Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction

Research output: Contribution to journalArticle

Abstract

The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

Details

Authors
  • Antonis C Antoniou
  • Jonathan Beesley
  • Lesley McGuffog
  • Olga M Sinilnikova
  • Sue Healey
  • Susan L Neuhausen
  • Yuan Chun Ding
  • Timothy R Rebbeck
  • Jeffrey N Weitzel
  • Henry T Lynch
  • Claudine Isaacs
  • Patricia A Ganz
  • Gail Tomlinson
  • Olufunmilayo I Olopade
  • Fergus J Couch
  • Xianshu Wang
  • Noralane M Lindor
  • Vernon S Pankratz
  • Paolo Radice
  • Siranoush Manoukian
  • Bernard Peissel
  • Daniela Zaffaroni
  • Monica Barile
  • Alessandra Viel
  • Anna Allavena
  • Valentina Dall'Olio
  • Paolo Peterlongo
  • Csilla I Szabo
  • Michal Zikan
  • Kathleen Claes
  • Bruce Poppe
  • Lenka Foretova
  • Phuong L Mai
  • Mark H Greene
  • Gad Rennert
  • Flavio Lejbkowicz
  • Gord Glendon
  • Hilmi Ozcelik
  • Irene L Andrulis
  • Mads Thomassen
  • Anne-Marie Gerdes
  • Lone Sunde
  • Dorthe Cruger
  • Uffe Birk Jensen
  • Maria Caligo
  • Eitan Friedman
  • Bella Kaufman
  • Yael Laitman
  • Helena Jernström
  • Marie Stenmark-Askmalm
  • Ontario Cancer Genetics Network
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology

Keywords

  • Adult, Aged, Aged, 80 and over, Alleles, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Female, Genetic Predisposition to Disease, Genotype, Heterozygote, Humans, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Receptors, Progesterone, Risk Assessment, Risk Factors, Sodium-Bicarbonate Symporters, Survival Analysis, Vesicular Transport Proteins
Original languageEnglish
Pages (from-to)9742-54
Number of pages13
JournalCancer Research
Volume70
Issue number23
Publication statusPublished - 2010 Dec 1
Publication categoryResearch
Peer-reviewedYes