- Title
- The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
- Creator
- Figlioli, Gisella; Bogliolo, Massimo; Catucci, Irene; Caleca, Laura; Lasheras, Sandra Viz; Pujol, Roser; Kiiski, Johanna I.; Muranen, Taru A.; Barnes, Daniel R.; Dennis, Joe; Michailidou, Kyriaki; Bolla, Manjeet K.; Leslie, Goska; Aalfs, Cora M.; Adank, Muriel A.; Adlard, Julian; Agata, Simona; Cadoo, Karen; Agnarsson, Bjarni A.; Ahearn, Thomas; Braye, Stephen; Forbes, John; Scott, Rodney
- Relation
- NPJ Breast Cancer Vol. 5, Issue 1, no. 38
- Publisher Link
- http://dx.doi.org/10.1038/s41523-019-0127-5
- Publisher
- Nature Publishing Group
- Resource Type
- journal article
- Date
- 2019
- Description
- 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.
- Subject
- FANCM; triple-negative breast cancer; protein-truncating variants; cell survival; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1455467
- Identifier
- uon:45092
- Identifier
- ISSN:2374-4677
- Rights
- Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2019
- Language
- eng
- Full Text
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