Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness

V.L. Patel; E.L. Busch; T.M. Friebel; A. Cronin; G. Leslie; L. McGuffog; J. Adlard; S. Agata; B.A. Agnarsson; M. Ahmed; K. Aittomaki; E. Alducci; I.L. Andrulis; A. Arason; N. Arnold; G. Artioli; B. Arver; B. Auber; J. Azzollini; J. Balmana; R.B. Barkardottir; D.R. Barnes; A. Barroso; D. Barrowdale; M. Belotti; J. Benitez; B. Bertelsen; M.J. Blok; I. Bodrogi; V. Bonadona; B. Bonanni; D. Bondavalli; S.E. Boonen; J. Borde; A. Borg; A.R. Bradbury; A. Brady; C. Brewer; J. Brunet; B. Buecher; S.S. Buys; S. Cabezas-Camarero; T. Caldes; A. Caliebe; M.A. Caligo; M. Calvello; I.G. Campbell; I. Carnevali; E. Carrasco; T.L. Chan; EMBRACE Collaborators; GEMO Study Collaborators; HEBON Investigators; KConFab Investigators; Timothy R. Rebbeck

doi:10.1158/0008-5472.can-19-1840

Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness

V.L. Patel, E.L. Busch, T.M. Friebel, A. Cronin, G. Leslie, L. McGuffog, J. Adlard, S. Agata, B.A. Agnarsson, M. Ahmed, K. Aittomaki, E. Alducci, I.L. Andrulis, A. Arason, N. Arnold, G. Artioli, B. Arver, B. Auber, J. Azzollini, J. BalmanaR.B. Barkardottir, D.R. Barnes, A. Barroso, D. Barrowdale, M. Belotti, J. Benitez, B. Bertelsen, M.J. Blok, I. Bodrogi, V. Bonadona, B. Bonanni, D. Bondavalli, S.E. Boonen, J. Borde, A. Borg, A.R. Bradbury, A. Brady, C. Brewer, J. Brunet, B. Buecher, S.S. Buys, S. Cabezas-Camarero, T. Caldes, A. Caliebe, M.A. Caligo, M. Calvello, I.G. Campbell, I. Carnevali, E. Carrasco, T.L. Chan, EMBRACE Collaborators, GEMO Study Collaborators, HEBON Investigators, KConFab Investigators, Timothy R. Rebbeck^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. Weevaluated whether PSVs inBRCA1/2 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 = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 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.Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Original language	English
Pages (from-to)	624-638
Number of pages	15
Journal	Cancer Research
Volume	80
Issue number	3
DOIs	https://doi.org/10.1158/0008-5472.can-19-1840
Publication status	Published - 1 Feb 2020

Keywords

APC
BREAST-CANCER
CARRIERS
GENE
GERMLINE MUTATIONS
IDENTIFICATION
INCREASE
MESSENGER-RNA DECAY
OVARIAN
PHENOTYPE
apc
breast-cancer
carriers
gene
germline mutations
identification
increase
messenger-rna decay
ovarian
phenotype

Access to Document

10.1158/0008-5472.can-19-1840

Cite this

Patel, V. L., Busch, E. L., Friebel, T. M., Cronin, A., Leslie, G., McGuffog, L., Adlard, J., Agata, S., Agnarsson, B. A., Ahmed, M., Aittomaki, K., Alducci, E., Andrulis, I. L., Arason, A., Arnold, N., Artioli, G., Arver, B., Auber, B., Azzollini, J., ... Rebbeck, T. R. (2020). Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness. Cancer Research, 80(3), 624-638. https://doi.org/10.1158/0008-5472.can-19-1840

@article{aaa83173717849ae83908dace47187f9,

title = "Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness",

abstract = "Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. Weevaluated whether PSVs inBRCA1/2 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 = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 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.Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.",

keywords = "APC, BREAST-CANCER, CARRIERS, GENE, GERMLINE MUTATIONS, IDENTIFICATION, INCREASE, MESSENGER-RNA DECAY, OVARIAN, PHENOTYPE, apc, breast-cancer, carriers, gene, germline mutations, identification, increase, messenger-rna decay, ovarian, phenotype",

author = "V.L. Patel and E.L. Busch and T.M. Friebel and A. Cronin and G. Leslie and L. McGuffog and J. Adlard and S. Agata and B.A. Agnarsson and M. Ahmed and K. Aittomaki and E. Alducci and I.L. Andrulis and A. Arason and N. Arnold and G. Artioli and B. Arver and B. Auber and J. Azzollini and J. Balmana and R.B. Barkardottir and D.R. Barnes and A. Barroso and D. Barrowdale and M. Belotti and J. Benitez and B. Bertelsen and M.J. Blok and I. Bodrogi and V. Bonadona and B. Bonanni and D. Bondavalli and S.E. Boonen and J. Borde and A. Borg and A.R. Bradbury and A. Brady and C. Brewer and J. Brunet and B. Buecher and S.S. Buys and S. Cabezas-Camarero and T. Caldes and A. Caliebe and M.A. Caligo and M. Calvello and I.G. Campbell and I. Carnevali and E. Carrasco and T.L. Chan and {EMBRACE Collaborators} and {GEMO Study Collaborators} and {HEBON Investigators} and {KConFab Investigators} and Rebbeck, {Timothy R.}",

note = "Funding Information: CHU Limoges, France: Laurence V{\'e}nat-Bouvet. CHU Nantes, France: St{\'e}phane B{\'e}zieau, Capucine Delnatte. CHU Bretonneau, Tours, and Centre Hospitalier de Bourges France: Isabelle Mortemousque. Groupe Hospitalier Piti{\'e}-Salp{\'e}tri{\`e}re, Paris, France: Chrystelle Colas, Florence Coulet, Florent Soubrier, Mathilde Warcoin. CHU Vandoeuvre-les-Nancy, France: Myriam Bronner, Johanna Soko-lowska. CHU Besanc¸on, France: Marie-Agn{\`e}s Collonge-Rame, Alexandre Damette. CHU Poitiers, Centre Hospitalier d{\textquoteright}Angoul{\^e}me, and Centre Hospitalier de Niort, France: Hakima Lallaoui. CHU N^mes Car{\'e}meau, France: Jean Chiesa. CHI Poissy, France: Denise Molina-Gomes. CHU Angers, France: Olivier Ingster; Ilse Coene en Brecht Crombez; Ilse Coene and Brecht Crombez; Alicia Tosar and Paula Diaque; Sofia Khan, Taru A. Muranen, Carl Blomqvist, Irja Erkkil€a, and Virpi Palola; The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N. S. Russell, D.J. Jenner; Erasmus Medical Center, Rotterdam, NL: J.M. Coll{\'e}e, A.M. W. van den Ouweland, M.J. Hooning, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center, NL: J.T. Wijnen, R.A.E.M. Tollenaar, P. Devilee, T.C.T. E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C.M. Kets; University Medical Center Utrecht, NL: M.G.E.M. Ausems, C.C. van der Pol; Amsterdam Medical Center, NL: C.M. Aalfs, T.A.M. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz; University Medical Center Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Foundation for the detection of hereditary tumors, Leiden, NL: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J.Verloop; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek; Hong Kong Sanatorium and Hospital; the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Aniko Bozsik, Timea Pocza, Zoltan Matrai, Miklos Kasler, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary), and the clinicians and patients for their contributions to this study; the Oncogenetics Group (VHIO) and the High Risk and Cancer Prevention Unit of the University Hospital Vall d{\textquoteright}Hebron, and the Cellex Foundation for providing research facilities and equipment; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; Dr Martine Dumont for sample management and skillful assistance; Pedro Pinto; members of the Center of Molecular Diagnosis, Oncogenetics Department and Molecular Oncology Research Center of Barretos Cancer Hospital; Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the NIH) for their contributions to this resource, and the many families who contribute to kConFab; the KOBRA Study Group; Csilla Szabo (National Human Genome Research Institute, NIH, Bethesda, MD), Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and Masaryk University, Brno, Czech Republic); and Michal Zikan, Petr Pohlreich, and Zdenek Kleibl (Oncogynecologic Center and Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic); Anne Lincoln, Lauren Jacobs; the NICCC National Familial Cancer Consultation Service team led by Sara Dishon, the lab team led by Dr. Flavio Lejbkowicz, and the research field operations team led by Dr. Mila Pinchev; the investigators of the Australia New Zealand NRG Oncology group; members and participants in the Ontario Cancer Genetics Network; Kevin Sweet, Caroline Craven, Julia Cooper, and Michelle O'Conor; Yip Cheng Har, Nur Aishah Mohd Taib, Phuah Sze Yee, Norhashimah Hassan, and all the research nurses, research assistants, and doctors involved in the MyBrCa Study for assistance in patient recruitment, data collection, and sample preparation, Philip Iau, Sng Jen-Hwei, and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study, respectively; the Meirav Comprehensive breast cancer center team at the Sheba Medical Center; Christina Selkirk; Ha°kan Olsson, Helena Jernstrom, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Of€ verholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Gisela Barbany Bustinza; from Umea° University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Maritta Hellstrom Pigg, Richard Rosenquist; from Linkoping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren; Cecilia Zvocec, Qun Niu; Joyce Seldon and Lorna Kwan; Dr. Robert Nussbaum, Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco, and Peggy Conrad and Salina Chan; Simon Gayther, Susan Ramus, Paul Pharoah, Carole Pye, Patricia Harrington, and Eva Wozniak; Geoffrey Funding Information: Lindeman, Marion Harris, Martin Delatycki, Sarah Sawyer, Rebecca Driessen, and Ella Thompson for performing all DNA amplification. E.L. Busch was supported by grants from the National Cancer Institute (5T32CA009001, P60-CA105641). The CIMBA data management and data analysis were supported by Cancer Research – UK grants C12292/A20861, C12292/A11174. A.C. Antoniou is a Cancer Research-UK Senior Cancer Research Fellow. G. Chenevix-Trench and A.B. Spurdle are NHMRC Research Fellows. iCOGS: the European Community's Seventh Frame-work Programme under grant agreement no. 223175 (HEALTH-F2–2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the NIH (CA128978), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112 - the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy, Science and Innovation through Genome Qu{\'e}bec, and The Quebec Breast Cancer Foundation. BCFR: UM1 CA164920 from the National Cancer Institute. BFBOCC: Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015. BIDMC: Breast Cancer Research Foundation. BMBSA: Cancer Association of South Africa (principal investigator: Elizabeth J. van Rensburg). CNIO: Spanish Ministry of Health PI16/00440 supported by FEDER funds, the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER). COH-CCGCRN: Research reported in this publication was supported by the NCI of the NIH under grant numbers R25CA112486 and RC4CA153828 (principal investigator: J. Weitzel) from the NCI and the Office of the Director, NIH. CONSIT: Associazione Italiana Ricerca sul Cancro (AIRC; IG2014 no.15547 to P. Radice). Italian Association for Cancer Research (AIRC; grant no.16933 to L. Ottini). Associazione Italiana Ricerca sul Cancro (AIRC; IG2015 no.16732 to P. Peterlongo). Associazione Italiana Ricerca sul Cancro (AIRC grant IG17734 to G. Giannini). DEMOKRITOS: European Union (European Social Fund – ESF) and Greek national funds through the Operational Program {"}Education and Lifelong Learning{"} of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund. DFKZ: German Cancer Research Center. EMBRACE: Cancer Research UK Grants C1287/A10118 and C1287/ A11990. Fiona Lalloo is supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Elizabeth Bancroft is supported by Cancer Research UK Grant C5047/A8385FCCC: The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K. Godwin was funded by R0 1CA140323, R01 CA214545, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. FPGMX: FISPI05/2275 and Mutua Madrile{\~n}a Foundation (FMMA). GC-HBOC: German Cancer Aid (grant no 110837 to R.K. Schmutzler) and the European Regional Development Fund and Free State of Saxony, Germany (LIFE - Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/ 2470, 14575/2470). GEMO: Ligue Nationale Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award, the Canadian Institutes of Health Research for the {"}CIHR Team in Familial Risks of Breast Cancer{"} program and the French National Institute of Cancer (INCa). GEORGETOWN: the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Hereditary Cancer and Clinical Genomics Research, and Swing Fore the Cure. G-FAST: Bruce Poppe is a senior clinical investigator of FWO. Mattias Van Heetvelde obtained funding from IWT. HCSC: Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301 CIBER-ONC from ISCIII (Spain), partially supported by European Regional Development FEDER funds. HEBCS: Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, and the Sigrid Juselius Foundation. HEBON: the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46, and the Transcan grant JTC 2012 Cancer 12-054. HEBON thanks the registration teams of Dutch Cancer Registry (IKNL; S. Siesling, J. Verloop) and the Dutch Pathology database (PALGA; L. Overbeek) for part of the data collection. HRBCP: Hong Kong Sanatorium and Hospital, Dr Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation, NIH1R 03CA130065, and North California Cancer Center. HUNBOCS: Hungarian Research Grants KTIA-OTKA CK-80745 and OTKA K-112228. ICO: The authors would like to particularly acknowledge the support of the Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Econom{\'i}a y Competitividad) and “Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa” (PI10/01422, PI13/00285, PIE13/ 00022, PI15/00854, PI16/00563 and CIBERONC), and the Institut Catal{\`a}de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338, and PERIS Project MedPerCan). IHCC: PBZ_KBN_122/P05/2004. ILUH: Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund. INHERIT: Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program – grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. IOVHBOCS: Ministero della Salute and “5 ⨯ 1000′′ Istituto Oncologico Veneto grant. IPOBCS: Liga Portuguesa Contra o Cancro. kConFab: The National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. MAYO: NIH grants CA116167, CA192393, and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201),and a grant from the Breast Cancer Research Foundation. MCGILL: Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. MSKCC: the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support Grant/Core Grant (P30 CA008748). NAROD: 1R01 CA149429-01. NCI: the Intramural Research Program of the NCI, NIH, and by support services contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP-65504 with Westat, Inc, Rockville, MD. NICCC: Clalit Health Services in Israel, the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. NNPIO: the Russian Federation for Basic Research (grants 15-04-01744, 16-54-00055, and 17-54-12007). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA 37517) and the Intramural Research Program, NCI. OSUCCG: Ohio State University Comprehensive Cancer Center. PBCS: Italian Association of Cancer Research (AIRC) [IG 2013 N.14477] and Tuscany Institute for Tumors (ITT) grant 2014-2015-2016. SEABASS: Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM. C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. SMC: the Israeli Cancer Association. SWE-BRCA: the Swedish Cancer Society. UCHICAGO: NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032, and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance, and the Breast Cancer research Foundation. O.I. Olopade is an ACS Clinical Research Professor. UCLA: Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UKFOCR: Cancer Research UK. UPENN: Breast Cancer Research Foundation; Susan G. Komen Foundation for the Cure, Basser Center for BRCA. UPITT/MWH: Hackers for Hope Pittsburgh. VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. WCP: Dr Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS; grant no. UL1TR000124). S. Guti{\'e}rrez-Enr{\'i}quez is supported by the Miguel Servet Progam (CP10/00617). Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",

year = "2020",

month = feb,

day = "1",

doi = "10.1158/0008-5472.can-19-1840",

language = "English",

volume = "80",

pages = "624--638",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "3",

}

Patel, VL, Busch, EL, Friebel, TM, Cronin, A, Leslie, G, McGuffog, L, Adlard, J, Agata, S, Agnarsson, BA, Ahmed, M, Aittomaki, K, Alducci, E, Andrulis, IL, Arason, A, Arnold, N, Artioli, G, Arver, B, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barroso, A, Barrowdale, D, Belotti, M, Benitez, J, Bertelsen, B, Blok, MJ, Bodrogi, I, Bonadona, V, Bonanni, B, Bondavalli, D, Boonen, SE, Borde, J, Borg, A, Bradbury, AR, Brady, A, Brewer, C, Brunet, J, Buecher, B, Buys, SS, Cabezas-Camarero, S, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Campbell, IG, Carnevali, I, Carrasco, E, Chan, TL, EMBRACE Collaborators, GEMO Study Collaborators, HEBON Investigators, KConFab Investigators & Rebbeck, TR 2020, 'Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness', Cancer Research, vol. 80, no. 3, pp. 624-638. https://doi.org/10.1158/0008-5472.can-19-1840

TY - JOUR

T1 - Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness

AU - Patel, V.L.

AU - Busch, E.L.

AU - Friebel, T.M.

AU - Cronin, A.

AU - Leslie, G.

AU - McGuffog, L.

AU - Adlard, J.

AU - Agata, S.

AU - Agnarsson, B.A.

AU - Ahmed, M.

AU - Aittomaki, K.

AU - Alducci, E.

AU - Andrulis, I.L.

AU - Arason, A.

AU - Arnold, N.

AU - Artioli, G.

AU - Arver, B.

AU - Auber, B.

AU - Azzollini, J.

AU - Balmana, J.

AU - Barkardottir, R.B.

AU - Barnes, D.R.

AU - Barroso, A.

AU - Barrowdale, D.

AU - Belotti, M.

AU - Benitez, J.

AU - Bertelsen, B.

AU - Blok, M.J.

AU - Bodrogi, I.

AU - Bonadona, V.

AU - Bonanni, B.

AU - Bondavalli, D.

AU - Boonen, S.E.

AU - Borde, J.

AU - Borg, A.

AU - Bradbury, A.R.

AU - Brady, A.

AU - Brewer, C.

AU - Brunet, J.

AU - Buecher, B.

AU - Buys, S.S.

AU - Cabezas-Camarero, S.

AU - Caldes, T.

AU - Caliebe, A.

AU - Caligo, M.A.

AU - Calvello, M.

AU - Campbell, I.G.

AU - Carnevali, I.

AU - Carrasco, E.

AU - Chan, T.L.

AU - EMBRACE Collaborators

AU - GEMO Study Collaborators

AU - HEBON Investigators

AU - KConFab Investigators

AU - Rebbeck, Timothy R.

N1 - Funding Information: CHU Limoges, France: Laurence Vénat-Bouvet. CHU Nantes, France: Stéphane Bézieau, Capucine Delnatte. CHU Bretonneau, Tours, and Centre Hospitalier de Bourges France: Isabelle Mortemousque. Groupe Hospitalier Pitié-Salpétrière, Paris, France: Chrystelle Colas, Florence Coulet, Florent Soubrier, Mathilde Warcoin. CHU Vandoeuvre-les-Nancy, France: Myriam Bronner, Johanna Soko-lowska. CHU Besanc¸on, France: Marie-Agnès Collonge-Rame, Alexandre Damette. CHU Poitiers, Centre Hospitalier d’Angoulême, and Centre Hospitalier de Niort, France: Hakima Lallaoui. CHU N^mes Carémeau, France: Jean Chiesa. CHI Poissy, France: Denise Molina-Gomes. CHU Angers, France: Olivier Ingster; Ilse Coene en Brecht Crombez; Ilse Coene and Brecht Crombez; Alicia Tosar and Paula Diaque; Sofia Khan, Taru A. Muranen, Carl Blomqvist, Irja Erkkil€a, and Virpi Palola; The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N. S. Russell, D.J. Jenner; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, A.M. W. van den Ouweland, M.J. Hooning, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center, NL: J.T. Wijnen, R.A.E.M. Tollenaar, P. Devilee, T.C.T. E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C.M. Kets; University Medical Center Utrecht, NL: M.G.E.M. Ausems, C.C. van der Pol; Amsterdam Medical Center, NL: C.M. Aalfs, T.A.M. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz; University Medical Center Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Foundation for the detection of hereditary tumors, Leiden, NL: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J.Verloop; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek; Hong Kong Sanatorium and Hospital; the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Aniko Bozsik, Timea Pocza, Zoltan Matrai, Miklos Kasler, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary), and the clinicians and patients for their contributions to this study; the Oncogenetics Group (VHIO) and the High Risk and Cancer Prevention Unit of the University Hospital Vall d’Hebron, and the Cellex Foundation for providing research facilities and equipment; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; Dr Martine Dumont for sample management and skillful assistance; Pedro Pinto; members of the Center of Molecular Diagnosis, Oncogenetics Department and Molecular Oncology Research Center of Barretos Cancer Hospital; Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the NIH) for their contributions to this resource, and the many families who contribute to kConFab; the KOBRA Study Group; Csilla Szabo (National Human Genome Research Institute, NIH, Bethesda, MD), Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and Masaryk University, Brno, Czech Republic); and Michal Zikan, Petr Pohlreich, and Zdenek Kleibl (Oncogynecologic Center and Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic); Anne Lincoln, Lauren Jacobs; the NICCC National Familial Cancer Consultation Service team led by Sara Dishon, the lab team led by Dr. Flavio Lejbkowicz, and the research field operations team led by Dr. Mila Pinchev; the investigators of the Australia New Zealand NRG Oncology group; members and participants in the Ontario Cancer Genetics Network; Kevin Sweet, Caroline Craven, Julia Cooper, and Michelle O'Conor; Yip Cheng Har, Nur Aishah Mohd Taib, Phuah Sze Yee, Norhashimah Hassan, and all the research nurses, research assistants, and doctors involved in the MyBrCa Study for assistance in patient recruitment, data collection, and sample preparation, Philip Iau, Sng Jen-Hwei, and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study, respectively; the Meirav Comprehensive breast cancer center team at the Sheba Medical Center; Christina Selkirk; Ha°kan Olsson, Helena Jernstrom, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Of€ verholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Gisela Barbany Bustinza; from Umea° University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Maritta Hellstrom Pigg, Richard Rosenquist; from Linkoping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren; Cecilia Zvocec, Qun Niu; Joyce Seldon and Lorna Kwan; Dr. Robert Nussbaum, Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco, and Peggy Conrad and Salina Chan; Simon Gayther, Susan Ramus, Paul Pharoah, Carole Pye, Patricia Harrington, and Eva Wozniak; Geoffrey Funding Information: Lindeman, Marion Harris, Martin Delatycki, Sarah Sawyer, Rebecca Driessen, and Ella Thompson for performing all DNA amplification. E.L. Busch was supported by grants from the National Cancer Institute (5T32CA009001, P60-CA105641). The CIMBA data management and data analysis were supported by Cancer Research – UK grants C12292/A20861, C12292/A11174. A.C. Antoniou is a Cancer Research-UK Senior Cancer Research Fellow. G. Chenevix-Trench and A.B. Spurdle are NHMRC Research Fellows. iCOGS: the European Community's Seventh Frame-work Programme under grant agreement no. 223175 (HEALTH-F2–2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the NIH (CA128978), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112 - the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy, Science and Innovation through Genome Québec, and The Quebec Breast Cancer Foundation. BCFR: UM1 CA164920 from the National Cancer Institute. BFBOCC: Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015. BIDMC: Breast Cancer Research Foundation. BMBSA: Cancer Association of South Africa (principal investigator: Elizabeth J. van Rensburg). CNIO: Spanish Ministry of Health PI16/00440 supported by FEDER funds, the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER). COH-CCGCRN: Research reported in this publication was supported by the NCI of the NIH under grant numbers R25CA112486 and RC4CA153828 (principal investigator: J. Weitzel) from the NCI and the Office of the Director, NIH. CONSIT: Associazione Italiana Ricerca sul Cancro (AIRC; IG2014 no.15547 to P. Radice). Italian Association for Cancer Research (AIRC; grant no.16933 to L. Ottini). Associazione Italiana Ricerca sul Cancro (AIRC; IG2015 no.16732 to P. Peterlongo). Associazione Italiana Ricerca sul Cancro (AIRC grant IG17734 to G. Giannini). DEMOKRITOS: European Union (European Social Fund – ESF) and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund. DFKZ: German Cancer Research Center. EMBRACE: Cancer Research UK Grants C1287/A10118 and C1287/ A11990. Fiona Lalloo is supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Elizabeth Bancroft is supported by Cancer Research UK Grant C5047/A8385FCCC: The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K. Godwin was funded by R0 1CA140323, R01 CA214545, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. FPGMX: FISPI05/2275 and Mutua Madrileña Foundation (FMMA). GC-HBOC: German Cancer Aid (grant no 110837 to R.K. Schmutzler) and the European Regional Development Fund and Free State of Saxony, Germany (LIFE - Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/ 2470, 14575/2470). GEMO: Ligue Nationale Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award, the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and the French National Institute of Cancer (INCa). GEORGETOWN: the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Hereditary Cancer and Clinical Genomics Research, and Swing Fore the Cure. G-FAST: Bruce Poppe is a senior clinical investigator of FWO. Mattias Van Heetvelde obtained funding from IWT. HCSC: Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301 CIBER-ONC from ISCIII (Spain), partially supported by European Regional Development FEDER funds. HEBCS: Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, and the Sigrid Juselius Foundation. HEBON: the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46, and the Transcan grant JTC 2012 Cancer 12-054. HEBON thanks the registration teams of Dutch Cancer Registry (IKNL; S. Siesling, J. Verloop) and the Dutch Pathology database (PALGA; L. Overbeek) for part of the data collection. HRBCP: Hong Kong Sanatorium and Hospital, Dr Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation, NIH1R 03CA130065, and North California Cancer Center. HUNBOCS: Hungarian Research Grants KTIA-OTKA CK-80745 and OTKA K-112228. ICO: The authors would like to particularly acknowledge the support of the Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economía y Competitividad) and “Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa” (PI10/01422, PI13/00285, PIE13/ 00022, PI15/00854, PI16/00563 and CIBERONC), and the Institut Catalàde la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338, and PERIS Project MedPerCan). IHCC: PBZ_KBN_122/P05/2004. ILUH: Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund. INHERIT: Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program – grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. IOVHBOCS: Ministero della Salute and “5 ⨯ 1000′′ Istituto Oncologico Veneto grant. IPOBCS: Liga Portuguesa Contra o Cancro. kConFab: The National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. MAYO: NIH grants CA116167, CA192393, and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201),and a grant from the Breast Cancer Research Foundation. MCGILL: Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. MSKCC: the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support Grant/Core Grant (P30 CA008748). NAROD: 1R01 CA149429-01. NCI: the Intramural Research Program of the NCI, NIH, and by support services contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP-65504 with Westat, Inc, Rockville, MD. NICCC: Clalit Health Services in Israel, the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. NNPIO: the Russian Federation for Basic Research (grants 15-04-01744, 16-54-00055, and 17-54-12007). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA 37517) and the Intramural Research Program, NCI. OSUCCG: Ohio State University Comprehensive Cancer Center. PBCS: Italian Association of Cancer Research (AIRC) [IG 2013 N.14477] and Tuscany Institute for Tumors (ITT) grant 2014-2015-2016. SEABASS: Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM. C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. SMC: the Israeli Cancer Association. SWE-BRCA: the Swedish Cancer Society. UCHICAGO: NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032, and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance, and the Breast Cancer research Foundation. O.I. Olopade is an ACS Clinical Research Professor. UCLA: Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UKFOCR: Cancer Research UK. UPENN: Breast Cancer Research Foundation; Susan G. Komen Foundation for the Cure, Basser Center for BRCA. UPITT/MWH: Hackers for Hope Pittsburgh. VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. WCP: Dr Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS; grant no. UL1TR000124). S. Gutiérrez-Enríquez is supported by the Miguel Servet Progam (CP10/00617). Publisher Copyright: © 2020 American Association for Cancer Research.

PY - 2020/2/1

Y1 - 2020/2/1

N2 - Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. Weevaluated whether PSVs inBRCA1/2 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 = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 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.Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

AB - Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. Weevaluated whether PSVs inBRCA1/2 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 = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 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.Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

KW - APC

KW - BREAST-CANCER

KW - CARRIERS

KW - GENE

KW - GERMLINE MUTATIONS

KW - IDENTIFICATION

KW - INCREASE

KW - MESSENGER-RNA DECAY

KW - OVARIAN

KW - PHENOTYPE

KW - apc

KW - breast-cancer

KW - carriers

KW - gene

KW - germline mutations

KW - identification

KW - increase

KW - messenger-rna decay

KW - ovarian

KW - phenotype

U2 - 10.1158/0008-5472.can-19-1840

DO - 10.1158/0008-5472.can-19-1840

M3 - Article

C2 - 31723001

SN - 0008-5472

VL - 80

SP - 624

EP - 638

JO - Cancer Research

JF - Cancer Research

IS - 3

ER -