The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.

Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients

“…In our series, we also detected an enrichment of the c.5791C > T variant in FANCM. This alteration is the most common pathogenic FANCM variant in Southern Europe [34] and was associated with estrogen receptorER-negative breast cancer risk (OR = 1.96; p = 0.006) in a large case-control study with more than 50,000 cases and controls [15]. However, in the present study, we could not find a significant association with breast cancer risk (odds ratio = 1.46 (95% confidence interval 0.3-4.8) p = 0.467).…”

“…However, the role of monoallelic mutations in the remaining FA genes regarding cancer predisposition is a matter of discussion. Over the last few years, several case-controls studies have indicated that monoallelic FANCM [7][8][9][10][11][12][13][14][15] truncating mutations are breast cancer risk factors; in addition, there are inconsistent results regarding FANCA [16][17][18][19], FANCC [20][21][22][23][24], SLX4 [25][26][27] and XRCC2 [28][29][30].…”

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies new candidate susceptibility genes for breast and ovarian cancer

“…FANCA encodes one of eight subunits that together form the core Fanconi Anemia (FA) complex that repairs blockages in DNA replication due to cross-linking (31). Several members of the FA family of proteins have been implicated in breast and ovarian cancer predisposition including, BRCA2 (FANCD1), BRIP1 (FANCJ), PALB2 (FANCN), and FANCM and it is possible that FANCA may represent another or possibly the true target breast cancer susceptibility gene in this region given this biological function and its overlap with ZNF276 (31,32). ZNF276 in its own right has also been implicated as a candidate tumor suppressor gene in breast cancer (30).…”

The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases

“…We recently tested p.Arg658*, p.Gln1701*, and p.Arg1931* in 67,112 European breast cancer cases and 53,766 controls. In these analyses, we observed that p.Arg658* was associated with increased risk of ER-negative disease and TNBC with ORs of 2.44 and 3.79, respectively, and that p.Arg1931* was associated with the risk of ER-negative breast cancer with an OR of 1.96 [10].…”