Breast Cancer Research and Treatment

, Volume 134, Issue 1, pp 429–433 | Cite as

Predisposition gene identification in common cancers by exome sequencing: insights from familial breast cancer

  • Katie Snape
  • Elise Ruark
  • Patrick Tarpey
  • Anthony Renwick
  • Clare Turnbull
  • Sheila Seal
  • Anne Murray
  • Sandra Hanks
  • Jenny Douglas
  • Michael R. Stratton
  • Nazneen Rahman
Brief Report

Abstract

The genetic component of breast cancer predisposition remains largely unexplained. Candidate gene case–control resequencing has identified predisposition genes characterised by rare, protein truncating mutations that confer moderate risks of disease. In theory, exome sequencing should yield additional genes of this class. Here, we explore the feasibility and design considerations of this approach. We performed exome sequencing in 50 individuals with familial breast cancer, applying frequency and protein function filters to identify variants most likely to be pathogenic. We identified 867,378 variants that passed the call quality filters of which 1,296 variants passed the frequency and protein truncation filters. The median number of validated, rare, protein truncating variants was 10 in individuals with, and without, mutations in known genes. The functional candidacy of mutated genes was similar in both groups. Without prior knowledge, the known genes would not have been recognisable as breast cancer predisposition genes. Everyone carries multiple rare mutations that are plausibly related to disease. Exome sequencing in common conditions will therefore require intelligent sample and variant prioritisation strategies in large case–control studies to deliver robust genetic evidence of disease association.

Keywords

Breast cancer predisposition Exome sequencing Common disease genetics Missing heritability 

Abbreviations

RR

Relative risk

FBCS

Familial breast cancer study

PTV

Protein truncating variant

Supplementary material

10549_2012_2057_MOESM1_ESM.docx (44 kb)
Supplementary material 1 (DOCX 48 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Katie Snape
    • 1
  • Elise Ruark
    • 1
  • Patrick Tarpey
    • 2
  • Anthony Renwick
    • 1
  • Clare Turnbull
    • 1
  • Sheila Seal
    • 1
  • Anne Murray
    • 1
  • Sandra Hanks
    • 1
  • Jenny Douglas
    • 1
  • Michael R. Stratton
    • 2
  • Nazneen Rahman
    • 1
  1. 1.Division of Genetics and EpidemiologyInstitute of Cancer ResearchSutton, SurreyUK
  2. 2.The Wellcome Trust Sanger InstituteHinxton, CambridgeUK

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