Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/168083
Title: The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
Author: Figlioli, Gisella
Lázaro García, Conxi
Pujana Genestar, M. Ángel
ABCTB Investigators
GEMO Study Collaborators
KConFab Investigators
Keywords: Càncer de mama
Expressió gènica
Breast cancer
gene expression
Issue Date: 1-Nov-2019
Publisher: Nature Publishing Group
Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PAM, 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 pArg1931* 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.
Note: Reproducció del document publicat a: https://doi.org/10.1038/s41523-019-0127-5
It is part of: Npj Breast Cancer, 2019, Vol. 5 num. 38
URI: http://hdl.handle.net/2445/168083
Related resource: https://doi.org/10.1038/s41523-019-0127-5
Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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