Journal Article

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

Vilske, Sara, Hart, Steven N., Shimelis, Hermela, Aittomäki, Kristiina, Couch, Fergus J., Barkardottir, Rosa B., Blomqvist, Carl, Schleutker, Johanna, Bützow, Ralf, Nevanlinna, Heli, Kiiski, Johanna I., Reynisdottir, Inga, Kallioniemi, Anne, Khan, Sofia, Leminen, Arto, Pelttari, Liisa M., Freysteinsdottir, Edda S.

2014

Overview

Significance The major portion of hereditary breast cancer still remains unexplained, and many susceptibility loci are yet to be found. Exome sequencing of 24 high-risk familial BRCA1/2 -negative breast cancer patients and further genotyping of a large sample set of breast/ovarian cancer cases and controls was used to discover previously unidentified susceptibility alleles and genes. A significant association of a FANCM nonsense mutation with breast cancer, especially triple-negative breast cancer, identifies FANCM as a breast cancer susceptibility gene. Identification of such risk alleles is expected to improve cancer risk assessment for breast cancer patients and families, and may lead to improvements in the prevention, early diagnosis, and treatment of cancer. 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.

• Publisher: National Academy of Sciences
• Subject: Aged / Alleles / animal ovaries / Biological Sciences / Breast cancer / breast neoplasms / Case-Control Studies / Codon, Nonsense / Deoxyribonucleic acid / DNA / DNA Helicases - genetics / DNA repair / early diagnosis / Exome / Female / Finland / Gene Expression Regulation, Neoplastic / Genes, BRCA1 / Genes, BRCA2 / Genetic mutation / Genetic Predisposition to Disease / Genetic Variation / Genetics / Genomes / Genotype / genotyping / Humans / loci / Middle Aged / Models, Genetic / Mutation / nonsense mutation / Odds Ratio / Ovarian cancer / ovarian neoplasms / Ovarian Neoplasms - genetics / patients / Population control / Proteins / risk / Risk Assessment / RNA, Messenger - metabolism / sequence analysis / Sequencing / Triple Negative Breast Neoplasms - genetics / tumor suppressor proteins