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Brief Report
December 29, 2016

Association Between Loss-of-Function Mutations Within the FANCM Gene and Early-Onset Familial Breast Cancer

Author Affiliations
  • 1Center for Familial Breast and Ovarian Cancer and Center for Integrated Oncology, Medical Faculty, University Hospital Cologne, Cologne, Germany
  • 2Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
  • 3Department of Gynaecology and Obstetrics, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
  • 4Department of Human Genetics and Biozentrum, University Würzburg, Würzburg, Germany
  • 5Institute for Clinical Genetics, Technische Universität Dresden, Dresden, Germany
  • 6Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
  • 7Department of Obstetrics and Gynecology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
  • 8Institute of Human Genetics, University of Bonn, Bonn, Germany
  • 9Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
  • 10Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
  • 11Institute of Epidemiology and Biobank PopGen, Christian-Albrechts-University of Kiel, Kiel, Germany
  • 12Cologne Center for Genomics, University of Cologne, Cologne, Germany
  • 13Institute of Human Genetics, University of Cologne, Cologne, Germany
  • 14Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Cologne, Germany
  • 15Department for Gynecology and Obstetrics, LMU Munich, Munich, Germany
  • 16German Center for Neurodegenerative Diseases, Bonn, Germany
  • 17Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany
  • 18Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany
  • 19Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
JAMA Oncol. Published online December 29, 2016. doi:10.1001/jamaoncol.2016.5592
Key Points

Question  Do inactivating germline mutations within the FANCM gene increase breast cancer and/or ovarian cancer risk?

Findings  This case-control study included 2047 BRCA1 and BRCA2–negative familial breast cancer cases and 2187 controls and revealed an association of FANCM mutations with breast cancer. More pronounced associations were identified for early-onset (before age 51 years) breast cancer and triple-negative breast cancer. Analysis of 628 unselected ovarian cancer cases revealed no significant association.

Meaning  We suggest FANCM be included in diagnostic gene panel testing for individual breast cancer risk assessment.

Abstract

Importance  Germline mutations in established moderately or highly penetrant risk genes for breast cancer (BC) and/or ovarian cancer (OC), including BRCA1 and BRCA2, explain fewer than half of all familial BC and/or OC cases. Based on the genotyping of 2 loss-of-function (LoF) variants c.5101C>T (p.GIn1701Ter [rs147021911]) and c.5791C>T (p.Arg1931Ter [rs144567652]), the FANCM gene has been suggested as a novel BC predisposition gene, while the analysis of the entire coding region of the FANCM gene in familial index cases and geographically matched controls is pending.

Objectives  To assess the mutational spectrum within the FANCM gene, and to determine a potential association of LoF germline mutations within the FANCM gene with BC and/or OC risk.

Design, Setting, and Participants  For the purpose of identification and characterization of novel BC and/or OC predisposition genes, a total of 2047 well-characterized familial BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for LoF mutations within the FANCM gene by next-generation sequencing. All patients previously tested negative for pathogenic BRCA1 and BRCA2 mutations. All data collection occurred between June 1, 2013, and April 30, 2016. Data analysis was performed from May 1, 2016, to July 1, 2016.

Main Outcomes and Measures  FANCM LoF mutation frequencies in patients with BC and/or OC were compared with the FANCM LoF mutation frequencies in geographically matched controls by univariate logistic regression. Positive associations were stratified by age at onset and cancer family history.

Results  In this case-control study, 2047 well-characterized familial female BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for truncating FANCM alterations. Heterozygous LoF mutations within the FANCM gene were significantly associated with familial BC risk, with an overall odds ratio (OR) of 2.05 (95% CI, 0.94-4.54; P = .049) and a mutation frequency of 1.03% in index cases. In familial patients whose BC onset was before age 51 years, an elevated OR of 2.44 (95% CI, 1.08-5.59; P = .02) was observed. A more pronounced association was identified for patients with a triple-negative BC tumor phenotype (OR, 3.75; 95% CI, 1.00-12.85; P = .02). No significant association was detected for unselected OC cases (OR, 1.74; 95% CI, 0.57-5.08; P = .27).

Conclusions and Relevance  Based on the significant associations of heterozygous LoF mutations with early-onset or triple-negative BC, FANCM should be included in diagnostic gene panel testing for individual risk assessment. Larger studies are required to determine age-dependent disease risks for BC and to assess a potential role of FANCM mutations in OC pathogenesis.

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