Dataset Information

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. 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 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.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.

SUBMITTER: Patel VL

PROVIDER: S-EPMC7553241 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Patel Vivek L VL Busch Evan L EL Friebel Tara M TM Cronin Angel A Leslie Goska G McGuffog Lesley L Adlard Julian J Agata Simona S Agnarsson Bjarni A BA Ahmed Munaza M Aittomäki Kristiina K Alducci Elisa E Andrulis Irene L IL Arason Adalgeir A Arnold Norbert N Artioli Grazia G Arver Brita B Auber Bernd B Azzollini Jacopo J Balmaña Judith J Barkardottir Rosa B RB Barnes Daniel R DR Barroso Alicia A Barrowdale Daniel D Belotti Muriel M Benitez Javier J Bertelsen Birgitte B Blok Marinus J MJ Bodrogi Istvan I Bonadona Valérie V Bonanni Bernardo B Bondavalli Davide D Boonen Susanne E SE Borde Julika J Borg Ake A Bradbury Angela R AR Brady Angela A Brewer Carole C Brunet Joan J Buecher Bruno B Buys Saundra S SS Cabezas-Camarero Santiago S Caldés Trinidad T Caliebe Almuth A Caligo Maria A MA Calvello Mariarosaria M Campbell Ian G IG Carnevali Ileana I Carrasco Estela E Chan Tsun L TL Chu Annie T W ATW Chung Wendy K WK Claes Kathleen B M KBM Collaborators Gemo Study GS Collaborators Embrace E Cook Jackie J Cortesi Laura L Couch Fergus J FJ Daly Mary B MB Damante Giuseppe G Darder Esther E Davidson Rosemarie R de la Hoya Miguel M Puppa Lara Della LD Dennis Joe J Díez Orland O Ding Yuan Chun YC Ditsch Nina N Domchek Susan M SM Donaldson Alan A Dworniczak Bernd B Easton Douglas F DF Eccles Diana M DM Eeles Rosalind A RA Ehrencrona Hans H Ejlertsen Bent B Engel Christoph C Evans D Gareth DG Faivre Laurence L Faust Ulrike U Feliubadaló Lídia L Foretova Lenka L Fostira Florentia F Fountzilas George G Frost Debra D García-Barberán Vanesa V Garre Pilar P Gauthier-Villars Marion M Géczi Lajos L Gehrig Andrea A Gerdes Anne-Marie AM Gesta Paul P Giannini Giuseppe G Glendon Gord G Godwin Andrew K AK Goldgar David E DE Greene Mark H MH Gutierrez-Barrera Angelica M AM Hahnen Eric E Hamann Ute U Hauke Jan J Herold Natalie N Hogervorst Frans B L FBL Honisch Ellen E Hopper John L JL Hulick Peter J PJ Investigators KConFab K Investigators Hebon H Izatt Louise L Jager Agnes A James Paul P Janavicius Ramunas R Jensen Uffe Birk UB Jensen Thomas Dyrso TD Johannsson Oskar Th OT John Esther M EM Joseph Vijai V Kang Eunyoung E Kast Karin K Kiiski Johanna I JI Kim Sung-Won SW Kim Zisun Z Ko Kwang-Pil KP Konstantopoulou Irene I Kramer Gero G Krogh Lotte L Kruse Torben A TA Kwong Ava A Larsen Mirjam M Lasset Christine C Lautrup Charlotte C Lazaro Conxi C Lee Jihyoun J Lee Jong Won JW Lee Min Hyuk MH Lemke Johannes J Lesueur Fabienne F Liljegren Annelie A Lindblom Annika A Llovet Patricia P Lopez-Fernández Adria A Lopez-Perolio Irene I Lorca Victor V Loud Jennifer T JT Ma Edmond S K ESK Mai Phuong L PL Manoukian Siranoush S Mari Veronique V Martin Lynn L Matricardi Laura L Mebirouk Noura N Medici Veronica V Meijers-Heijboer Hanne E J HEJ Meindl Alfons A Mensenkamp Arjen R AR Miller Clare C Gomes Denise Molina DM Montagna Marco M Mooij Thea M TM Moserle Lidia L Mouret-Fourme Emmanuelle E Mulligan Anna Marie AM Nathanson Katherine L KL Navratilova Marie M Nevanlinna Heli H Niederacher Dieter D Nielsen Finn C Cilius FCC Nikitina-Zake Liene L Offit Kenneth K Olah Edith E Olopade Olufunmilayo I OI Ong Kai-Ren KR Osorio Ana A Ott Claus-Eric CE Palli Domenico D Park Sue K SK Parsons Michael T MT Pedersen Inge Sokilde IS Peissel Bernard B Peixoto Ana A Pérez-Segura Pedro P Peterlongo Paolo P Petersen Annabeth Høgh AH Porteous Mary E ME Pujana Miguel Angel MA Radice Paolo P Ramser Juliane J Rantala Johanna J Rashid Muhammad U MU Rhiem Kerstin K Rizzolo Piera P Robson Mark E ME Rookus Matti A MA Rossing Caroline M CM Ruddy Kathryn J KJ Santos Catarina C Saule Claire C Scarpitta Rosa R Schmutzler Rita K RK Schuster Hélène H Senter Leigha L Seynaeve Caroline M CM Shah Payal D PD Sharma Priyanka P Shin Vivian Y VY Silvestri Valentina V Simard Jacques J Singer Christian F CF Skytte Anne-Bine AB Snape Katie K Solano Angela R AR Soucy Penny P Southey Melissa C MC Spurdle Amanda B AB Steele Linda L Steinemann Doris D Stoppa-Lyonnet Dominique D Stradella Agostina A Sunde Lone L Sutter Christian C Tan Yen Y YY Teixeira Manuel R MR Teo Soo Hwang SH Thomassen Mads M Tibiletti Maria Grazia MG Tischkowitz Marc M Tognazzo Silvia S Toland Amanda E AE Tommasi Stefania S Torres Diana D Toss Angela A Trainer Alison H AH Tung Nadine N van Asperen Christi J CJ van der Baan Frederieke H FH van der Kolk Lizet E LE van der Luijt Rob B RB van Hest Liselotte P LP Varesco Liliana L Varon-Mateeva Raymonda R Viel Alessandra A Vierstraete Jeroen J Villa Roberta R von Wachenfeldt Anna A Wagner Philipp P Wang-Gohrke Shan S Wappenschmidt Barbara B Weitzel Jeffrey N JN Wieme Greet G Yadav Siddhartha S Yannoukakos Drakoulis D Yoon Sook-Yee SY Zanzottera Cristina C Zorn Kristin K KK D'Amico Anthony V AV Freedman Matthew L ML Pomerantz Mark M MM Chenevix-Trench Georgia G Antoniou Antonis C AC Neuhausen Susan L SL Ottini Laura L Nielsen Henriette Roed HR Rebbeck Timothy R TR

Cancer research 20191113 3

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 t ...[more]

PMID: 31723001

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Project description:Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer.To estimate risk and mortality reduction stratified by mutation and prior cancer status.Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009.Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality.No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, women who underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 [95% CI, 0.12-0.69]), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 [95% CI, 0.41-0.96]) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 [95% CI, 0.16-0.82]). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 [95% CI, 0.26-0.61]), breast cancer-specific mortality (6% vs 2%; HR, 0.44 [95% CI, 0.26-0.76]), and ovarian cancer-specific mortality (3% vs 0.4%; HR, 0.21 [95% CI, 0.06-0.80]).Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality.

Project description:ImportanceWomen with pathogenic variants in BRCA1 and BRCA2 are at high risk of developing breast and ovarian cancers. They usually undergo intensive cancer surveillance and may also consider surgical interventions, such as risk-reducing mastectomy or risk-reducing salpingo-oophorectomy (RRSO). Risk-reducing salpingo-oophorectomy has been shown to reduce ovarian cancer risk, but its association with breast cancer risk is less clear.ObjectiveTo assess the association of RRSO with the risk of breast cancer in women with BRCA1 and BRCA2 pathogenic variants.Design, setting, and participantsThis case series included families enrolled in the Breast Cancer Family Registry between 1996 and 2000 that carried an inherited pathogenic variant in BRCA1 (498 families) or BRCA2 (378 families). A survival analysis approach was used that was designed specifically to assess the time-varying association of RRSO with breast cancer risk and accounting for other potential biases. Data were analyzed from August 2019 to November 2020.ExposureRisk-reducing salpingo-oophorectomy.Main outcomes and measuresIn all analyses, the primary end point was the time to a first primary breast cancer.ResultsA total of 876 families were evaluated, including 498 with BRCA1 (2650 individuals; mean [SD] event age, 55.8 [19.1] years; 437 White probands [87.8%]) and 378 with BRCA2 (1925 individuals; mean [SD] event age, 57.0 [18.6] years; 299 White probands [79.1%]). Risk-reducing salpingo-oophorectomy was associated with a reduced risk of breast cancer for BRCA1 and BRCA2 pathogenic variant carriers within 5 years after surgery (hazard ratios [HRs], 0.28 [95% CI, 0.10-0.63] and 0.19 [95% CI, 0.06-0.71], respectively), whereas the corresponding HRs were weaker after 5 years postsurgery (HRs, 0.64 [95% CI, 0.38-0.97] and 0.99 [95% CI; 0.84-1.00], respectively). For BRCA1 and BRCA2 pathogenic variant carriers who underwent RRSO at age 40 years, the cause-specific cumulative risk of breast cancer was 49.7% (95% CI, 40.0-60.3) and 52.7% (95% CI, 47.9-58.7) by age 70 years, respectively, compared with 61.0% (95% CI, 56.7-66.0) and 54.0% (95% CI, 49.3-60.1), respectively, for women without RRSO.Conclusions and relevanceAlthough the primary indication for RRSO is the prevention of ovarian cancer, it is also critical to assess its association with breast cancer risk in order to guide clinical decision-making about RRSO use and timing. The results of this case series suggest a reduced risk of breast cancer associated with RRSO in the immediate 5 years after surgery in women carrying BRCA1 and BRCA2 pathogenic variants, and a longer-term association with cumulative breast cancer risk in women carrying BRCA1 pathogenic variants.

Project description:ImportanceLimited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.ObjectiveTo identify mutation-specific cancer risks for carriers of BRCA1/2.Design, setting, and participantsObservational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.ExposuresMutations of BRCA1 or BRCA2.Main outcomes and measuresBreast and ovarian cancer risks.ResultsAmong BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.Conclusions and relevanceBreast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

Project description:ImportanceThe clinical importance of genetic testing of BRCA1 and BRCA2 in breast, ovarian, prostate, and pancreatic cancers is widely recognized. However, there is insufficient evidence to include other cancer types that are potentially associated with BRCA1 and BRCA2 in clinical management guidelines.ObjectiveTo evaluate the association of BRCA1 and BRCA2 pathogenic variants with additional cancer types and their clinical characteristics in 100 914 individuals across 14 cancer types.Design, setting, and participantsThis case-control analysis to identify cancer types and clinical characteristics associated with pathogenic variants in BRCA1 and BRCA2 included DNA samples and clinical information from 63 828 patients with 14 common cancer types and 37 086 controls that were sourced from a multi-institutional hospital-based registry, BioBank Japan, between April 2003 and March 2018. The data were analyzed between August 2019 and October 2021.Main outcomes and measuresGermline pathogenic variants in coding regions and 2 bp flanking intronic sequences in BRCA1 and BRCA2 were identified by a multiplex polymerase chain reaction-based target sequence method. Associations of (likely) pathogenic variants with each cancer type were assessed by comparing pathogenic variant carrier frequency between patients in each cancer type and controls.ResultsA total of 65 108 patients (mean [SD] age at diagnosis, 64.1 [11.6] years; 27 531 [42.3%] female) and 38 153 controls (mean [SD] age at registration, 61.8 [14.6] years; 17 911 [46.9%] female) were included in this study. A total of 315 unique pathogenic variants were identified. Pathogenic variants were associated with P < 1 × 10-4 with an odds ratio (OR) of greater than 4.0 in biliary tract cancer (OR, 17.4; 95% CI, 5.8-51.9) in BRCA1, esophageal cancer (OR, 5.6; 95% CI, 2.9-11.0) in BRCA2, and gastric cancer (OR, 5.2; 95% CI, 2.6-10.5) in BRCA1, and (OR, 4.7; 95% CI, 3.1-7.1) in BRCA2 in addition to the 4 established cancer types. We also observed an association with 2 and 4 other cancer types in BRCA1 and BRCA2, respectively. Biliary tract, female breast, ovarian, and prostate cancers showed enrichment of carrier patients according to the increased number of reported cancer types in relatives.Conclusions and relevanceThe results of this large-scale registry-based case-control study suggest that pathogenic variants in BRCA1 and BRCA2 were associated with the risk of 7 cancer types. These results indicate broader clinical relevance of BRCA1 and BRCA2 genetic testing.

Dataset Information

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

Publications

Association of Genomic Domains in <i>BRCA1</i> and <i>BRCA2</i> with Prostate Cancer Risk and Aggressiveness.

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