https://ogma.newcastle.edu.au/vital/access/ /manager/Index ${session.getAttribute("locale")} 5 https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:27801 Wed 04 Apr 2018 17:04:59 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:38374 Wed 01 Sep 2021 14:04:39 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:45092 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.]]> Thu 27 Oct 2022 15:50:42 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:19125 C) were found. In addition, five variants predicted to be protein-affecting were also identified. Our study shows that the prevalence of PALB2 germline mutations in individuals with TNBC is ~1%, similar to the prevalence of PALB2 germline mutation of 1% in familial non-BRCA1/2 breast cancer cohorts.]]> Sat 24 Mar 2018 07:55:57 AEDT ]]>