Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2
Authors: Mulligan Anna Marie , Couch Fergus J , Barrowdale Daniel , Domchek Susan M , Eccles Diana , Nevanlinna Heli , Ramus Susan J , Robson Mark , Sherman Mark , Spurdle Amanda B , Wappenschmidt Barbara , Lee Andrew , McGuffog Lesley , Healey Sue , Sinilnikova Olga M , Janavicius Ramunas , Hansen Thomas vO , Nielsen Finn C , Ejlertsen Bent , Osorio Ana , Muñoz-Repeto Iván , Durán Mercedes , Godino Javier , Pertesi Maroulio , Benítez Javier , Peterlongo Paolo , Manoukian Siranoush , Peissel Bernard , Zaffaroni Daniela , Cattaneo Elisa , Bonanni Bernardo , Viel Alessandra , Pasini Barbara , Papi Laura , Ottini Laura , Savarese Antonella , Bernard Loris , Radice Paolo , Hamann Ute , Verheus Martijn , Meijers-Heijboer Hanne EJ , Wijnen Juul , Gómez García Encarna B , Nelen Marcel R , Kets C Marleen , Seynaeve Caroline , Tilanus-Linthorst Madeleine MA , van der Luijt Rob B , Os Theo van , Rookus Matti , Frost Debra , Jones J Louise , Evans D Gareth , Lalloo Fiona , Eeles Ros , Izatt Louise , Adlard Julian , Davidson Rosemarie , Cook Jackie , Donaldson Alan , Dorkins Huw , Gregory Helen , Eason Jacqueline , Houghton Catherine , Barwell Julian , Side Lucy E , McCann Emma , Murray Alex , Peock Susan , Godwin Andrew K , Schmutzler Rita K , Rhiem Kerstin , Engel Christoph , Meindl Alfons , Ruehl Ina , Arnold Norbert , Niederacher Dieter , Sutter Christian , Deissler Helmut , Gadzicki Dorothea , Kast Karin , Preisler-Adams Sabine , Varon-Mateeva Raymonda , Schoenbuchner Ines , Fiebig Britta , Heinritz Wolfram , Schäfer Dieter , Gevensleben Heidrun , Caux-Moncoutier Virginie , Fassy-Colcombet Marion , Cornelis François , Mazoyer Sylvie , Léoné Mélanie , Boutry-Kryza Nadia , Hardouin Agnès , Berthet Pascaline , Muller Danièle , Fricker Jean-Pierre , Mortemousque Isabelle , Pujol Pascal , Coupier Isabelle , Lebrun Marine , Kientz Caroline , Longy Michel , Sevenet Nicolas , Stoppa-Lyonnet Dominique , Isaacs Claudine , Caldes Trinidad , de la Hoya Miguel , Heikkinen Tuomas , Aittomäki Kristiina , Blanco Ignacio , Lazaro Conxi , Barkardottir Rosa B , Soucy Penny , Dumont Martine , Simard Jacques , Montagna Marco , Tognazzo Silvia , D'Andrea Emma , Fox Stephen , Yan Max , Rebbeck Tim , Olopade Olufunmilayo I , Weitzel Jeffrey N , Lynch Henry T , Ganz Patricia A , Tomlinson Gail E , Wang Xianshu , Fredericksen Zachary , Pankratz Vernon S , Lindor Noralane M , Szabo Csilla , Offit Kenneth , Sakr Rita , Gaudet Mia , Bhatia Jasmine , Kauff Noah , Singer Christian F , Tea Muy-Kheng , Gschwantler-Kaulich Daphne , Fink-Retter Anneliese , Mai Phuong L , Greene Mark H , Imyanitov Evgeny , O'Malley Frances P , Ozcelik Hilmi , Glendon Gordon , Toland Amanda E , Gerdes Anne-Marie , Thomassen Mads , Kruse Torben A , Jensen Uffe Birk , Skytte Anne-Bine , Caligo Maria A , Soller Maria , Henriksson Karin , Wachenfeldt von Anna , Arver Brita , Stenmark-Askmalm Marie , Karlsson Per , Ding Yuan Chun , Neuhausen Susan L , Beattie Mary , Pharoah Paul DP , Moysich Kirsten B , Nathanson Katherine L , Karlan Beth Y , Gross Jenny , John Esther M , Daly Mary B , Buys Saundra M , Southey Melissa C , Hopper John L , Terry Mary Beth , Chung Wendy , Miron Alexander F , Goldgar David , Chenevix-Trench Georgia , Easton Douglas F , Andrulis Irene L , Antoniou Antonis C ,   Breast Cancer Family Registry,   EMBRACE,   GEMO Study Collaborators,   HEBON,   kConFab Investigators,   Ontario Cancer Genetics Network,   SWE-BRCA,   CIMBA
Published: November 2011

Abstract
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.