title: Association Between Loss-of-Function Mutations Within the FANCM Gene and Early-Onset Familial Breast Cancer.
abstract: OBJECTIVE
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Center for Familial Breast and Ovarian Cancer and Center for Integrated Oncology, Medical Faculty, University Hospital Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Neidhardt
authors.affiliation: Center for Familial Breast and Ovarian Cancer and Center for Integrated Oncology, Medical Faculty, University Hospital Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Hauke
authors.affiliation: Department of Gynaecology and Obstetrics, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Ramser
authors.affiliation: Department of Gynaecology and Obstetrics, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Groß
authors.affiliation: Department of Human Genetics and Biozentrum, University Würzburg, Würzburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gehrig
authors.affiliation: Department of Human Genetics and Biozentrum, University Würzburg, Würzburg, Germany.
authors.forename: Clemens R
authors.initials: CR
authors.lastname: Müller
authors.affiliation: Institute for Clinical Genetics, Technische Universität Dresden, Dresden, Germany.|Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Anne-Karin
authors.initials: AK
authors.lastname: Kahlert
authors.affiliation: Institute for Clinical Genetics, Technische Universität Dresden, Dresden, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Hackmann
authors.affiliation: Department of Obstetrics and Gynecology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Honisch
authors.affiliation: Department of Obstetrics and Gynecology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Niederacher
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heilmann-Heimbach
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Franke
authors.affiliation: Institute of Epidemiology and Biobank PopGen, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.|Institute of Human Genetics, University of Cologne, Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.|Cologne Center for Genomics, University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Center for Familial Breast and Ovarian Cancer and Center for Integrated Oncology, Medical Faculty, University Hospital Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Klaschik
authors.affiliation: Center for Familial Breast and Ovarian Cancer and Center for Integrated Oncology, Medical Faculty, University Hospital Cologne, Cologne, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Ernst
authors.affiliation: Department for Gynecology and Obstetrics, LMU Munich, Munich, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Ditsch
authors.affiliation: German Center for Neurodegenerative Diseases, Bonn, Germany.|Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Jessen
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.|Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ramirez
authors.affiliation: Center for Familial Breast and Ovarian Cancer and Center for Integrated Oncology, Medical Faculty, University Hospital Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Wappenschmidt
authors.affiliation: Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Engel
authors.affiliation: Center for Familial Breast and Ovarian Cancer and Center for Integrated Oncology, Medical Faculty, University Hospital Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Rhiem
authors.affiliation: Department of Gynaecology and Obstetrics, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.affiliation: Center for Familial Breast and Ovarian Cancer and Center for Integrated Oncology, Medical Faculty, University Hospital Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Rita K
authors.initials: RK
authors.lastname: Schmutzler
authors.affiliation: Center for Familial Breast and Ovarian Cancer and Center for Integrated Oncology, Medical Faculty, University Hospital Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Hahnen
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D004265:DNA Helicases / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D059645:Mutation Rate; D010051:Ovarian Neoplasms / Q000235:genetics*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics
chemical_list: C518295:FANCM protein, human; D004265:DNA Helicases