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

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@article{623cf53087874c87a1af5ce778205d7a,
title = "The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer",
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 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.",
author = "Gisella Figlioli and Massimo Bogliolo and Irene Catucci and Laura Caleca and Lasheras, {Sandra Viz} and Roser Pujol and Kiiski, {Johanna I} and Muranen, {Taru A} and Barnes, {Daniel R} and Joe Dennis and Kyriaki Michailidou and Bolla, {Manjeet K} and Goska Leslie and Aalfs, {Cora M} and Adank, {Muriel A} and Julian Adlard and Simona Agata and Karen Cadoo and Agnarsson, {Bjarni A} and Thomas Ahearn and Kristiina Aittom{\"a}ki and Ambrosone, {Christine B} and Lesley Andrews and Hoda Anton-Culver and Antonenkova, {Natalia N} and Volker Arndt and Norbert Arnold and Aronson, {Kristan J} and Arun, {Banu K} and Ella Asseryanis and Bernd Auber and P{\"a}ivi Auvinen and Jacopo Azzollini and Judith Balma{\~n}a and Barkardottir, {Rosa B} and Daniel Barrowdale and Julian Barwell and {Beane Freeman}, {Laura E} and Beauparlant, {Charles Joly} and Beckmann, {Matthias W} and Sabine Behrens and Javier Benitez and Raanan Berger and Marina Bermisheva and Blanco, {Amie M} and Carl Blomqvist and Bojesen, {Stig E} and Henrik Flyger and Nielsen, {Finn Cilius} and Maria Rossing and {ABCTB Investigators}",
note = "{\circledC} The Author(s) 2019.",
year = "2019",
doi = "10.1038/s41523-019-0127-5",
language = "English",
volume = "5",
pages = "38",
journal = "Current Medical Literature. Breast Cancer",
issn = "0956-6511",
publisher = "Remedica Medical Education and Publishing Ltd",

}

RIS

TY - JOUR

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 - 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 - Asseryanis, Ella

AU - Auber, Bernd

AU - Auvinen, Päivi

AU - Azzollini, Jacopo

AU - Balmaña, Judith

AU - Barkardottir, Rosa B

AU - Barrowdale, Daniel

AU - Barwell, Julian

AU - Beane Freeman, Laura E

AU - Beauparlant, Charles Joly

AU - Beckmann, Matthias W

AU - Behrens, Sabine

AU - Benitez, Javier

AU - Berger, Raanan

AU - Bermisheva, Marina

AU - Blanco, Amie M

AU - Blomqvist, Carl

AU - Bojesen, Stig E

AU - Flyger, Henrik

AU - Nielsen, Finn Cilius

AU - Rossing, Maria

AU - ABCTB Investigators

N1 - © The Author(s) 2019.

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

VL - 5

SP - 38

JO - Current Medical Literature. Breast Cancer

JF - Current Medical Literature. Breast Cancer

SN - 0956-6511

ER -

ID: 58983776