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.

Keywords: DNA repair; FANCM; breast cancer; exome sequencing; triple-negative breast cancer.

Fig. 1.

Pedigrees of eight FANCM c.5101C>T families. The FANCM c.5101C>T genotype is denoted above genotyped individuals. Cancer type and age at diagnosis are indicated below cancer patients. BC, breast cancer; Bm, bone marrow; Ct, connective tissue; Gb, glioblastoma; Mel, melanoma; OC, ovarian cancer; Pa, pancreatic cancer; Pr, prostate cancer.

Fig. 2.

Drawing of FANCM indicating protein domains, the position of the c.5101C>T nonsense mutation, and positions of the mutations found from a single FA patient carrying FANCM and FANCA defects. Mutations and protein domains are mapped to the corresponding exons of FANCM.