Breast Cancer Research and Treatment

, Volume 130, Issue 3, pp 1043–1049

FAN1 variants identified in multiple-case early-onset breast cancer families via exome sequencing: no evidence for association with risk for breast cancer

  • Daniel J. Park
  • Fabrice A. Odefrey
  • Fleur Hammet
  • Graham G. Giles
  • Laura Baglietto
  • ABCFS
  • MCCS
  • John L. Hopper
  • Daniel F. Schmidt
  • Enes Makalic
  • Olga M. Sinilnikova
  • David E. Goldgar
  • Melissa C. Southey
Brief Report

DOI: 10.1007/s10549-011-1704-y

Cite this article as:
Park, D.J., Odefrey, F.A., Hammet, F. et al. Breast Cancer Res Treat (2011) 130: 1043. doi:10.1007/s10549-011-1704-y

Abstract

We are interested in the characterisation of previously undescribed contributions to the heritable component of human cancers. To this end, we applied whole-exome capture, followed by massively parallel sequence analysis to the germline DNA of two greater than third-degree affected relatives from four multiple-case, early-onset breast cancer families. Prior testing for variants in known breast cancer susceptibility, genes in these families did not identify causal mutations. We detected and confirmed two different variants in the DNA damage repair gene FAN1 (R377W, chr15:31197995 C>T and R507H, chr15:31202961 G>A [hg19]) which were not present in dbSNP131. In one family, FAN1 R377W, predicted to be damaging by SIFT and PolyPhen2, was present in all six tested members with cancer (five with breast cancer, one with malignant melanoma). In another family, FAN1 R507H, predicted to be damaging by SIFT but benign by PolyPhen2, was observed in one of two tested members with breast cancer. We genotyped FAN1 R377W and R507H variants across 1417 population-based cases and 1490 unaffected population-based controls (frequency-matched for age). These variants were rare in the Australian population (minor allele frequencies of 0.0064 and 0.010, respectively) and were not associated with breast cancer risk (OR = 0.80, 95% CI[0.39–1.61], P = 0.50 and OR = 0.74, 95% CI[0.41–1.29], P = 0.26, respectively). Analysis of breast cancer risks for relatives of case and control carriers did not find evidence of an increased risk. Despite the biological role of FAN1, the plausibility of its role as a breast cancer predisposition gene, and the possible deleterious nature of the identified variants, these two variants do not appear to be causal for breast cancer. Future studies to extend the genetic analysis of FAN1 will further explore its possible role as a breast cancer susceptibility gene.

Keywords

Whole-exome sequencing Massively parallel sequencing Breast cancer FAN1 

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Daniel J. Park
    • 1
  • Fabrice A. Odefrey
    • 1
  • Fleur Hammet
    • 1
  • Graham G. Giles
    • 2
    • 5
  • Laura Baglietto
    • 2
    • 5
  • ABCFS
    • 3
  • MCCS
    • 4
  • John L. Hopper
    • 5
  • Daniel F. Schmidt
    • 5
  • Enes Makalic
    • 5
  • Olga M. Sinilnikova
    • 6
  • David E. Goldgar
    • 7
  • Melissa C. Southey
    • 1
  1. 1.Genetic Epidemiology Laboratory, Department of PathologyThe University of MelbourneMelbourneAustralia
  2. 2.Cancer Epidemiology Centre, The Cancer Council VictoriaMelbourneAustralia
  3. 3.Australian Breast Cancer Family StudyMelbourneAustralia
  4. 4.Melbourne Collaborative Cohort StudyMelbourneAustralia
  5. 5.Centre for Molecular Environmental Genetic and Analytical Epidemiology, School of Population HealthThe University of MelbourneCarltonAustralia
  6. 6.INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche En Cancérologie de Lyon, and Unité Mixte de Génétique Constitutionelle Des Cancers FréquentsCentre Hospitalier Universitaire de Lyon/Centre Léon BérardLyonFrance
  7. 7.Department of DermatologyUniversity of Utah School of MedicineSalt Lake CityUSA

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