The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
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Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genesBRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, hasbeen 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* forassociation 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-derivedimmortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated withincreased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restrictedanalysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated withER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleteriousaffecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, weconfirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBCsubtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in thegene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
