2026-04-17T06:29:12Zhttps://recercat.cat/oai/request

oai:recercat.cat:11351/57902025-05-03T03:19:35Zcom_2072_378070com_2072_378040col_2072_378092

00925njm 22002777a 4500 dc Figlioli, Gisella author Catucci, Irene author Caleca, Laura author Lasheras, Sandra Viz author Pujol, Roser author Balmaña Gelpí, Judith author Diez Gibert, Orland author Bogliolo, Massimo author 2021-03-23T14:42:57Z 2021-03-23T14:42:57Z 2019-11-01 Càncer de mama; Genètica del càncer Cáncer de mama; Genética del cáncer Breast cancer; Cancer genetics 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. Peterlongo laboratory is supported by Associazione Italiana Ricerca sul Cancro (AIRC; IG2015 no.16732) to P. Peterlongo and by a fellowship from Fondazione Umberto Veronesi to G. Figlioli. Surrallés laboratory is supported by the ICREA-Academia program, the Spanish Ministry of Health (projects FANCOSTEM and FANCOLEN), the Spanish Ministry of Economy and Competiveness (projects CB06/07/0023 and RTI2018-098419-B-I00), the European Commission (EUROFANCOLEN project HEALTH-F5-2012-305421 and P-SPHERE COFUND project), the Fanconi Anemia Research Fund Inc, and the “Fondo Europeo de Desarrollo Regional, una manera de hacer Europa” (FEDER). CIBERER is an initiative of the Instituto de Salud Carlos III, Spain. Mama - Càncer Càncer - Aspectes genètics DISEASES::Neoplasms::Neoplasms by Site::Breast Neoplasms::Triple Negative Breast Neoplasms Other subheadings::Other subheadings::Other subheadings::/genetics ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias de la mama::neoplasias de mama triple negativos Otros calificadores::Otros calificadores::Otros calificadores::/genética The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer