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Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15172-7. doi: 10.1073/pnas.1407909111. Epub 2014 Oct 6.

Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer.

Author information

1
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Biomedicum Helsinki, FIN-00029 HUS, Helsinki, Finland;
2
Molecular Pathology Unit, Department of Pathology, Landspitali University Hospital, 101 Reykjavik, Iceland;
3
Cell Biology Unit, Department of Pathology, Landspitali University Hospital, 101 Reykjavik, Iceland; Biomedical Center, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland;
4
Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905;
5
BioMediTech, University of Tampere and Fimlab Laboratories, FIN-33014, Tampere, Finland;
6
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.
7
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Biomedicum Helsinki, FIN-00029 HUS, Helsinki, Finland; Departments of Pathology.
8
Oncology, and.
9
Molecular Pathology Unit, Department of Pathology, Landspitali University Hospital, 101 Reykjavik, Iceland; Biomedical Center, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland;
10
Clinical Genetics, Helsinki University Central Hospital, FIN-00029 HUS, Helsinki, Finland.
11
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Biomedicum Helsinki, FIN-00029 HUS, Helsinki, Finland; heli.nevanlinna@hus.fi.

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.

KEYWORDS:

DNA repair; FANCM; breast cancer; exome sequencing; triple-negative breast cancer

PMID:
25288723
PMCID:
PMC4210278
DOI:
10.1073/pnas.1407909111
[Indexed for MEDLINE]
Free PMC Article

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