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 triplenegative 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.breast cancer | DNA repair | FANCM | exome sequencing | triple-negative breast cancer B reast cancer is the most common cancer affecting women worldwide. It is also the principal cause of death from cancer among women globally, accounting for 14% of all cancer deaths (1). The etiology of breast cancer is multifactorial, and the risk depends on various factors like age, family history, and reproductive, hormonal, or dietary factors. The majority of breast cancers are sporadic, but approximately 15% of cases show familial aggregation (2, 3). Since the identification of the first breast and ovarian cancer susceptibility genes breast cancer 1 and 2 (BRCA1 and BRCA2, respectively) by linkage analysis and positional cloning, several breast cancer susceptibility genes and alleles with different levels of risk and prevalence in the population have been recognized. BRCA1 and BRCA2 mutation carriers have more than 10-fold increased risk of breast cancer compared with women in

Germline Mutations in Triple-Negative Breast Cancer

“…This notion is based on i) the generally early age of onset which is similar to that observed for patients carrying germline mutations in breast cancer predisposition genes, ii) the high rate of TNBC cases with a positive family history of cancer, iii) the high prevalence of germline mutations, and, vice versa, iv) the association of a small subset of breast cancer predisposition genes (e.g., BRCA1 , BRCA2 , PALB2 , FANCM ) with the TNBC phenotype [12,13,14,15]. Most breast cancer predisposition genes, including BRCA1/2 , are critical genes in the process of homologous recombination (HR) repair of double-strand DNA breaks [13,16,17,18,19]. Heterozygous germline inactivation of HR genes may be accompanied by a somatic inactivation of the second allele, resulting in a HR deficiency and limited DNA repair capacities of the tumor cells [20].…”

Identification of point mutations and large intragenic deletions in Fanconi anemia using next‐generation sequencing technology

“…Although is not regarded anymore as an FA gene, it is a susceptibility gene for breast cancer and individuals (P9 and P20) carrying some of its variants could be at risk of developing this malignancy (Kiiski et al. 2014; Lim et al. 2014).…”

Defects in homologous recombination repair behind the human diseases: FA and HBOC

“…Thus, to date, there have been no human FA patients identified with causative mutations solely in FANCM. Furthermore, in the Finnish population, individuals with homozygous loss-of-function FANCM mutations do not show any FA phenotype (Lim et al 2014), suggesting that FANCM is not a bona fide FA gene, though it clearly contributes to the function of the FA pathway and is a candidate HBOC gene (Kiiski et al 2014, Peterlongo et al 2015.…”

“…However, this prediction turned out to be a bit too simplistic. Genes encoding the core complex components and FANCD2/FANCI are unlikely to be a high-penetrance HBOC gene (Seal et al 2003, Berwick et al 2007, although there are some reports indicating FANCM (Kiiski et al 2014, Peterlongo et al 2015 or FANCC (Berwick et al 2007, Thompson et al 2012) could be considered as candidate HBOC genes.…”