title: Limited evidence that cancer susceptibility regions are preferential targets for somatic mutation.
abstract: BACKGROUND
  Genome wide-association studies have successfully identified several hundred independent loci harboring common cancer susceptibility alleles that are distinct from the more than 110 cancer predisposition genes. The latter are generally characterized by disruptive mutations in coding genes that have been established as 'drivers' of cancer in large somatic sequencing studies. We set out to determine whether, similarly, common cancer susceptibility loci map to genes that have altered frequencies of mutation.
  
  
  RESULTS
  In our analysis of the intervals defined by the cancer susceptibility markers, we observed that cancer susceptibility regions have gene mutation frequencies comparable to background mutation frequencies. Restricting analyses to genes that have been determined to be pleiotropic across cancer types, genes affected by expression quantitative trait loci, or functional genes indicates that most cancer susceptibility genes classified into these subgroups do not display mutation frequencies that deviate from those expected. We observed limited evidence that cancer susceptibility regions that harbor common alleles with small estimated effect sizes are preferential targets for altered somatic mutation frequencies.
  
  
  CONCLUSIONS
  Our findings suggest a complex interplay between germline susceptibility and somatic mutation, underscoring the cumulative effect of common variants on redundant pathways as opposed to driver genes. Complex biological pathways and networks likely link these genetic features of carcinogenesis, particularly as they relate to distinct polygenic models for each cancer type.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, 20892, USA. mitchell.machiela@nih.gov.
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Machiela
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, 20892, USA. bmh5@rice.edu.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Ho
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, 20892, USA. fisherva@mail.nih.gov.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Fisher
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, 20892, USA. xing.hua@nih.gov.
authors.forename: Xing
authors.initials: X
authors.lastname: Hua
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, 20892, USA. chanocks@mail.nih.gov.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
mesh_terms: D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D059645:Mutation Rate; D009369:Neoplasms / Q000235:genetics*; D040641:Quantitative Trait Loci