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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
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 novel 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 risk for 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.

Figlioli, Gisella
19d2e636-8e21-472a-9247-5eff91747ca3
Peterlongo, Paolo
af3f3db4-e3fc-45db-bbb4-91954fe857fb
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
et al.
Figlioli, Gisella
19d2e636-8e21-472a-9247-5eff91747ca3
Peterlongo, Paolo
af3f3db4-e3fc-45db-bbb4-91954fe857fb
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23

Figlioli, Gisella , et al. (2019) The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer. npj Breast Cancer, 5, [38]. (doi:10.1038/s41523-019-0127-5).

Record type: Article

Abstract

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 novel 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 risk for 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.

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Accepted/In Press date: 30 August 2019
Published date: 1 November 2019

Identifiers

Local EPrints ID: 435755
URI: http://eprints.soton.ac.uk/id/eprint/435755
PURE UUID: 26323725-3926-4b41-82e1-267d1dcc7fb4
ORCID for Diana Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 19 Nov 2019 17:30
Last modified: 26 Nov 2021 02:34

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Contributors

Author: Gisella Figlioli
Author: Paolo Peterlongo
Author: Diana Eccles ORCID iD
Corporate Author: et al.

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