title: Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer.
abstract: Inherited predisposition to breast cancer is known to be caused by loss-of-function mutations in BRCA1, BRCA2, PALB2, CHEK2, and other genes involved in DNA repair. However, most families severely affected by breast cancer do not harbor mutations in any of these genes. In Finland, founder mutations have been observed in each of these genes, suggesting that the Finnish population may be an excellent resource for the identification of other such genes. To this end, we carried out exome sequencing of constitutional genomic DNA from 24 breast cancer patients from 11 Finnish breast cancer families. From all rare damaging variants, 22 variants in 21 DNA repair genes were genotyped in 3,166 breast cancer patients, 569 ovarian cancer patients, and 2,090 controls, all from the Helsinki or Tampere regions of Finland. In Fanconi anemia complementation gene M (FANCM), nonsense mutation c.5101C>T (p.Q1701X) was significantly more frequent among breast cancer patients than among controls [odds ratio (OR) = 1.86, 95% CI = 1.26-2.75; P = 0.0018], with particular enrichment among patients with triple-negative breast cancer (TNBC; OR = 3.56, 95% CI = 1.81-6.98, P = 0.0002). In the Helsinki and Tampere regions, respectively, carrier frequencies of FANCM p.Q1701X were 2.9% and 4.0% of breast cancer patients, 5.6% and 6.6% of TNBC patients, 2.2% of ovarian cancer patients (from Helsinki), and 1.4% and 2.5% of controls. These findings identify FANCM as a breast cancer susceptibility gene, mutations in which confer a particularly strong predisposition for TNBC.
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Biomedicum Helsinki, FIN-00029 HUS, Helsinki, Finland;
authors.forename: Johanna I
authors.initials: JI
authors.lastname: Kiiski
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Biomedicum Helsinki, FIN-00029 HUS, Helsinki, Finland;
authors.forename: Liisa M
authors.initials: LM
authors.lastname: Pelttari
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Biomedicum Helsinki, FIN-00029 HUS, Helsinki, Finland;
authors.forename: Sofia
authors.initials: S
authors.lastname: Khan
authors.affiliation: Molecular Pathology Unit, Department of Pathology, Landspitali University Hospital, 101 Reykjavik, Iceland;
authors.forename: Edda S
authors.initials: ES
authors.lastname: Freysteinsdottir
authors.affiliation: Cell Biology Unit, Department of Pathology, Landspitali University Hospital, 101 Reykjavik, Iceland; Biomedical Center, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland;
authors.forename: Inga
authors.initials: I
authors.lastname: Reynisdottir
authors.affiliation: Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905;
authors.forename: Steven N
authors.initials: SN
authors.lastname: Hart
authors.affiliation: Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905;
authors.forename: Hermela
authors.initials: H
authors.lastname: Shimelis
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Biomedicum Helsinki, FIN-00029 HUS, Helsinki, Finland;
authors.forename: Sara
authors.initials: S
authors.lastname: Vilske
authors.affiliation: BioMediTech, University of Tampere and Fimlab Laboratories, FIN-33014, Tampere, Finland;
authors.forename: Anne
authors.initials: A
authors.lastname: Kallioniemi
authors.affiliation: BioMediTech, University of Tampere and Fimlab Laboratories, FIN-33014, Tampere, Finland; Department of Medical Biochemistry and Genetics, Institute of Biomedicine, University of Turku, FIN-20520, Turku, Finland; and.
authors.forename: Johanna
authors.initials: J
authors.lastname: Schleutker
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Biomedicum Helsinki, FIN-00029 HUS, Helsinki, Finland;
authors.forename: Arto
authors.initials: A
authors.lastname: Leminen
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Biomedicum Helsinki, FIN-00029 HUS, Helsinki, Finland; Departments of Pathology.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bützow
authors.affiliation: Oncology, and.
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.affiliation: Molecular Pathology Unit, Department of Pathology, Landspitali University Hospital, 101 Reykjavik, Iceland; Biomedical Center, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland;
authors.forename: Rosa B
authors.initials: RB
authors.lastname: Barkardottir
authors.affiliation: Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905;
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.affiliation: Clinical Genetics, Helsinki University Central Hospital, FIN-00029 HUS, Helsinki, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Biomedicum Helsinki, FIN-00029 HUS, Helsinki, Finland; heli.nevanlinna@hus.fi.
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
mesh_terms: D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D018389:Codon, Nonsense; D004265:DNA Helicases / Q000235:genetics*; D059472:Exome; D005260:Female; D005387:Finland; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation; D016017:Odds Ratio; D010051:Ovarian Neoplasms / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D018570:Risk Assessment; D064726:Triple Negative Breast Neoplasms / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D012333:RNA, Messenger; C518295:FANCM protein, human; D004265:DNA Helicases
keywords: DNA repair; FANCM; breast cancer; exome sequencing; triple-negative breast cancer