The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer. / ABCTB Investigators; GEMO Study Collaborators; kConFab.
I: npj Breast Cancer, Bind 5, Nr. 1, 38, 2019.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
AU - Figlioli, Gisella
AU - Bogliolo, Massimo
AU - Catucci, Irene
AU - Caleca, Laura
AU - Lasheras, Sandra Viz
AU - Pujol, Roser
AU - Kiiski, Johanna I.
AU - Muranen, Taru A.
AU - Barnes, Daniel R.
AU - Dennis, Joe
AU - Michailidou, Kyriaki
AU - Bolla, Manjeet K.
AU - Leslie, Goska
AU - Aalfs, Cora M.
AU - Balleine, Rosemary
AU - Baxter, Robert
AU - Braye, Stephen
AU - Carpenter, Jane
AU - Dahlstrom, Jane
AU - Forbes, John
AU - Lee, C. Soon
AU - Marsh, Deborah
AU - Morey, Adrienne
AU - Pathmanathan, Nirmala
AU - Scott, Rodney
AU - Simpson, Peter
AU - Spigelman, Allan
AU - Wilcken, Nicholas
AU - Yip, Desmond
AU - Zeps, Nikolajs
AU - Adank, Muriel A.
AU - Adlard, Julian
AU - Agata, Simona
AU - Cadoo, Karen
AU - Agnarsson, Bjarni A.
AU - Ahearn, Thomas
AU - Aittomäki, Kristiina
AU - Ambrosone, Christine B.
AU - Andrews, Lesley
AU - Anton-Culver, Hoda
AU - Antonenkova, Natalia N.
AU - Arndt, Volker
AU - Arnold, Norbert
AU - Aronson, Kristan J.
AU - Arun, Banu K.
AU - Bojesen, Anders
AU - Bojesen, Stig E.
AU - Flyger, Henrik
AU - Luben, Robert N.
AU - Nielsen, Finn Cilius
AU - ABCTB Investigators
AU - GEMO Study Collaborators
AU - kConFab
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
U2 - 10.1038/s41523-019-0127-5
DO - 10.1038/s41523-019-0127-5
M3 - Journal article
C2 - 31700994
AN - SCOPUS:85074364016
VL - 5
JO - npj Breast Cancer
JF - npj Breast Cancer
SN - 2374-4677
IS - 1
M1 - 38
ER -
ID: 235594891