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A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population.

ABSTRACT: Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P(trend) = 2.3 × 10?? to P(trend) = 3.9 × 10??), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P(trend) = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P(trend) = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (P(trend) = 1 × 10??) to P(trend) = 8 × 10??; rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P(trend) = 1.1 × 10??

SUBMITTER: Antoniou AC

PROVIDER: S-EPMC3130795 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population.

Antoniou Antonis C AC Wang Xianshu X Fredericksen Zachary S ZS McGuffog Lesley L Tarrell Robert R Sinilnikova Olga M OM Healey Sue S Morrison Jonathan J Kartsonaki Christiana C Lesnick Timothy T Ghoussaini Maya M Barrowdale Daniel D Peock Susan S Cook Margaret M Oliver Clare C Frost Debra D Eccles Diana D Evans D Gareth DG Eeles Ros R Izatt Louise L Chu Carol C Douglas Fiona F Paterson Joan J Stoppa-Lyonnet Dominique D Houdayer Claude C Mazoyer Sylvie S Giraud Sophie S Lasset Christine C Remenieras Audrey A Caron Olivier O Hardouin Agnès A Berthet Pascaline P Hogervorst Frans B L FB Rookus Matti A MA Jager Agnes A van den Ouweland Ans A Hoogerbrugge Nicoline N van der Luijt Rob B RB Meijers-Heijboer Hanne H Gómez García Encarna B EB Devilee Peter P Vreeswijk Maaike P G MP Lubinski Jan J Jakubowska Anna A Gronwald Jacek J Huzarski Tomasz T Byrski Tomasz T Górski Bohdan B Cybulski Cezary C Spurdle Amanda B AB Holland Helene H Goldgar David E DE John Esther M EM Hopper John L JL Southey Melissa M Buys Saundra S SS Daly Mary B MB Terry Mary-Beth MB Schmutzler Rita K RK Wappenschmidt Barbara B Engel Christoph C Meindl Alfons A Preisler-Adams Sabine S Arnold Norbert N Niederacher Dieter D Sutter Christian C Domchek Susan M SM Nathanson Katherine L KL Rebbeck Timothy T Blum Joanne L JL Piedmonte Marion M Rodriguez Gustavo C GC Wakeley Katie K Boggess John F JF Basil Jack J Blank Stephanie V SV Friedman Eitan E Kaufman Bella B Laitman Yael Y Milgrom Roni R Andrulis Irene L IL Glendon Gord G Ozcelik Hilmi H Kirchhoff Tomas T Vijai Joseph J Gaudet Mia M MM Altshuler David D Guiducci Candace C Loman Niklas N Harbst Katja K Rantala Johanna J Ehrencrona Hans H Gerdes Anne-Marie AM Thomassen Mads M Sunde Lone L Peterlongo Paolo P Manoukian Siranoush S Bonanni Bernardo B Viel Alessandra A Radice Paolo P Caldes Trinidad T de la Hoya Miguel M Singer Christian F CF Fink-Retter Anneliese A Greene Mark H MH Mai Phuong L PL Loud Jennifer T JT Guidugli Lucia L Lindor Noralane M NM Hansen Thomas V O TV Nielsen Finn C FC Blanco Ignacio I Lazaro Conxi C Garber Judy J Ramus Susan J SJ Gayther Simon A SA Phelan Catherine C Narod Stephen S Szabo Csilla I CI Benitez Javier J Osorio Ana A Nevanlinna Heli H Heikkinen Tuomas T Caligo Maria A MA Beattie Mary S MS Hamann Ute U Godwin Andrew K AK Montagna Marco M Casella Cinzia C Neuhausen Susan L SL Karlan Beth Y BY Tung Nadine N Toland Amanda E AE Weitzel Jeffrey J Olopade Olofunmilayo O Simard Jacques J Soucy Penny P Rubinstein Wendy S WS Arason Adalgeir A Rennert Gad G Martin Nicholas G NG Montgomery Grant W GW Chang-Claude Jenny J Flesch-Janys Dieter D Brauch Hiltrud H Severi Gianluca G Baglietto Laura L Cox Angela A Cross Simon S SS Miron Penelope P Gerty Sue M SM Tapper William W Yannoukakos Drakoulis D Fountzilas George G Fasching Peter A PA Beckmann Matthias W MW Dos Santos Silva Isabel I Peto Julian J Lambrechts Diether D Paridaens Robert R Rüdiger Thomas T Försti Asta A Winqvist Robert R Pylkäs Katri K Diasio Robert B RB Lee Adam M AM Eckel-Passow Jeanette J Vachon Celine C Blows Fiona F Driver Kristy K Dunning Alison A Pharoah Paul P D PP Offit Kenneth K Pankratz V Shane VS Hakonarson Hakon H Chenevix-Trench Georgia G Easton Douglas F DF Couch Fergus J FJ

Nature genetics 20100919 10

Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with ...[more]

PMID: 20852631

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Project description:Importance:Prophylactic bilateral salpingo-oophorectomy is recommended for BRCA1 mutation carriers to prevent ovarian cancer. Whether or not hormone replacement therapy (HRT) initiated after oophorectomy is associated with an increased risk of breast cancer has not been evaluated in a prospective study. Objective:To determine the association between HRT use and BRCA1-associated breast cancer. Design, Setting, and Participants:A prospective, longitudinal cohort study of BRCA1 and BRCA2 mutation carriers from 80 participating centers in 17 countries was conducted between 1995 and 2017 with a mean follow-up of 7.6 years. Participants had sought genetic testing for a BRCA1 or BRCA2 mutation because of a personal or family history of breast and/or ovarian cancer. Carriers of BRCA1 mutation with no personal medical history of cancer who underwent bilateral oophorectomy following enrollment were eligible for the cohort study. Exposures:A follow-up questionnaire was administered every 2 years to obtain detailed information on HRT use. A left-truncated Cox proportional hazard analysis was used to estimate the hazard ratios (HRs) and 95% CIs associated with the initiation of HRT use postoophorectomy. Main Outcomes and Measures:Incident breast cancer. Results:A total of 872 BRCA1 mutation carriers with a mean postoophorectomy follow-up period of 7.6 years (range, 0.4-22.1) were included in this study. Mean (SD) age of participants was 43.4 (8.5) years. Among these, 92 (10.6%) incident breast cancers were diagnosed. Overall, HRT use after oophorectomy was not associated with an increased risk of breast cancer. The HR was 0.97 (95% CI, 0.62-1.52; P = .89) for ever use of any type of HRT vs no use; however, the effects of estrogen alone and combination hormonal therapy were different. After 10 years of follow-up, the cumulative incidence of breast cancer among women who used estrogen-alone HRT was 12% compared with 22% among women who used estrogen plus progesterone HRT (absolute difference, 10%; log rank P = .04). Conclusions and Relevance:These findings suggest that use of estrogen after oophorectomy does not increase the risk of breast cancer among women with a BRCA1 mutation and should reassure BRCA1 mutation carriers considering preventive surgery that HRT is safe. The possible adverse effect of progesterone-containing HRT warrants further study.

Dataset Information

A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population.

Publications

A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population.

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