiler G., Phillips K.-A., Prajzendanc K., Pujana M.A., Radice P., Ramser J., Ramus S.J., Rantala J., Rennert G., Risch H.A., Robson M., Ronlund K., Salani R., Schuster H., Senter L., Shah P.D., Sharma P., Side L.E., Singer C.F., Slavin T.P., Soucy P., Southey M.C., Spurdle A.B., Steinemann D., Steinsnyder Z., Stoppa-Lyonnet D., Sutter C., Tan Y.Y., Teixeira M.R., Teo S.H., Thull D.L., Tischkowitz M., Tognazzo S., Toland A.E., Trainer A.H., Tung N., van Engelen K., van Rensburg E.J., Vega A., Vierstraete J., Wagner G., Walker L., Wang-Gohrke S., Wappenschmidt B., Weitzel J.N., Yadav S., Yang X., Yannoukakos D., Zimbalatti D., Offit K., Thomassen M., Couch F.J., Schmutzler R.K., Simard J., Easton D.F., Antoniou A.C., GEMO Study Collaborators, EMBRACE Collaborators, kConFab Investigators, HEBON Investigators, GENEPSO Investigators, Barnes D.R., Rookus M.A., McGuffog L., Leslie G., Mooij T.M., Dennis J., Mavaddat N., Aittomaki K., Andrulis I.L., Arnold N., Arun B.K., Azzollini J., Balmana J., Barkardottir R.B., Benitez J., Bialkowska K., Blanco A.M., Blok M.J., Bonanni B., Boonen S.E., Borg A., Bozsik A., Bradbury A.R., Brunet J., Buys S.S., Caldes T., Caligo M.A., Campbell I., Christensen L.L., Chung W.K., Claes K.B.M., Berthet P., Colas C., Adlard J., Ahmed M., Antoniou A., Barrowdale D., Brennan P., Brewer C., Easton D., Evans D.G., Side L., Collonge-Rame M.-A., Cook J., Daly M.B., Davidson R., de la Hoya M., de Putter R., Delnatte C., Diez O., Ding Y.C., Domchek S.M., Dorfling C.M., Dumont M., Eeles R., Ejlertsen B., Engel C., Faivre L., Foretova L., Fostira F., Friedlander M., Friedman E., Frost D., Ganz P.A., Garber J., Gehrig A., Gerdes A.-M., Giraud S., Glendon G., Godwin A.K., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Gschwantler-Kaulich D., Hahnen E., Hamann U., Hanson H., Hentschel J., Hogervorst F.B.L., Hooning M.J., Horvath J., Hu C., Hulick P.J., Imyanitov E.N., Chenevix-Trench G., Spurdle A., Blok M., Devilee P., Hogervorst F., Hooning M., Mensenkamp A., Meijers-Heijboer H., Rookus M., Engelen K., Andrieu N., Isaacs C., Izatt L., Izquierdo A., Jakubowska A., James P.A., Janavicius R., John E.M., Joseph V., Karlan B.Y., Kast K., Koudijs M., Kruse T.A., Kwong A., Laitman Y., Lasset C., Lazaro C., Lester J., Lesueur F., Liljegren A., Loud J.T., Lubinski J., Mai P.L., Manoukian S., Mari V., Mebirouk N., Meijers-Heijboer H.E.J., Meindl A., Mensenkamp A.R., Miller A., Montagna M., Mouret-Fourme E., and Mukherjee S.
Abstract: Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. Method(s): Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Result(s): The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3x10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7x10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3x10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4x10-12) carriers. The associations in the prospective cohort were similar. Conclusion(s): Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.Copyright © 2020, The Author(s).
Published: 2021

2. Characterization of the Cancer Spectrum in Men with Germline BRCA1 and BRCA2 Pathogenic Variants: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

Author: Joseph V., Easton D.F., Ejlertsen B., Engel C., Evans D.G., Feliubadalo L., Foretova L., Fostira F., Geczi L., Gerdes A.-M., Glendon G., Godwin A.K., Goldgar D.E., Hahnen E., Hogervorst F.B.L., Hopper J.L., Hulick P.J., Isaacs C., Izquierdo A., James P.A., Janavicius R., Jensen U.B., John E.M., Konstantopoulou I., Kurian A.W., Kwong A., Landucci E., Lesueur F., Loud J.T., Machackova E., Mai P.L., Majidzadeh-A K., Manoukian S., Montagna M., Moserle L., Mulligan A.M., Nathanson K.L., Nevanlinna H., Ngeow Yuen Ye J., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Osorio A., Papi L., Park S.K., Pedersen I.S., Perez-Segura P., Petersen A.H., Pinto P., Porfirio B., Pujana M.A., Radice P., Rantala J., Rashid M.U., Rosenzweig B., Rossing M., Santamarina M., Schmutzler R.K., Senter L., Simard J., Singer C.F., Solano A.R., Southey M.C., Steele L., Steinsnyder Z., Stoppa-Lyonnet D., Tan Y.Y., Teixeira M.R., Teo S.H., Terry M.B., Thomassen M., Toland A.E., Torres-Esquius S., Tung N., Van Asperen C.J., Vega A., Viel A., Vierstraete J., Wappenschmidt B., Weitzel J.N., Wieme G., Yoon S.-Y., Zorn K.K., Mcguffog L., Parsons M.T., Hamann U., Greene M.H., Kirk J.A., Neuhausen S.L., Rebbeck T.R., Tischkowitz M., Chenevix-Trench G., Antoniou A.C., Friedman E., Ottini L., Silvestri V., Leslie G., Barnes D.R., Agnarsson B.A., Aittomaki K., Alducci E., Andrulis I.L., Barkardottir R.B., Barroso A., Barrowdale D., Benitez J., Bonanni B., Borg A., Buys S.S., Caldes T., Caligo M.A., Capalbo C., Campbell I., Chung W.K., Claes K.B.M., Colonna S.V., Cortesi L., Couch F.J., De La Hoya M., Diez O., Ding Y.C., Domchek S., Joseph V., Easton D.F., Ejlertsen B., Engel C., Evans D.G., Feliubadalo L., Foretova L., Fostira F., Geczi L., Gerdes A.-M., Glendon G., Godwin A.K., Goldgar D.E., Hahnen E., Hogervorst F.B.L., Hopper J.L., Hulick P.J., Isaacs C., Izquierdo A., James P.A., Janavicius R., Jensen U.B., John E.M., Konstantopoulou I., Kurian A.W., Kwong A., Landucci E., Lesueur F., Loud J.T., Machackova E., Mai P.L., Majidzadeh-A K., Manoukian S., Montagna M., Moserle L., Mulligan A.M., Nathanson K.L., Nevanlinna H., Ngeow Yuen Ye J., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Osorio A., Papi L., Park S.K., Pedersen I.S., Perez-Segura P., Petersen A.H., Pinto P., Porfirio B., Pujana M.A., Radice P., Rantala J., Rashid M.U., Rosenzweig B., Rossing M., Santamarina M., Schmutzler R.K., Senter L., Simard J., Singer C.F., Solano A.R., Southey M.C., Steele L., Steinsnyder Z., Stoppa-Lyonnet D., Tan Y.Y., Teixeira M.R., Teo S.H., Terry M.B., Thomassen M., Toland A.E., Torres-Esquius S., Tung N., Van Asperen C.J., Vega A., Viel A., Vierstraete J., Wappenschmidt B., Weitzel J.N., Wieme G., Yoon S.-Y., Zorn K.K., Mcguffog L., Parsons M.T., Hamann U., Greene M.H., Kirk J.A., Neuhausen S.L., Rebbeck T.R., Tischkowitz M., Chenevix-Trench G., Antoniou A.C., Friedman E., Ottini L., Silvestri V., Leslie G., Barnes D.R., Agnarsson B.A., Aittomaki K., Alducci E., Andrulis I.L., Barkardottir R.B., Barroso A., Barrowdale D., Benitez J., Bonanni B., Borg A., Buys S.S., Caldes T., Caligo M.A., Capalbo C., Campbell I., Chung W.K., Claes K.B.M., Colonna S.V., Cortesi L., Couch F.J., De La Hoya M., Diez O., Ding Y.C., and Domchek S.
Abstract: Importance: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. Objective(s): To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. Design, Setting, and Participant(s): Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. Main Outcomes and Measures: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. Result(s): Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P <.001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P <.001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P <.001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P <.001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P =.008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P =.001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P =.003) of being a BRCA2 PV carrier. Conclusions and Relevance: Significant differences in the cancer spectrum w
Published: 2021

3. Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores.

Author: Barnes D.R., Silvestri V., Leslie G., McGuffog L., Dennis J., Yang X., Adlard J., Agnarsson B.A., Ahmed M., Aittomaki K., Andrulis I.L., Arason A., Arnold N., Auber B., Azzollini J., Balmana J., Barkardottir R.B., Barrowdale D., Barwell J., Belotti M., Benitez J., Berthet P., Boonen S.E., Borg A., Bozsik A., Brady A., Brennan P., Brewer C., Brunet J., Bucalo A., Buys S.S., Caldes T., Caligo M.A., Campbell I., Cassingham H., Lotte Christensen L., Cini G., Claes K.B.M., Cook J., Coppa A., Cortesi L., Damante G., Darder E., Davidson R., de la Hoya M., De Leeneer K., de Putter R., Del Valle J., Diez O., Chun Ding Y., Domchek S.M., Donaldson A., Eason J., Eeles R., Engel C., Gareth Evans D., Feliubadalo L., Fostira F., Frone M., Frost D., Gallagher D., Gehrig A., Giraud S., Glendon G., Godwin A.K., Goldgar D.E., Greene M.H., Gregory H., Gross E., Hahnen E., Hamann U., Hansen T.V.O., Hanson H., Hentschel J., Horvath J., Izatt L., Izquierdo A., James P.A., Janavicius R., Birk Jensen U., Johannsson O.T., John E.M., Kramer G., Kroeldrup L., Kruse T.A., Lautrup C., Lazaro C., Lesueur F., Lopez-Fernandez A., Mai P.L., Manoukian S., Matrai Z., Matricardi L., Maxwell K.N., Mebirouk N., Meindl A., Montagna M., Monteiro A.N., Morrison P.J., Muranen T.A., Murray A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nguyen-Dumont T., Niederacher D., Olah E., Olopade O.I., Palli D., Parsons M.T., Sokilde Pedersen I., Peissel B., Perez-Segura P., Peterlongo P., Petersen A.H., Pinto P., Porteous M.E., Pottinger C., Angel Pujana M., Radice P., Ramser J., Rantala J., Robson M., Rogers M.T., Ronlund K., Rump A., Maria Sanchez de Abajo A., Shah P.D., Sharif S., Side L.E., Singer C.F., Stadler Z., Steele L., Stoppa-Lyonnet D., Sutter C., Yen Tan Y., Teixeira M.R., Teule A., Thull D.L., Tischkowitz M., Toland A.E., Tommasi S., Toss A., Trainer A.H., Tripathi V., Valentini V., van Asperen C.J., Venturelli M., Viel A., Vijai J., Walker L., Wang-Gohrke S., Wappenschmidt B., Whaite A., Zanna I., Offit K., Thomassen M., Couch F.J., Schmutzler R.K., Simard J., Easton D.F., Chenevix-Trench G., Antoniou A.C., Ottini L., Barnes D.R., Silvestri V., Leslie G., McGuffog L., Dennis J., Yang X., Adlard J., Agnarsson B.A., Ahmed M., Aittomaki K., Andrulis I.L., Arason A., Arnold N., Auber B., Azzollini J., Balmana J., Barkardottir R.B., Barrowdale D., Barwell J., Belotti M., Benitez J., Berthet P., Boonen S.E., Borg A., Bozsik A., Brady A., Brennan P., Brewer C., Brunet J., Bucalo A., Buys S.S., Caldes T., Caligo M.A., Campbell I., Cassingham H., Lotte Christensen L., Cini G., Claes K.B.M., Cook J., Coppa A., Cortesi L., Damante G., Darder E., Davidson R., de la Hoya M., De Leeneer K., de Putter R., Del Valle J., Diez O., Chun Ding Y., Domchek S.M., Donaldson A., Eason J., Eeles R., Engel C., Gareth Evans D., Feliubadalo L., Fostira F., Frone M., Frost D., Gallagher D., Gehrig A., Giraud S., Glendon G., Godwin A.K., Goldgar D.E., Greene M.H., Gregory H., Gross E., Hahnen E., Hamann U., Hansen T.V.O., Hanson H., Hentschel J., Horvath J., Izatt L., Izquierdo A., James P.A., Janavicius R., Birk Jensen U., Johannsson O.T., John E.M., Kramer G., Kroeldrup L., Kruse T.A., Lautrup C., Lazaro C., Lesueur F., Lopez-Fernandez A., Mai P.L., Manoukian S., Matrai Z., Matricardi L., Maxwell K.N., Mebirouk N., Meindl A., Montagna M., Monteiro A.N., Morrison P.J., Muranen T.A., Murray A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nguyen-Dumont T., Niederacher D., Olah E., Olopade O.I., Palli D., Parsons M.T., Sokilde Pedersen I., Peissel B., Perez-Segura P., Peterlongo P., Petersen A.H., Pinto P., Porteous M.E., Pottinger C., Angel Pujana M., Radice P., Ramser J., Rantala J., Robson M., Rogers M.T., Ronlund K., Rump A., Maria Sanchez de Abajo A., Shah P.D., Sharif S., Side L.E., Singer C.F., Stadler Z., Steele L., Stoppa-Lyonnet D., Sutter C., Yen Tan Y., Teixeira M.R., Teule A., Thull D.L., Tischkowitz M., Toland A.E., Tommasi S., Toss A., Trainer A.H., Tripathi V., Valentini V., van Asperen C.J., Venturelli M., Viel A., Vijai J., Walker L., Wang-Gohrke S., Wappenschmidt B., Whaite A., Zanna I., Offit K., Thomassen M., Couch F.J., Schmutzler R.K., Simard J., Easton D.F., Chenevix-Trench G., Antoniou A.C., and Ottini L.
Abstract: BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. METHOD(S): 483 BRCA1 and 1,318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were three versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen-receptor (ER) negative (PRSER-) or ER-positive (PRSER+) breast cancer risk. RESULT(S): PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07-1.83) for BRCA1 and 1.33 (95% CI=1.16-1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for both BRCA1 (OR=1.73, 95% CI=1.28-2.33) and BRCA2 (OR=1.60, 95% CI=1.34-1.91) carriers. The estimated breast cancer ORs were larger after adjusting for female relative breast cancer family history. By age 85years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. CONCLUSION(S): Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and to inform clinical management.Copyright © The Author(s) 2021. Published by Oxford University Press.
Published: 2021

4. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants.

Author: Gesta P., Mulligan A.M., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Niederacher D., Nielsen F.C., Nikitina-Zake L., Nogues C., Olah E., Olopade O.I., Ong K.-R., O'Shaughnessy-Kirwan A., Osorio A., Ott C.-E., Papi L., Park S.K., Parsons M.T., Pedersen I.S., Peissel B., Peixoto A., Peterlongo P., Pfeiler G., Phillips K.-A., Prajzendanc K., Pujana M.A., Radice P., Ramser J., Ramus S.J., Rantala J., Rennert G., Risch H.A., Robson M., Ronlund K., Salani R., Schuster H., Senter L., Shah P.D., Sharma P., Side L.E., Singer C.F., Slavin T.P., Soucy P., Southey M.C., Spurdle A.B., Steinemann D., Steinsnyder Z., Stoppa-Lyonnet D., Sutter C., Tan Y.Y., Teixeira M.R., Teo S.H., Thull D.L., Tischkowitz M., Tognazzo S., Toland A.E., Trainer A.H., Tung N., van Engelen K., van Rensburg E.J., Vega A., Vierstraete J., Wagner G., Walker L., Wang-Gohrke S., Wappenschmidt B., Weitzel J.N., Yadav S., Yang X., Yannoukakos D., Zimbalatti D., Offit K., Thomassen M., Couch F.J., Schmutzler R.K., Simard J., Easton D.F., Antoniou A.C., GEMO Study Collaborators, EMBRACE Collaborators, kConFab Investigators, HEBON Investigators, GENEPSO Investigators, Barnes D.R., Rookus M.A., McGuffog L., Leslie G., Mooij T.M., Dennis J., Mavaddat N., Aittomaki K., Andrulis I.L., Arnold N., Arun B.K., Azzollini J., Balmana J., Barkardottir R.B., Benitez J., Bialkowska K., Blanco A.M., Blok M.J., Bonanni B., Boonen S.E., Borg A., Bozsik A., Bradbury A.R., Brunet J., Buys S.S., Caldes T., Caligo M.A., Campbell I., Christensen L.L., Chung W.K., Claes K.B.M., Berthet P., Colas C., Adlard J., Ahmed M., Antoniou A., Barrowdale D., Brennan P., Brewer C., Easton D., Evans D.G., Side L., Collonge-Rame M.-A., Cook J., Daly M.B., Davidson R., de la Hoya M., de Putter R., Delnatte C., Diez O., Ding Y.C., Domchek S.M., Dorfling C.M., Dumont M., Eeles R., Ejlertsen B., Engel C., Faivre L., Foretova L., Fostira F., Friedlander M., Friedman E., Frost D., Ganz P.A., Garber J., Gehrig A., Gerdes A.-M., Giraud S., Glendon G., Godwin A.K., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Gschwantler-Kaulich D., Hahnen E., Hamann U., Hanson H., Hentschel J., Hogervorst F.B.L., Hooning M.J., Horvath J., Hu C., Hulick P.J., Imyanitov E.N., Chenevix-Trench G., Spurdle A., Blok M., Devilee P., Hogervorst F., Hooning M., Mensenkamp A., Meijers-Heijboer H., Rookus M., Engelen K., Andrieu N., Isaacs C., Izatt L., Izquierdo A., Jakubowska A., James P.A., Janavicius R., John E.M., Joseph V., Karlan B.Y., Kast K., Koudijs M., Kruse T.A., Kwong A., Laitman Y., Lasset C., Lazaro C., Lester J., Lesueur F., Liljegren A., Loud J.T., Lubinski J., Mai P.L., Manoukian S., Mari V., Mebirouk N., Meijers-Heijboer H.E.J., Meindl A., Mensenkamp A.R., Miller A., Montagna M., Mouret-Fourme E., Mukherjee S., Gesta P., Mulligan A.M., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Niederacher D., Nielsen F.C., Nikitina-Zake L., Nogues C., Olah E., Olopade O.I., Ong K.-R., O'Shaughnessy-Kirwan A., Osorio A., Ott C.-E., Papi L., Park S.K., Parsons M.T., Pedersen I.S., Peissel B., Peixoto A., Peterlongo P., Pfeiler G., Phillips K.-A., Prajzendanc K., Pujana M.A., Radice P., Ramser J., Ramus S.J., Rantala J., Rennert G., Risch H.A., Robson M., Ronlund K., Salani R., Schuster H., Senter L., Shah P.D., Sharma P., Side L.E., Singer C.F., Slavin T.P., Soucy P., Southey M.C., Spurdle A.B., Steinemann D., Steinsnyder Z., Stoppa-Lyonnet D., Sutter C., Tan Y.Y., Teixeira M.R., Teo S.H., Thull D.L., Tischkowitz M., Tognazzo S., Toland A.E., Trainer A.H., Tung N., van Engelen K., van Rensburg E.J., Vega A., Vierstraete J., Wagner G., Walker L., Wang-Gohrke S., Wappenschmidt B., Weitzel J.N., Yadav S., Yang X., Yannoukakos D., Zimbalatti D., Offit K., Thomassen M., Couch F.J., Schmutzler R.K., Simard J., Easton D.F., Antoniou A.C., GEMO Study Collaborators, EMBRACE Collaborators, kConFab Investigators, HEBON Investigators, GENEPSO Investigators, Barnes D.R., Rookus M.A., McGuffog L., Leslie G., Mooij T.M., Dennis J., Mavaddat N., Aittomaki K., Andrulis I.L., Arnold N., Arun B.K., Azzollini J., Balmana J., Barkardottir R.B., Benitez J., Bialkowska K., Blanco A.M., Blok M.J., Bonanni B., Boonen S.E., Borg A., Bozsik A., Bradbury A.R., Brunet J., Buys S.S., Caldes T., Caligo M.A., Campbell I., Christensen L.L., Chung W.K., Claes K.B.M., Berthet P., Colas C., Adlard J., Ahmed M., Antoniou A., Barrowdale D., Brennan P., Brewer C., Easton D., Evans D.G., Side L., Collonge-Rame M.-A., Cook J., Daly M.B., Davidson R., de la Hoya M., de Putter R., Delnatte C., Diez O., Ding Y.C., Domchek S.M., Dorfling C.M., Dumont M., Eeles R., Ejlertsen B., Engel C., Faivre L., Foretova L., Fostira F., Friedlander M., Friedman E., Frost D., Ganz P.A., Garber J., Gehrig A., Gerdes A.-M., Giraud S., Glendon G., Godwin A.K., Goldgar D.E., Gonzalez-Neira A., Greene M.H., Gschwantler-Kaulich D., Hahnen E., Hamann U., Hanson H., Hentschel J., Hogervorst F.B.L., Hooning M.J., Horvath J., Hu C., Hulick P.J., Imyanitov E.N., Chenevix-Trench G., Spurdle A., Blok M., Devilee P., Hogervorst F., Hooning M., Mensenkamp A., Meijers-Heijboer H., Rookus M., Engelen K., Andrieu N., Isaacs C., Izatt L., Izquierdo A., Jakubowska A., James P.A., Janavicius R., John E.M., Joseph V., Karlan B.Y., Kast K., Koudijs M., Kruse T.A., Kwong A., Laitman Y., Lasset C., Lazaro C., Lester J., Lesueur F., Liljegren A., Loud J.T., Lubinski J., Mai P.L., Manoukian S., Mari V., Mebirouk N., Meijers-Heijboer H.E.J., Meindl A., Mensenkamp A.R., Miller A., Montagna M., Mouret-Fourme E., and Mukherjee S.
Abstract: Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. Method(s): Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Result(s): The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3x10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7x10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3x10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4x10-12) carriers. The associations in the prospective cohort were similar. Conclusion(s): Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.Copyright © 2020, The Author(s).
Published: 2021

5. Characterization of the Cancer Spectrum in Men with Germline BRCA1 and BRCA2 Pathogenic Variants: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

Author: Joseph V., Easton D.F., Ejlertsen B., Engel C., Evans D.G., Feliubadalo L., Foretova L., Fostira F., Geczi L., Gerdes A.-M., Glendon G., Godwin A.K., Goldgar D.E., Hahnen E., Hogervorst F.B.L., Hopper J.L., Hulick P.J., Isaacs C., Izquierdo A., James P.A., Janavicius R., Jensen U.B., John E.M., Konstantopoulou I., Kurian A.W., Kwong A., Landucci E., Lesueur F., Loud J.T., Machackova E., Mai P.L., Majidzadeh-A K., Manoukian S., Montagna M., Moserle L., Mulligan A.M., Nathanson K.L., Nevanlinna H., Ngeow Yuen Ye J., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Osorio A., Papi L., Park S.K., Pedersen I.S., Perez-Segura P., Petersen A.H., Pinto P., Porfirio B., Pujana M.A., Radice P., Rantala J., Rashid M.U., Rosenzweig B., Rossing M., Santamarina M., Schmutzler R.K., Senter L., Simard J., Singer C.F., Solano A.R., Southey M.C., Steele L., Steinsnyder Z., Stoppa-Lyonnet D., Tan Y.Y., Teixeira M.R., Teo S.H., Terry M.B., Thomassen M., Toland A.E., Torres-Esquius S., Tung N., Van Asperen C.J., Vega A., Viel A., Vierstraete J., Wappenschmidt B., Weitzel J.N., Wieme G., Yoon S.-Y., Zorn K.K., Mcguffog L., Parsons M.T., Hamann U., Greene M.H., Kirk J.A., Neuhausen S.L., Rebbeck T.R., Tischkowitz M., Chenevix-Trench G., Antoniou A.C., Friedman E., Ottini L., Silvestri V., Leslie G., Barnes D.R., Agnarsson B.A., Aittomaki K., Alducci E., Andrulis I.L., Barkardottir R.B., Barroso A., Barrowdale D., Benitez J., Bonanni B., Borg A., Buys S.S., Caldes T., Caligo M.A., Capalbo C., Campbell I., Chung W.K., Claes K.B.M., Colonna S.V., Cortesi L., Couch F.J., De La Hoya M., Diez O., Ding Y.C., Domchek S., Joseph V., Easton D.F., Ejlertsen B., Engel C., Evans D.G., Feliubadalo L., Foretova L., Fostira F., Geczi L., Gerdes A.-M., Glendon G., Godwin A.K., Goldgar D.E., Hahnen E., Hogervorst F.B.L., Hopper J.L., Hulick P.J., Isaacs C., Izquierdo A., James P.A., Janavicius R., Jensen U.B., John E.M., Konstantopoulou I., Kurian A.W., Kwong A., Landucci E., Lesueur F., Loud J.T., Machackova E., Mai P.L., Majidzadeh-A K., Manoukian S., Montagna M., Moserle L., Mulligan A.M., Nathanson K.L., Nevanlinna H., Ngeow Yuen Ye J., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Osorio A., Papi L., Park S.K., Pedersen I.S., Perez-Segura P., Petersen A.H., Pinto P., Porfirio B., Pujana M.A., Radice P., Rantala J., Rashid M.U., Rosenzweig B., Rossing M., Santamarina M., Schmutzler R.K., Senter L., Simard J., Singer C.F., Solano A.R., Southey M.C., Steele L., Steinsnyder Z., Stoppa-Lyonnet D., Tan Y.Y., Teixeira M.R., Teo S.H., Terry M.B., Thomassen M., Toland A.E., Torres-Esquius S., Tung N., Van Asperen C.J., Vega A., Viel A., Vierstraete J., Wappenschmidt B., Weitzel J.N., Wieme G., Yoon S.-Y., Zorn K.K., Mcguffog L., Parsons M.T., Hamann U., Greene M.H., Kirk J.A., Neuhausen S.L., Rebbeck T.R., Tischkowitz M., Chenevix-Trench G., Antoniou A.C., Friedman E., Ottini L., Silvestri V., Leslie G., Barnes D.R., Agnarsson B.A., Aittomaki K., Alducci E., Andrulis I.L., Barkardottir R.B., Barroso A., Barrowdale D., Benitez J., Bonanni B., Borg A., Buys S.S., Caldes T., Caligo M.A., Capalbo C., Campbell I., Chung W.K., Claes K.B.M., Colonna S.V., Cortesi L., Couch F.J., De La Hoya M., Diez O., Ding Y.C., and Domchek S.
Abstract: Importance: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. Objective(s): To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. Design, Setting, and Participant(s): Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. Main Outcomes and Measures: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. Result(s): Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P <.001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P <.001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P <.001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P <.001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P =.008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P =.001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P =.003) of being a BRCA2 PV carrier. Conclusions and Relevance: Significant differences in the cancer spectrum w
Published: 2021

6. Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores.

Author: Barnes D.R., Silvestri V., Leslie G., McGuffog L., Dennis J., Yang X., Adlard J., Agnarsson B.A., Ahmed M., Aittomaki K., Andrulis I.L., Arason A., Arnold N., Auber B., Azzollini J., Balmana J., Barkardottir R.B., Barrowdale D., Barwell J., Belotti M., Benitez J., Berthet P., Boonen S.E., Borg A., Bozsik A., Brady A., Brennan P., Brewer C., Brunet J., Bucalo A., Buys S.S., Caldes T., Caligo M.A., Campbell I., Cassingham H., Lotte Christensen L., Cini G., Claes K.B.M., Cook J., Coppa A., Cortesi L., Damante G., Darder E., Davidson R., de la Hoya M., De Leeneer K., de Putter R., Del Valle J., Diez O., Chun Ding Y., Domchek S.M., Donaldson A., Eason J., Eeles R., Engel C., Gareth Evans D., Feliubadalo L., Fostira F., Frone M., Frost D., Gallagher D., Gehrig A., Giraud S., Glendon G., Godwin A.K., Goldgar D.E., Greene M.H., Gregory H., Gross E., Hahnen E., Hamann U., Hansen T.V.O., Hanson H., Hentschel J., Horvath J., Izatt L., Izquierdo A., James P.A., Janavicius R., Birk Jensen U., Johannsson O.T., John E.M., Kramer G., Kroeldrup L., Kruse T.A., Lautrup C., Lazaro C., Lesueur F., Lopez-Fernandez A., Mai P.L., Manoukian S., Matrai Z., Matricardi L., Maxwell K.N., Mebirouk N., Meindl A., Montagna M., Monteiro A.N., Morrison P.J., Muranen T.A., Murray A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nguyen-Dumont T., Niederacher D., Olah E., Olopade O.I., Palli D., Parsons M.T., Sokilde Pedersen I., Peissel B., Perez-Segura P., Peterlongo P., Petersen A.H., Pinto P., Porteous M.E., Pottinger C., Angel Pujana M., Radice P., Ramser J., Rantala J., Robson M., Rogers M.T., Ronlund K., Rump A., Maria Sanchez de Abajo A., Shah P.D., Sharif S., Side L.E., Singer C.F., Stadler Z., Steele L., Stoppa-Lyonnet D., Sutter C., Yen Tan Y., Teixeira M.R., Teule A., Thull D.L., Tischkowitz M., Toland A.E., Tommasi S., Toss A., Trainer A.H., Tripathi V., Valentini V., van Asperen C.J., Venturelli M., Viel A., Vijai J., Walker L., Wang-Gohrke S., Wappenschmidt B., Whaite A., Zanna I., Offit K., Thomassen M., Couch F.J., Schmutzler R.K., Simard J., Easton D.F., Chenevix-Trench G., Antoniou A.C., Ottini L., Barnes D.R., Silvestri V., Leslie G., McGuffog L., Dennis J., Yang X., Adlard J., Agnarsson B.A., Ahmed M., Aittomaki K., Andrulis I.L., Arason A., Arnold N., Auber B., Azzollini J., Balmana J., Barkardottir R.B., Barrowdale D., Barwell J., Belotti M., Benitez J., Berthet P., Boonen S.E., Borg A., Bozsik A., Brady A., Brennan P., Brewer C., Brunet J., Bucalo A., Buys S.S., Caldes T., Caligo M.A., Campbell I., Cassingham H., Lotte Christensen L., Cini G., Claes K.B.M., Cook J., Coppa A., Cortesi L., Damante G., Darder E., Davidson R., de la Hoya M., De Leeneer K., de Putter R., Del Valle J., Diez O., Chun Ding Y., Domchek S.M., Donaldson A., Eason J., Eeles R., Engel C., Gareth Evans D., Feliubadalo L., Fostira F., Frone M., Frost D., Gallagher D., Gehrig A., Giraud S., Glendon G., Godwin A.K., Goldgar D.E., Greene M.H., Gregory H., Gross E., Hahnen E., Hamann U., Hansen T.V.O., Hanson H., Hentschel J., Horvath J., Izatt L., Izquierdo A., James P.A., Janavicius R., Birk Jensen U., Johannsson O.T., John E.M., Kramer G., Kroeldrup L., Kruse T.A., Lautrup C., Lazaro C., Lesueur F., Lopez-Fernandez A., Mai P.L., Manoukian S., Matrai Z., Matricardi L., Maxwell K.N., Mebirouk N., Meindl A., Montagna M., Monteiro A.N., Morrison P.J., Muranen T.A., Murray A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nguyen-Dumont T., Niederacher D., Olah E., Olopade O.I., Palli D., Parsons M.T., Sokilde Pedersen I., Peissel B., Perez-Segura P., Peterlongo P., Petersen A.H., Pinto P., Porteous M.E., Pottinger C., Angel Pujana M., Radice P., Ramser J., Rantala J., Robson M., Rogers M.T., Ronlund K., Rump A., Maria Sanchez de Abajo A., Shah P.D., Sharif S., Side L.E., Singer C.F., Stadler Z., Steele L., Stoppa-Lyonnet D., Sutter C., Yen Tan Y., Teixeira M.R., Teule A., Thull D.L., Tischkowitz M., Toland A.E., Tommasi S., Toss A., Trainer A.H., Tripathi V., Valentini V., van Asperen C.J., Venturelli M., Viel A., Vijai J., Walker L., Wang-Gohrke S., Wappenschmidt B., Whaite A., Zanna I., Offit K., Thomassen M., Couch F.J., Schmutzler R.K., Simard J., Easton D.F., Chenevix-Trench G., Antoniou A.C., and Ottini L.
Abstract: BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. METHOD(S): 483 BRCA1 and 1,318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were three versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen-receptor (ER) negative (PRSER-) or ER-positive (PRSER+) breast cancer risk. RESULT(S): PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07-1.83) for BRCA1 and 1.33 (95% CI=1.16-1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for both BRCA1 (OR=1.73, 95% CI=1.28-2.33) and BRCA2 (OR=1.60, 95% CI=1.34-1.91) carriers. The estimated breast cancer ORs were larger after adjusting for female relative breast cancer family history. By age 85years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. CONCLUSION(S): Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and to inform clinical management.Copyright © The Author(s) 2021. Published by Oxford University Press.
Published: 2021

7. Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness.

Author: Engel C., Schmutzler R.K., Schuster H., Senter L., Seynaeve C.M., Shah P.D., Sharma P., Shin V.Y., Silvestri V., Simard J., Singer C.F., Skytte A.-B., Snape K., Solano A.R., Soucy P., Southey M.C., Spurdle A.B., Steele L., Steinemann D., Stoppa-Lyonnet D., Stradella A., Sunde L., Sutter C., Tan Y.Y., Teixeira M.R., Teo S.H., Thomassen M., Tibiletti M.G., Tischkowitz M., Tognazzo S., Toland A.E., Tommasi S., Torres D., Toss A., Trainer A.H., Tung N., Van Asperen C.J., Van Der Baan F.H., Van Der Kolk L.E., Van Der Luijt R.B., Van Hest L.P., Varesco L., Varon-Mateeva R., Viel A., Vierstrate J., Villa R., Von Wachenfeldt A., Wagner P., Wang-Gohrke S., Wappenschmidt B., Weitzel J.N., Wieme G., Yadav S., Yannoukakos D., Yoon S.-Y., Zanzottera C., Zorn K.K., D'Amico A.V., Freedman M.L., Pomerantz M.M., Chenevix-Trench G., Antoniou A.C., Neuhausen S.L., Ottini L., Nielsen H.R., Rebbeck T.R., Patel V.L., Busch E.L., Friebel T.M., Cronin A., Leslie G., McGuffog L., Adlard J., Agata S., Agnarsson B.A., Ahmed M., Aittom K., Alducci E., Andrulis I.L., Arason A., Arnold N., Artioli G., Arver B., Auber B., Azzollini J., Balmana J., Barkardottir R.B., Barnes D.R., Barroso A., Barrowdale D., Belotti M., Benitez J., Bertelsen B., Blok M.J., Bodrogi I., Bonadona V., Bonanni B., Bondavalli D., Boonen S.E., Borde J., Borg A., Bradbury A.R., Brady A., Brewer C., Brunet J., Buecher B., Buys S.S., Cabezas-Camarero S., Caldes T., Caliebe A., Caligo M.A., Calvello M., Campbell I.G., Carnevali I., Carrasco E., Chan T.L., Chu A.T.W., Chung W.K., Claes K.B.M., Cook J., Cortesi L., Couch F.J., Daly M.B., Damante G., Darder E., Davidson R., De La Hoya M., Della Puppa L., Dennis J., Diez O., Ding Y.C., Ditsch N., Domchek S.M., Donaldson A., Dworniczak B., Easton D.F., Eccles D.M., Eeles R.A., Ehrencrona H., Ejlertsen B., Evans D.G., Faivre L., Faust U., Feliubadalo L., Foretova L., Fostira F., Fountzilas G., Frost D., Garcia-Barberan V., Garre P., Gauthier-Villars M., Geczi L., Gehrig A., Gerdes A.-M., Gesta P., Giannini G., Glendon G., Godwin A.K., Goldgar D.E., Greene M.H., Gutierrez-Barrera A.M., Hahnen E., Hamann U., Hauke J., Herold N., Hogervorst F.B.L., Honisch E., Hopper J.L., Hulick P.J., Izatt L., Jager A., James P., Janavicius R., Jensen U.B., Jensen T.D., Johannsson O.Th., John E.M., Joseph V., Kang E., Kast K., Kiiski J.I., Kim S.-W., Kim Z., Ko K.-P., Konstantopoulou I., Kramer G., Krogh L., Kruse T.A., Kwong A., Larsen M., Lasset C., Lautrup C., Lazaro C., Lee J., Lee J.W., Lee M.H., Lemke J., Lesueur F., Liljegren A., Lindblom A., Llovet P., Lopez-Fernandez A., Lopez-Perolio I., Lorca V., Loud J.T., Ma E.S.K., Mai P.L., Manoukian S., Mari V., Martin L., Matricardi L., Mebirouk N., Medici V., Meijers-Heijboer H.E.J., Meindl A., Mensenkamp A.R., Miller C., Gomes D.M., Montagna M., Mooij T.M., Moserle L., Mouret-Fourme E., Mulligan A.M., Nathanson K.L., Navratilova M., Nevanlinna H., Niederacher D., Cilius Nielsen F.C., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Ong K.-R., Osorio A., Ott C.-E., Palli D., Park S.K., Parsons M.T., Pedersen I.S., Peissel B., Peixoto A., Perez-Segura P., Peterlongo P., Petersen A.H., Porteous M.E., Pujana M.A., Radice P., Ramser J., Rantala J., Rashid M.U., Rhiem K., Rizzolo P., Robson M.E., Rookus M.A., Rossing C.M., Ruddy K.J., Santos C., Saule C., Scarpitta R., Engel C., Schmutzler R.K., Schuster H., Senter L., Seynaeve C.M., Shah P.D., Sharma P., Shin V.Y., Silvestri V., Simard J., Singer C.F., Skytte A.-B., Snape K., Solano A.R., Soucy P., Southey M.C., Spurdle A.B., Steele L., Steinemann D., Stoppa-Lyonnet D., Stradella A., Sunde L., Sutter C., Tan Y.Y., Teixeira M.R., Teo S.H., Thomassen M., Tibiletti M.G., Tischkowitz M., Tognazzo S., Toland A.E., Tommasi S., Torres D., Toss A., Trainer A.H., Tung N., Van Asperen C.J., Van Der Baan F.H., Van Der Kolk L.E., Van Der Luijt R.B., Van Hest L.P., Varesco L., Varon-Mateeva R., Viel A., Vierstrate J., Villa R., Von Wachenfeldt A., Wagner P., Wang-Gohrke S., Wappenschmidt B., Weitzel J.N., Wieme G., Yadav S., Yannoukakos D., Yoon S.-Y., Zanzottera C., Zorn K.K., D'Amico A.V., Freedman M.L., Pomerantz M.M., Chenevix-Trench G., Antoniou A.C., Neuhausen S.L., Ottini L., Nielsen H.R., Rebbeck T.R., Patel V.L., Busch E.L., Friebel T.M., Cronin A., Leslie G., McGuffog L., Adlard J., Agata S., Agnarsson B.A., Ahmed M., Aittom K., Alducci E., Andrulis I.L., Arason A., Arnold N., Artioli G., Arver B., Auber B., Azzollini J., Balmana J., Barkardottir R.B., Barnes D.R., Barroso A., Barrowdale D., Belotti M., Benitez J., Bertelsen B., Blok M.J., Bodrogi I., Bonadona V., Bonanni B., Bondavalli D., Boonen S.E., Borde J., Borg A., Bradbury A.R., Brady A., Brewer C., Brunet J., Buecher B., Buys S.S., Cabezas-Camarero S., Caldes T., Caliebe A., Caligo M.A., Calvello M., Campbell I.G., Carnevali I., Carrasco E., Chan T.L., Chu A.T.W., Chung W.K., Claes K.B.M., Cook J., Cortesi L., Couch F.J., Daly M.B., Damante G., Darder E., Davidson R., De La Hoya M., Della Puppa L., Dennis J., Diez O., Ding Y.C., Ditsch N., Domchek S.M., Donaldson A., Dworniczak B., Easton D.F., Eccles D.M., Eeles R.A., Ehrencrona H., Ejlertsen B., Evans D.G., Faivre L., Faust U., Feliubadalo L., Foretova L., Fostira F., Fountzilas G., Frost D., Garcia-Barberan V., Garre P., Gauthier-Villars M., Geczi L., Gehrig A., Gerdes A.-M., Gesta P., Giannini G., Glendon G., Godwin A.K., Goldgar D.E., Greene M.H., Gutierrez-Barrera A.M., Hahnen E., Hamann U., Hauke J., Herold N., Hogervorst F.B.L., Honisch E., Hopper J.L., Hulick P.J., Izatt L., Jager A., James P., Janavicius R., Jensen U.B., Jensen T.D., Johannsson O.Th., John E.M., Joseph V., Kang E., Kast K., Kiiski J.I., Kim S.-W., Kim Z., Ko K.-P., Konstantopoulou I., Kramer G., Krogh L., Kruse T.A., Kwong A., Larsen M., Lasset C., Lautrup C., Lazaro C., Lee J., Lee J.W., Lee M.H., Lemke J., Lesueur F., Liljegren A., Lindblom A., Llovet P., Lopez-Fernandez A., Lopez-Perolio I., Lorca V., Loud J.T., Ma E.S.K., Mai P.L., Manoukian S., Mari V., Martin L., Matricardi L., Mebirouk N., Medici V., Meijers-Heijboer H.E.J., Meindl A., Mensenkamp A.R., Miller C., Gomes D.M., Montagna M., Mooij T.M., Moserle L., Mouret-Fourme E., Mulligan A.M., Nathanson K.L., Navratilova M., Nevanlinna H., Niederacher D., Cilius Nielsen F.C., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Ong K.-R., Osorio A., Ott C.-E., Palli D., Park S.K., Parsons M.T., Pedersen I.S., Peissel B., Peixoto A., Perez-Segura P., Peterlongo P., Petersen A.H., Porteous M.E., Pujana M.A., Radice P., Ramser J., Rantala J., Rashid M.U., Rhiem K., Rizzolo P., Robson M.E., Rookus M.A., Rossing C.M., Ruddy K.J., Santos C., Saule C., and Scarpitta R.
Abstract: Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 30 region of BRCA2 (c.7914) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001c.7913 [HR 1/4 1.78; 95% confidence interval (CI), 1.25-2.52; P 1/4 0.001], as well as elevated risk of Gleason 8 prostate cancer (HR 1/4 3.11; 95% CI, 1.63-5.95; P 1/4 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR 1/4 2.83; 95% CI, 1.71-4.68; P 1/4 0.00004) and elevated risk of Gleason 8 prostate cancer (HR 1/4 4.95; 95% CI, 2.12-11.54; P 1/4 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer.Copyright © 2020 American Association for Cancer Research.
Published: 2020

8. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

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

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

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

10. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Author: Goldgar D.E., Newman W.G., Nielsen F.C., Nikitina-Zake L., Nodora J., Offit K., Olah E., Olopade O.I., Olsson H., Orr N., Papi L., Papp J., Park-Simon T.-W., Parsons M.T., Peissel B., Peixoto A., Peshkin B., Peterlongo P., Peto J., Phillips K.-A., Piedmonte M., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Prokofyeva D., Rack B., Radice P., Ramus S.J., Rantala J., Rashid M.U., Rennert G., Rennert H.S., Risch H.A., Romero A., Rookus M.A., Rubner M., Rudiger T., Saloustros E., Sampson S., Sandler D.P., Sawyer E.J., Scheuner M.T., Schmutzler R.K., Schneeweiss A., Schoemaker M.J., Schottker B., Schurmann P., Senter L., Sharma P., Sherman M.E., Shu X.-O., Singer C.F., Smichkoska S., Soucy P., Southey M.C., Spinelli J.J., Stone J., Stoppa-Lyonnet D., Swerdlow A.J., Szabo C.I., Tamimi R.M., Tapper W.J., Taylor J.A., Teixeira M.R., Terry M.B., Thomassen M., Thull D.L., Tischkowitz M., Toland A.E., Tollenaar R.A.E.M., Tomlinson I., Torres D., Troester M.A., Truong T., Tung N., Untch M., Vachon C.M., van den Ouweland A.M.W., van der Kolk L.E., van Veen E.M., vanRensburg E.J., Vega A., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wildiers H., Winqvist R., Wolk A., Yang X.R., Yannoukakos D., Zheng W., Zorn K.K., Milne R.L., Kraft P., Simard J., Pharoah P.D.P., Michailidou K., Antoniou A.C., Schmidt M.K., Chenevix-Trench G., Easton D.F., Chatterjee N., Garcia-Closas M., Zhang H., Ahearn T.U., Lecarpentier J., Barnes D., Beesley J., Qi G., Jiang X., O'Mara T.A., Zhao N., Bolla M.K., Dunning A.M., Dennis J., Wang Q., Ful Z.A., Aittomaki K., Andrulis I.L., Anton-Culver H., Arndt V., Aronson K.J., Arun B.K., Auer P.L., Azzollini J., Barrowdale D., Becher H., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bialkowska K., Blanco A., Blomqvist C., Bogdanova N.V., Bojesen S.E., Bonanni B., Bondavalli D., Borg A., Brauch H., Brenner H., Briceno I., Broeks A., Brucker S.Y., Bruning T., Burwinkel B., Buys S.S., Byers H., Caldes T., Caligo M.A., Calvello M., Campa D., Castelao J.E., Chang-Claude J., Chanock S.J., Christiaens M., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Cornelissen S., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Devilee P., Diez O., Domchek S.M., Dork T., Dwek M., Eccles D.M., Ekici A.B., Evans D.G., Fasching P.A., Figueroa J., Foretova L., Fostira F., Friedman E., Frost D., Gago-Dominguez M., Gapstur S.M., Garber J., Garcia-Saenz J.A., Gaudet M.M., Gayther S.A., Giles G.G., Godwin A.K., Goldberg M.S., Gonzalez-Neira A., Greene M.H., Gronwald J., Guenel P., Haberle L., Hahnen E., Haiman C.A., Hake C.R., Hall P., Hamann U., Harkness E.F., Heemskerk-Gerritsen B.A.M., Hillemanns P., Hogervorst F.B.L., Holleczek B., Hollestelle A., Hooning M.J., Hoover R.N., Hopper J.L., Howell A., Huebner H., Hulick P.J., Imyanitov E.N., Isaacs C., Izatt L., Jager A., Jakimovska M., Jakubowska A., James P., Janavicius R., Janni W., John E.M., Jones M.E., Jung A., Kaaks R., Kapoor P.M., Karlan B.Y., Keeman R., Khan S., Khusnutdinova E., Kitahara C.M., Ko Y.-D., Konstantopoulou I., Koppert L.B., Koutros S., Kristensen V.N., Laenkholm A.-V., Lambrechts D., Larsson S.C., Laurent-Puig P., Lazaro C., Lazarova E., Lejbkowicz F., Leslie G., Lesueur F., Lindblom A., Lissowska J., Lo W.-Y., Loud J.T., Lubinski J., Lukomska A., MacInnis R.J., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Matricardi L., McGuffog L., McLean C., Mebirouk N., Meindl A., Menon U., Miller A., Mingazheva E., Montagna M., Mulligan A.M., Mulot C., Muranen T.A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Neven P., Goldgar D.E., Newman W.G., Nielsen F.C., Nikitina-Zake L., Nodora J., Offit K., Olah E., Olopade O.I., Olsson H., Orr N., Papi L., Papp J., Park-Simon T.-W., Parsons M.T., Peissel B., Peixoto A., Peshkin B., Peterlongo P., Peto J., Phillips K.-A., Piedmonte M., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Prokofyeva D., Rack B., Radice P., Ramus S.J., Rantala J., Rashid M.U., Rennert G., Rennert H.S., Risch H.A., Romero A., Rookus M.A., Rubner M., Rudiger T., Saloustros E., Sampson S., Sandler D.P., Sawyer E.J., Scheuner M.T., Schmutzler R.K., Schneeweiss A., Schoemaker M.J., Schottker B., Schurmann P., Senter L., Sharma P., Sherman M.E., Shu X.-O., Singer C.F., Smichkoska S., Soucy P., Southey M.C., Spinelli J.J., Stone J., Stoppa-Lyonnet D., Swerdlow A.J., Szabo C.I., Tamimi R.M., Tapper W.J., Taylor J.A., Teixeira M.R., Terry M.B., Thomassen M., Thull D.L., Tischkowitz M., Toland A.E., Tollenaar R.A.E.M., Tomlinson I., Torres D., Troester M.A., Truong T., Tung N., Untch M., Vachon C.M., van den Ouweland A.M.W., van der Kolk L.E., van Veen E.M., vanRensburg E.J., Vega A., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wildiers H., Winqvist R., Wolk A., Yang X.R., Yannoukakos D., Zheng W., Zorn K.K., Milne R.L., Kraft P., Simard J., Pharoah P.D.P., Michailidou K., Antoniou A.C., Schmidt M.K., Chenevix-Trench G., Easton D.F., Chatterjee N., Garcia-Closas M., Zhang H., Ahearn T.U., Lecarpentier J., Barnes D., Beesley J., Qi G., Jiang X., O'Mara T.A., Zhao N., Bolla M.K., Dunning A.M., Dennis J., Wang Q., Ful Z.A., Aittomaki K., Andrulis I.L., Anton-Culver H., Arndt V., Aronson K.J., Arun B.K., Auer P.L., Azzollini J., Barrowdale D., Becher H., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bialkowska K., Blanco A., Blomqvist C., Bogdanova N.V., Bojesen S.E., Bonanni B., Bondavalli D., Borg A., Brauch H., Brenner H., Briceno I., Broeks A., Brucker S.Y., Bruning T., Burwinkel B., Buys S.S., Byers H., Caldes T., Caligo M.A., Calvello M., Campa D., Castelao J.E., Chang-Claude J., Chanock S.J., Christiaens M., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Cornelissen S., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Devilee P., Diez O., Domchek S.M., Dork T., Dwek M., Eccles D.M., Ekici A.B., Evans D.G., Fasching P.A., Figueroa J., Foretova L., Fostira F., Friedman E., Frost D., Gago-Dominguez M., Gapstur S.M., Garber J., Garcia-Saenz J.A., Gaudet M.M., Gayther S.A., Giles G.G., Godwin A.K., Goldberg M.S., Gonzalez-Neira A., Greene M.H., Gronwald J., Guenel P., Haberle L., Hahnen E., Haiman C.A., Hake C.R., Hall P., Hamann U., Harkness E.F., Heemskerk-Gerritsen B.A.M., Hillemanns P., Hogervorst F.B.L., Holleczek B., Hollestelle A., Hooning M.J., Hoover R.N., Hopper J.L., Howell A., Huebner H., Hulick P.J., Imyanitov E.N., Isaacs C., Izatt L., Jager A., Jakimovska M., Jakubowska A., James P., Janavicius R., Janni W., John E.M., Jones M.E., Jung A., Kaaks R., Kapoor P.M., Karlan B.Y., Keeman R., Khan S., Khusnutdinova E., Kitahara C.M., Ko Y.-D., Konstantopoulou I., Koppert L.B., Koutros S., Kristensen V.N., Laenkholm A.-V., Lambrechts D., Larsson S.C., Laurent-Puig P., Lazaro C., Lazarova E., Lejbkowicz F., Leslie G., Lesueur F., Lindblom A., Lissowska J., Lo W.-Y., Loud J.T., Lubinski J., Lukomska A., MacInnis R.J., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Matricardi L., McGuffog L., McLean C., Mebirouk N., Meindl A., Menon U., Miller A., Mingazheva E., Montagna M., Mulligan A.M., Mulot C., Muranen T.A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., and Neven P.
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 x 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.Copyright © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
Published: 2020

11. Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness.

Author: Engel C., Schmutzler R.K., Schuster H., Senter L., Seynaeve C.M., Shah P.D., Sharma P., Shin V.Y., Silvestri V., Simard J., Singer C.F., Skytte A.-B., Snape K., Solano A.R., Soucy P., Southey M.C., Spurdle A.B., Steele L., Steinemann D., Stoppa-Lyonnet D., Stradella A., Sunde L., Sutter C., Tan Y.Y., Teixeira M.R., Teo S.H., Thomassen M., Tibiletti M.G., Tischkowitz M., Tognazzo S., Toland A.E., Tommasi S., Torres D., Toss A., Trainer A.H., Tung N., Van Asperen C.J., Van Der Baan F.H., Van Der Kolk L.E., Van Der Luijt R.B., Van Hest L.P., Varesco L., Varon-Mateeva R., Viel A., Vierstrate J., Villa R., Von Wachenfeldt A., Wagner P., Wang-Gohrke S., Wappenschmidt B., Weitzel J.N., Wieme G., Yadav S., Yannoukakos D., Yoon S.-Y., Zanzottera C., Zorn K.K., D'Amico A.V., Freedman M.L., Pomerantz M.M., Chenevix-Trench G., Antoniou A.C., Neuhausen S.L., Ottini L., Nielsen H.R., Rebbeck T.R., Patel V.L., Busch E.L., Friebel T.M., Cronin A., Leslie G., McGuffog L., Adlard J., Agata S., Agnarsson B.A., Ahmed M., Aittom K., Alducci E., Andrulis I.L., Arason A., Arnold N., Artioli G., Arver B., Auber B., Azzollini J., Balmana J., Barkardottir R.B., Barnes D.R., Barroso A., Barrowdale D., Belotti M., Benitez J., Bertelsen B., Blok M.J., Bodrogi I., Bonadona V., Bonanni B., Bondavalli D., Boonen S.E., Borde J., Borg A., Bradbury A.R., Brady A., Brewer C., Brunet J., Buecher B., Buys S.S., Cabezas-Camarero S., Caldes T., Caliebe A., Caligo M.A., Calvello M., Campbell I.G., Carnevali I., Carrasco E., Chan T.L., Chu A.T.W., Chung W.K., Claes K.B.M., Cook J., Cortesi L., Couch F.J., Daly M.B., Damante G., Darder E., Davidson R., De La Hoya M., Della Puppa L., Dennis J., Diez O., Ding Y.C., Ditsch N., Domchek S.M., Donaldson A., Dworniczak B., Easton D.F., Eccles D.M., Eeles R.A., Ehrencrona H., Ejlertsen B., Evans D.G., Faivre L., Faust U., Feliubadalo L., Foretova L., Fostira F., Fountzilas G., Frost D., Garcia-Barberan V., Garre P., Gauthier-Villars M., Geczi L., Gehrig A., Gerdes A.-M., Gesta P., Giannini G., Glendon G., Godwin A.K., Goldgar D.E., Greene M.H., Gutierrez-Barrera A.M., Hahnen E., Hamann U., Hauke J., Herold N., Hogervorst F.B.L., Honisch E., Hopper J.L., Hulick P.J., Izatt L., Jager A., James P., Janavicius R., Jensen U.B., Jensen T.D., Johannsson O.Th., John E.M., Joseph V., Kang E., Kast K., Kiiski J.I., Kim S.-W., Kim Z., Ko K.-P., Konstantopoulou I., Kramer G., Krogh L., Kruse T.A., Kwong A., Larsen M., Lasset C., Lautrup C., Lazaro C., Lee J., Lee J.W., Lee M.H., Lemke J., Lesueur F., Liljegren A., Lindblom A., Llovet P., Lopez-Fernandez A., Lopez-Perolio I., Lorca V., Loud J.T., Ma E.S.K., Mai P.L., Manoukian S., Mari V., Martin L., Matricardi L., Mebirouk N., Medici V., Meijers-Heijboer H.E.J., Meindl A., Mensenkamp A.R., Miller C., Gomes D.M., Montagna M., Mooij T.M., Moserle L., Mouret-Fourme E., Mulligan A.M., Nathanson K.L., Navratilova M., Nevanlinna H., Niederacher D., Cilius Nielsen F.C., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Ong K.-R., Osorio A., Ott C.-E., Palli D., Park S.K., Parsons M.T., Pedersen I.S., Peissel B., Peixoto A., Perez-Segura P., Peterlongo P., Petersen A.H., Porteous M.E., Pujana M.A., Radice P., Ramser J., Rantala J., Rashid M.U., Rhiem K., Rizzolo P., Robson M.E., Rookus M.A., Rossing C.M., Ruddy K.J., Santos C., Saule C., Scarpitta R., Engel C., Schmutzler R.K., Schuster H., Senter L., Seynaeve C.M., Shah P.D., Sharma P., Shin V.Y., Silvestri V., Simard J., Singer C.F., Skytte A.-B., Snape K., Solano A.R., Soucy P., Southey M.C., Spurdle A.B., Steele L., Steinemann D., Stoppa-Lyonnet D., Stradella A., Sunde L., Sutter C., Tan Y.Y., Teixeira M.R., Teo S.H., Thomassen M., Tibiletti M.G., Tischkowitz M., Tognazzo S., Toland A.E., Tommasi S., Torres D., Toss A., Trainer A.H., Tung N., Van Asperen C.J., Van Der Baan F.H., Van Der Kolk L.E., Van Der Luijt R.B., Van Hest L.P., Varesco L., Varon-Mateeva R., Viel A., Vierstrate J., Villa R., Von Wachenfeldt A., Wagner P., Wang-Gohrke S., Wappenschmidt B., Weitzel J.N., Wieme G., Yadav S., Yannoukakos D., Yoon S.-Y., Zanzottera C., Zorn K.K., D'Amico A.V., Freedman M.L., Pomerantz M.M., Chenevix-Trench G., Antoniou A.C., Neuhausen S.L., Ottini L., Nielsen H.R., Rebbeck T.R., Patel V.L., Busch E.L., Friebel T.M., Cronin A., Leslie G., McGuffog L., Adlard J., Agata S., Agnarsson B.A., Ahmed M., Aittom K., Alducci E., Andrulis I.L., Arason A., Arnold N., Artioli G., Arver B., Auber B., Azzollini J., Balmana J., Barkardottir R.B., Barnes D.R., Barroso A., Barrowdale D., Belotti M., Benitez J., Bertelsen B., Blok M.J., Bodrogi I., Bonadona V., Bonanni B., Bondavalli D., Boonen S.E., Borde J., Borg A., Bradbury A.R., Brady A., Brewer C., Brunet J., Buecher B., Buys S.S., Cabezas-Camarero S., Caldes T., Caliebe A., Caligo M.A., Calvello M., Campbell I.G., Carnevali I., Carrasco E., Chan T.L., Chu A.T.W., Chung W.K., Claes K.B.M., Cook J., Cortesi L., Couch F.J., Daly M.B., Damante G., Darder E., Davidson R., De La Hoya M., Della Puppa L., Dennis J., Diez O., Ding Y.C., Ditsch N., Domchek S.M., Donaldson A., Dworniczak B., Easton D.F., Eccles D.M., Eeles R.A., Ehrencrona H., Ejlertsen B., Evans D.G., Faivre L., Faust U., Feliubadalo L., Foretova L., Fostira F., Fountzilas G., Frost D., Garcia-Barberan V., Garre P., Gauthier-Villars M., Geczi L., Gehrig A., Gerdes A.-M., Gesta P., Giannini G., Glendon G., Godwin A.K., Goldgar D.E., Greene M.H., Gutierrez-Barrera A.M., Hahnen E., Hamann U., Hauke J., Herold N., Hogervorst F.B.L., Honisch E., Hopper J.L., Hulick P.J., Izatt L., Jager A., James P., Janavicius R., Jensen U.B., Jensen T.D., Johannsson O.Th., John E.M., Joseph V., Kang E., Kast K., Kiiski J.I., Kim S.-W., Kim Z., Ko K.-P., Konstantopoulou I., Kramer G., Krogh L., Kruse T.A., Kwong A., Larsen M., Lasset C., Lautrup C., Lazaro C., Lee J., Lee J.W., Lee M.H., Lemke J., Lesueur F., Liljegren A., Lindblom A., Llovet P., Lopez-Fernandez A., Lopez-Perolio I., Lorca V., Loud J.T., Ma E.S.K., Mai P.L., Manoukian S., Mari V., Martin L., Matricardi L., Mebirouk N., Medici V., Meijers-Heijboer H.E.J., Meindl A., Mensenkamp A.R., Miller C., Gomes D.M., Montagna M., Mooij T.M., Moserle L., Mouret-Fourme E., Mulligan A.M., Nathanson K.L., Navratilova M., Nevanlinna H., Niederacher D., Cilius Nielsen F.C., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Ong K.-R., Osorio A., Ott C.-E., Palli D., Park S.K., Parsons M.T., Pedersen I.S., Peissel B., Peixoto A., Perez-Segura P., Peterlongo P., Petersen A.H., Porteous M.E., Pujana M.A., Radice P., Ramser J., Rantala J., Rashid M.U., Rhiem K., Rizzolo P., Robson M.E., Rookus M.A., Rossing C.M., Ruddy K.J., Santos C., Saule C., and Scarpitta R.
Abstract: Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 30 region of BRCA2 (c.7914) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001c.7913 [HR 1/4 1.78; 95% confidence interval (CI), 1.25-2.52; P 1/4 0.001], as well as elevated risk of Gleason 8 prostate cancer (HR 1/4 3.11; 95% CI, 1.63-5.95; P 1/4 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR 1/4 2.83; 95% CI, 1.71-4.68; P 1/4 0.00004) and elevated risk of Gleason 8 prostate cancer (HR 1/4 4.95; 95% CI, 2.12-11.54; P 1/4 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer.Copyright © 2020 American Association for Cancer Research.
Published: 2020

12. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

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

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

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

14. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Author: Goldgar D.E., Newman W.G., Nielsen F.C., Nikitina-Zake L., Nodora J., Offit K., Olah E., Olopade O.I., Olsson H., Orr N., Papi L., Papp J., Park-Simon T.-W., Parsons M.T., Peissel B., Peixoto A., Peshkin B., Peterlongo P., Peto J., Phillips K.-A., Piedmonte M., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Prokofyeva D., Rack B., Radice P., Ramus S.J., Rantala J., Rashid M.U., Rennert G., Rennert H.S., Risch H.A., Romero A., Rookus M.A., Rubner M., Rudiger T., Saloustros E., Sampson S., Sandler D.P., Sawyer E.J., Scheuner M.T., Schmutzler R.K., Schneeweiss A., Schoemaker M.J., Schottker B., Schurmann P., Senter L., Sharma P., Sherman M.E., Shu X.-O., Singer C.F., Smichkoska S., Soucy P., Southey M.C., Spinelli J.J., Stone J., Stoppa-Lyonnet D., Swerdlow A.J., Szabo C.I., Tamimi R.M., Tapper W.J., Taylor J.A., Teixeira M.R., Terry M.B., Thomassen M., Thull D.L., Tischkowitz M., Toland A.E., Tollenaar R.A.E.M., Tomlinson I., Torres D., Troester M.A., Truong T., Tung N., Untch M., Vachon C.M., van den Ouweland A.M.W., van der Kolk L.E., van Veen E.M., vanRensburg E.J., Vega A., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wildiers H., Winqvist R., Wolk A., Yang X.R., Yannoukakos D., Zheng W., Zorn K.K., Milne R.L., Kraft P., Simard J., Pharoah P.D.P., Michailidou K., Antoniou A.C., Schmidt M.K., Chenevix-Trench G., Easton D.F., Chatterjee N., Garcia-Closas M., Zhang H., Ahearn T.U., Lecarpentier J., Barnes D., Beesley J., Qi G., Jiang X., O'Mara T.A., Zhao N., Bolla M.K., Dunning A.M., Dennis J., Wang Q., Ful Z.A., Aittomaki K., Andrulis I.L., Anton-Culver H., Arndt V., Aronson K.J., Arun B.K., Auer P.L., Azzollini J., Barrowdale D., Becher H., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bialkowska K., Blanco A., Blomqvist C., Bogdanova N.V., Bojesen S.E., Bonanni B., Bondavalli D., Borg A., Brauch H., Brenner H., Briceno I., Broeks A., Brucker S.Y., Bruning T., Burwinkel B., Buys S.S., Byers H., Caldes T., Caligo M.A., Calvello M., Campa D., Castelao J.E., Chang-Claude J., Chanock S.J., Christiaens M., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Cornelissen S., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Devilee P., Diez O., Domchek S.M., Dork T., Dwek M., Eccles D.M., Ekici A.B., Evans D.G., Fasching P.A., Figueroa J., Foretova L., Fostira F., Friedman E., Frost D., Gago-Dominguez M., Gapstur S.M., Garber J., Garcia-Saenz J.A., Gaudet M.M., Gayther S.A., Giles G.G., Godwin A.K., Goldberg M.S., Gonzalez-Neira A., Greene M.H., Gronwald J., Guenel P., Haberle L., Hahnen E., Haiman C.A., Hake C.R., Hall P., Hamann U., Harkness E.F., Heemskerk-Gerritsen B.A.M., Hillemanns P., Hogervorst F.B.L., Holleczek B., Hollestelle A., Hooning M.J., Hoover R.N., Hopper J.L., Howell A., Huebner H., Hulick P.J., Imyanitov E.N., Isaacs C., Izatt L., Jager A., Jakimovska M., Jakubowska A., James P., Janavicius R., Janni W., John E.M., Jones M.E., Jung A., Kaaks R., Kapoor P.M., Karlan B.Y., Keeman R., Khan S., Khusnutdinova E., Kitahara C.M., Ko Y.-D., Konstantopoulou I., Koppert L.B., Koutros S., Kristensen V.N., Laenkholm A.-V., Lambrechts D., Larsson S.C., Laurent-Puig P., Lazaro C., Lazarova E., Lejbkowicz F., Leslie G., Lesueur F., Lindblom A., Lissowska J., Lo W.-Y., Loud J.T., Lubinski J., Lukomska A., MacInnis R.J., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Matricardi L., McGuffog L., McLean C., Mebirouk N., Meindl A., Menon U., Miller A., Mingazheva E., Montagna M., Mulligan A.M., Mulot C., Muranen T.A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Neven P., Goldgar D.E., Newman W.G., Nielsen F.C., Nikitina-Zake L., Nodora J., Offit K., Olah E., Olopade O.I., Olsson H., Orr N., Papi L., Papp J., Park-Simon T.-W., Parsons M.T., Peissel B., Peixoto A., Peshkin B., Peterlongo P., Peto J., Phillips K.-A., Piedmonte M., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Prokofyeva D., Rack B., Radice P., Ramus S.J., Rantala J., Rashid M.U., Rennert G., Rennert H.S., Risch H.A., Romero A., Rookus M.A., Rubner M., Rudiger T., Saloustros E., Sampson S., Sandler D.P., Sawyer E.J., Scheuner M.T., Schmutzler R.K., Schneeweiss A., Schoemaker M.J., Schottker B., Schurmann P., Senter L., Sharma P., Sherman M.E., Shu X.-O., Singer C.F., Smichkoska S., Soucy P., Southey M.C., Spinelli J.J., Stone J., Stoppa-Lyonnet D., Swerdlow A.J., Szabo C.I., Tamimi R.M., Tapper W.J., Taylor J.A., Teixeira M.R., Terry M.B., Thomassen M., Thull D.L., Tischkowitz M., Toland A.E., Tollenaar R.A.E.M., Tomlinson I., Torres D., Troester M.A., Truong T., Tung N., Untch M., Vachon C.M., van den Ouweland A.M.W., van der Kolk L.E., van Veen E.M., vanRensburg E.J., Vega A., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wildiers H., Winqvist R., Wolk A., Yang X.R., Yannoukakos D., Zheng W., Zorn K.K., Milne R.L., Kraft P., Simard J., Pharoah P.D.P., Michailidou K., Antoniou A.C., Schmidt M.K., Chenevix-Trench G., Easton D.F., Chatterjee N., Garcia-Closas M., Zhang H., Ahearn T.U., Lecarpentier J., Barnes D., Beesley J., Qi G., Jiang X., O'Mara T.A., Zhao N., Bolla M.K., Dunning A.M., Dennis J., Wang Q., Ful Z.A., Aittomaki K., Andrulis I.L., Anton-Culver H., Arndt V., Aronson K.J., Arun B.K., Auer P.L., Azzollini J., Barrowdale D., Becher H., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bialkowska K., Blanco A., Blomqvist C., Bogdanova N.V., Bojesen S.E., Bonanni B., Bondavalli D., Borg A., Brauch H., Brenner H., Briceno I., Broeks A., Brucker S.Y., Bruning T., Burwinkel B., Buys S.S., Byers H., Caldes T., Caligo M.A., Calvello M., Campa D., Castelao J.E., Chang-Claude J., Chanock S.J., Christiaens M., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Cornelissen S., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Devilee P., Diez O., Domchek S.M., Dork T., Dwek M., Eccles D.M., Ekici A.B., Evans D.G., Fasching P.A., Figueroa J., Foretova L., Fostira F., Friedman E., Frost D., Gago-Dominguez M., Gapstur S.M., Garber J., Garcia-Saenz J.A., Gaudet M.M., Gayther S.A., Giles G.G., Godwin A.K., Goldberg M.S., Gonzalez-Neira A., Greene M.H., Gronwald J., Guenel P., Haberle L., Hahnen E., Haiman C.A., Hake C.R., Hall P., Hamann U., Harkness E.F., Heemskerk-Gerritsen B.A.M., Hillemanns P., Hogervorst F.B.L., Holleczek B., Hollestelle A., Hooning M.J., Hoover R.N., Hopper J.L., Howell A., Huebner H., Hulick P.J., Imyanitov E.N., Isaacs C., Izatt L., Jager A., Jakimovska M., Jakubowska A., James P., Janavicius R., Janni W., John E.M., Jones M.E., Jung A., Kaaks R., Kapoor P.M., Karlan B.Y., Keeman R., Khan S., Khusnutdinova E., Kitahara C.M., Ko Y.-D., Konstantopoulou I., Koppert L.B., Koutros S., Kristensen V.N., Laenkholm A.-V., Lambrechts D., Larsson S.C., Laurent-Puig P., Lazaro C., Lazarova E., Lejbkowicz F., Leslie G., Lesueur F., Lindblom A., Lissowska J., Lo W.-Y., Loud J.T., Lubinski J., Lukomska A., MacInnis R.J., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Matricardi L., McGuffog L., McLean C., Mebirouk N., Meindl A., Menon U., Miller A., Mingazheva E., Montagna M., Mulligan A.M., Mulot C., Muranen T.A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., and Neven P.
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 x 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.Copyright © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
Published: 2020

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14 results on '"Greene M.H."'

1. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants.

2. Characterization of the Cancer Spectrum in Men with Germline BRCA1 and BRCA2 Pathogenic Variants: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

3. Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores.

4. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants.

5. Characterization of the Cancer Spectrum in Men with Germline BRCA1 and BRCA2 Pathogenic Variants: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

6. Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores.

7. Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness.

8. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

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

10. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

11. Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness.

12. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

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

14. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

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14 results on '"Greene M.H."'

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