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.
Highlights
The genetic architecture of inherited breast cancer is complex and involves germline pathogenic variants in high and moderate-risk genes and polygenetic factors
We analyzed the association of three FANCM truncating variants, p.Arg658*, p.Gln1701*, and p.Arg1931*, with breast cancer risk for each variant separately and using a burden analysis
We tested 67,112 invasive breast cancer cases and 53,766 controls collected by the Breast Cancer Association Consortium (BCAC, http://bcac. ccge.medschl.cam.ac.uk/) and 26,662 carriers of BRCA1 or BRCA2 pathogenic variants collected by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA, http://cimba.ccge.medschl.cam. ac.uk/), of whom 13,497 were affected with breast cancer and 13,165 were unaffected
Summary
The genetic architecture of inherited breast cancer is complex and involves germline pathogenic variants in high and moderate-risk genes and polygenetic factors. The FANCM:p.Arg1931* was found to be associated with TNBC risk in the Finnish population (OR = 5.14; 95% CI = 1.65–16.0).[12] A burden analysis of truncating variants discovered by a re-sequencing analysis of the entire FANCM coding region in German cases and controls confirmed that FANCM pathogenic variants had a high risk for TNBC (OR = 3.75; 95% CI = 1.0–12.85).[13]. Gln1701*, and p.Arg1931*, within the OncoArray Consortium, a collaboration of consortia established to discover germline genetic variants predisposing to different human cancers (e.g., breast, colon, lung, ovary, endometrium and prostate cancers).[14]. These three variants were tested for association with breast cancer risk in 67,112 breast cancer cases, 53,766 controls, and 26,662 carriers of pathogenic variants in BRCA1 or BRCA2. 2 we measured survival and chromosome fragility after exposure to diepoxybutane (DEB) or the poly (ADP-ribose) polymerase inhibitor (PARPi) olaparib
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