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000147517 0247_ $$2doi$$a10.1038/s41523-019-0127-5
000147517 0247_ $$2pmid$$apmid:31700994
000147517 0247_ $$2pmc$$apmc:PMC6825205
000147517 0247_ $$2altmetric$$aaltmetric:69635633
000147517 037__ $$aDKFZ-2019-02571
000147517 041__ $$aeng
000147517 082__ $$a610
000147517 1001_ $$aFiglioli, Gisella$$b0
000147517 245__ $$aThe FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.
000147517 260__ $$aLondon$$bNature Publ. Group$$c2019
000147517 3367_ $$2DRIVER$$aarticle
000147517 3367_ $$2DataCite$$aOutput Types/Journal article
000147517 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1577095546_15304
000147517 3367_ $$2BibTeX$$aARTICLE
000147517 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000147517 3367_ $$00$$2EndNote$$aJournal Article
000147517 520__ $$aBreast 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.
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