Dataset Information

Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.

ABSTRACT: BACKGROUND:Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). METHODS:Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. RESULTS:We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 × 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 × 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 × 10(-3)). CONCLUSIONS:19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. IMPACT:These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers.

SUBMITTER: Couch FJ

PROVIDER: S-EPMC3319317 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.

Couch Fergus J FJ Gaudet Mia M MM Antoniou Antonis C AC Ramus Susan J SJ Kuchenbaecker Karoline B KB Soucy Penny P Beesley Jonathan J Chen Xiaoqing X Wang Xianshu X Kirchhoff Tomas T McGuffog Lesley L Barrowdale Daniel D Lee Andrew A Healey Sue S Sinilnikova Olga M OM Andrulis Irene L IL Ozcelik Hilmi H Mulligan Anna Marie AM Thomassen Mads M Gerdes Anne-Marie AM Jensen Uffe Birk UB Skytte Anne-Bine AB Kruse Torben A TA Caligo Maria A MA von Wachenfeldt Anna A Barbany-Bustinza Gisela G Loman Niklas N Soller Maria M Ehrencrona Hans H Karlsson Per P Nathanson Katherine L KL Rebbeck Timothy R TR Domchek Susan M SM Jakubowska Ania A Lubinski Jan J Jaworska Katarzyna K Durda Katarzyna K Zlowocka Elzbieta E Huzarski Tomasz T Byrski Tomasz T Gronwald Jacek J Cybulski Cezary C Górski Bohdan B Osorio Ana A Durán Mercedes M Tejada María Isabel MI Benitez Javier J Hamann Ute U Hogervorst Frans B L FB van Os Theo A TA van Leeuwen Flora E FE Meijers-Heijboer Hanne E J HE Wijnen Juul J Blok Marinus J MJ Kets Marleen M Hooning Maartje J MJ Oldenburg Rogier A RA Ausems Margreet G E M MG Peock Susan S Frost Debra D Ellis Steve D SD Platte Radka R Fineberg Elena E Evans D Gareth DG Jacobs Chris C Eeles Rosalind A RA Adlard Julian J Davidson Rosemarie R Eccles Diana M DM Cole Trevor T Cook Jackie J Paterson Joan J Brewer Carole C Douglas Fiona F Hodgson Shirley V SV Morrison Patrick J PJ Walker Lisa L Porteous Mary E ME Kennedy M John MJ Side Lucy E LE Bove Betsy B Godwin Andrew K AK Stoppa-Lyonnet Dominique D Fassy-Colcombet Marion M Castera Laurent L Cornelis François F Mazoyer Sylvie S Léoné Mélanie M Boutry-Kryza Nadia N Bressac-de Paillerets Brigitte B Caron Olivier O Pujol Pascal P Coupier Isabelle I Delnatte Capucine C Akloul Linda L Lynch Henry T HT Snyder Carrie L CL Buys Saundra S SS Daly Mary B MB Terry Marybeth M Chung Wendy K WK John Esther M EM Miron Alexander A Southey Melissa C MC Hopper John L JL Goldgar David E DE Singer Christian F CF Rappaport Christine C Tea Muy-Kheng M MK Fink-Retter Anneliese A Hansen Thomas V O TV Nielsen Finn C FC Arason Aðalgeir A Vijai Joseph J Shah Sohela S Sarrel Kara K Robson Mark E ME Piedmonte Marion M Phillips Kelly K Basil Jack J Rubinstein Wendy S WS Boggess John J Wakeley Katie K Ewart-Toland Amanda A Montagna Marco M Agata Simona S Imyanitov Evgeny N EN Isaacs Claudine C Janavicius Ramunas R Lazaro Conxi C Blanco Ignacio I Feliubadalo Lidia L Brunet Joan J Gayther Simon A SA Pharoah Paul P D PP Odunsi Kunle O KO Karlan Beth Y BY Walsh Christine S CS Olah Edith E Teo Soo Hwang SH Ganz Patricia A PA Beattie Mary S MS van Rensburg Elizabeth J EJ Dorfling Cecelia M CM Diez Orland O Kwong Ava A Schmutzler Rita K RK Wappenschmidt Barbara B Engel Christoph C Meindl Alfons A Ditsch Nina N Arnold Norbert N Heidemann Simone S Niederacher Dieter D Preisler-Adams Sabine S Gadzicki Dorothea D Varon-Mateeva Raymonda R Deissler Helmut H Gehrig Andrea A Sutter Christian C Kast Karin K Fiebig Britta B Heinritz Wolfram W Caldes Trinidad T de la Hoya Miguel M Muranen Taru A TA Nevanlinna Heli H Tischkowitz Marc D MD Spurdle Amanda B AB Neuhausen Susan L SL Ding Yuan Chun YC Lindor Noralane M NM Fredericksen Zachary Z Pankratz V Shane VS Peterlongo Paolo P Manoukian Siranoush S Peissel Bernard B Zaffaroni Daniela D Barile Monica M Bernard Loris L Viel Alessandra A Giannini Giuseppe G Varesco Liliana L Radice Paolo P Greene Mark H MH Mai Phuong L PL Easton Douglas F DF Chenevix-Trench Georgia G Offit Kenneth K Simard Jacques J

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20120220 4

<h4>Background</h4>Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).<h4>Methods</h4>Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies w ...[more]

PMID: 22351618

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Project description:INTRODUCTION:More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. METHODS:We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. RESULTS:The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC)?=?0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC?=?0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC?=?0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. CONCLUSIONS:Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.

Project description:INTRODUCTION:Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. METHODS:We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. RESULTS:The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. CONCLUSIONS:The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

Dataset Information

Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.

Publications

Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.

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