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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
IFOM FIRC Inst Mol Oncol, Genome Diagnost Program, Milan, Italy.ORCID iD: 0000-0002-0740-1363
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Stockholm, Sweden.ORCID iD: 0000-0001-7387-6845
Genome One, Darlinghurst, NSW, Australia.
Number of Authors: 4772019 (English)In: NPJ BREAST CANCER, ISSN 2374-4677, Vol. 5, article id 38Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 5, article id 38
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-397654DOI: 10.1038/s41523-019-0127-5ISI: 000493912600001PubMedID: 31700994OAI: oai:DiVA.org:uu-397654DiVA, id: diva2:1374882
Funder
EU, Horizon 2020, 634935EU, Horizon 2020, 633784EU, FP7, Seventh Framework Programme, 223175EU, FP7, Seventh Framework Programme, HEALTH-F2-2009-223175Swedish Cancer SocietySwedish Research CouncilSwedish Cancer SocietySwedish Research Council, 2017-00644EU, FP7, Seventh Framework Programme, 310018EU, European Research CouncilEuropean Regional Development Fund (ERDF), PI10/01422; PI13/00285; PIE13/00022; PI15/00854; PI16/00563; P18/01029European Regional Development Fund (ERDF), PI15/00059; PI16/01292; CB-161200301 CIBERONCEuropean Regional Development Fund (ERDF), PI16/00440NIH (National Institute of Health)Stockholm County CouncilGerman Research Foundation (DFG), EXC 2180 -390900677; Do 761/10-1Academy of Finland
Note

For complete list of authors see http://dx.doi.org/10.1038/s41523-019-0127-5

Available from: 2019-12-03 Created: 2019-12-03 Last updated: 2019-12-03Bibliographically approved

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