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

被引：28

作者：

Figlioli, Gisella ^{[1
]}

Bogliolo, Massimo ^{[2
,3
,4
]}

Catucci, Irene ^{[1
]}

Caleca, Laura ^{[5
]}

Viz Lasheras, Sandra ^{[2
]}

Pujol, Roser ^{[2
,3
,4
]}

Kiiski, Johanna, I ^{[6
]}

Muranen, Taru A. ^{[6
]}

Barnes, Daniel R. ^{[7
]}

Dennis, Joe ^{[7
]}

Michailidou, Kyriaki ^{[7
,8
,9
]}

Bolla, Manjeet K. ^{[7
]}

Leslie, Goska ^{[7
]}

Aalfs, Cora M. ^{[10
]}

Adank, Muriel A. ^{[11
]}

Adlard, Julian ^{[12
]}

Agata, Simona ^{[13
]}

Cadoo, Karen ^{[14
]}

Agnarsson, Bjarni A. ^{[15
,16
]}

Ahearn, Thomas ^{[17
]}

Aittomaki, Kristiina ^{[18
]}

Ambrosone, Christine B. ^{[19
]}

Andrews, Lesley ^{[20
]}

Anton-Culver, Hoda ^{[21
]}

Antonenkova, Natalia N. ^{[22
]}

Arndt, Volker ^{[23
]}

Arnold, Norbert ^{[24
,25
]}

Aronson, Kristan J. ^{[26
,27
]}

Arun, Banu K. ^{[28
]}

Asseryanis, Ella ^{[29
,30
]}

Auber, Bernd ^{[31
]}

Auvinen, Paivi ^{[32
,33
,34
]}

Azzollini, Jacopo ^{[35
]}

Balmana, Judith ^{[36
,37
]}

Barkardottir, Rosa B. ^{[15
,38
]}

Barrowdale, Daniel ^{[7
]}

Barwell, Julian ^{[39
]}

Freeman, Laura E. Beane ^{[17
]}

Beauparlant, Charles Joly ^{[40
]}

Beckmann, Matthias W. ^{[41
]}

Behrens, Sabine ^{[42
]}

Benitez, Javier ^{[43
,44
,45
]}

Berger, Raanan ^{[46
]}

Bermisheva, Marina ^{[47
]}

Blanco, Amie M. ^{[48
]}

Blomqvist, Carl ^{[49
,50
]}

Bogdanova, Natalia, V ^{[22
,51
,52
]}

Bojesen, Anders ^{[53
]}

Bojesen, Stig E. ^{[54
,55
,56
]}

Bonanni, Bernardo ^{[57
]}

机构：

[1] IFOM FIRC Inst Mol Oncol, Genome Diagnost Program, Milan, Italy

[2] Univ Autonoma Barcelona, Dept Genet & Microbiol, Barcelona, Spain

[3] Ctr Biomed Network Res Rare Dis CIBERER, Madrid, Spain

[4] St Pau Hosp, Inst Biomed Res, Barcelona, Spain

[5] Fdn IRCCS Ist Nazl Tumori, Dept Res, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy

[6] Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland

[7] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England

[8] Cyprus Inst Neurol & Genet, Dept Electron Microscopy Mol Pathol, Nicosia, Cyprus

[9] Cyprus Sch Mol Med, Nicosia, Cyprus

[10] Amsterdam UMC, Dept Clin Genet, Lokatie AMC, Amsterdam, Netherlands

[11] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands

[12] Chapel Allerton Hosp, Yorkshire Reg Genet Serv, Leeds, W Yorkshire, England

[13] Veneto Inst Oncol IOV IRCCS, Immunol & Mol Oncol Unit, Padua, Italy

[14] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

[15] Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland

[16] Univ Iceland, Sch Med, Reykjavik, Iceland

[17] NCI, NIH, US Dept HHS, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA

[18] Univ Helsinki, Helsinki Univ Hosp, Dept Clin Genet, Helsinki, Finland

[19] Roswell Park Canc Inst, Buffalo, NY 14263 USA

[20] Bright Alliance Bldg, Nelune Comprehens Canc Care Ctr, Randwick, NSW, Australia

[21] Univ Calif Irvine, Genet Epidemiol Res Inst, Dept Epidemiol, Irvine, CA USA

[22] NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, BELARUS

[23] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany

[24] Christian Albrechts Univ Kiel, Univ Hosp Schleswig Holstein, Dept Gynaecol & Obstet, Campus Kiel, Kiel, Germany

[25] Christian Albrechts Univ Kiel, Univ Hosp Schleswig Holstein, Inst Clin Mol Biol, Campus Kiel, Kiel, Germany

[26] Queens Univ, Dept Publ Hlth Sci, Kingston, ON, Canada

[27] Queens Univ, Canc Res Inst, Kingston, ON, Canada

[28] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA

[29] Med Univ Vienna, Dept OB GYN, Vienna, Austria

[30] Med Univ Vienna, Comprehens Canc Ctr, Vienna, Austria

[31] Hannover Med Sch, Inst Human Genet, Hannover, Germany

[32] Kuopio Univ Hosp, Canc Ctr, Kuopio, Finland

[33] Univ Eastern Finland, Inst Clin Med, Oncol, Kuopio, Finland

[34] Univ Eastern Finland, Translat Canc Res Area, Kuopio, Finland

[35] Fdn IRCCS Ist Nazl Tumori Milano, Dept Med Oncol & Hematol, Unit Med Genet, Milan, Italy

[36] Vall dHebron Inst Oncol, High Risk & Canc Prevent Grp, Barcelona, Spain

[37] Univ Hosp Vall dHebron, Dept Med Oncol, Barcelona, Spain

[38] Univ Iceland, Fac Med, BMC Biomed Ctr, Reykjavik, Iceland

[39] Univ Hosp Leicester NHS Trust, Leicestershire Clin Genet Serv, Leicester, Leics, England

[40] Univ Laval, Res Ctr, Genom Ctr, Ctr Hosp Univ Quebec, Quebec City, PQ, Canada

[41] Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Comprehens Canc Ctr ER EMN, Dept Gynecol & Obstet, Erlangen, Germany

[42] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany

[43] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Programme, Human Genet Grp, Madrid, Spain

[44] Spanish Network Rare Dis CIBERER, Madrid, Spain

[45] Spanish Natl Canc Res Ctr CNIO, Genotyping Unit CEGEN, Human Canc Genet Programme, Madrid, Spain

[46] Chaim Sheba Med Ctr, Inst Oncol, Ramat Gan, Israel

[47] Russian Acad Sci, Inst Biochem & Genet, Ufa Fed Res Ctr, Ufa, Russia

[48] Univ Calif San Francisco, Canc Genet & Prevent Program, San Francisco, CA 94143 USA

[49] Univ Helsinki, Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland

[50] Orebro Univ Hosp, Dept Oncol, Orebro, Sweden

来源：

NPJ BREAST CANCER | 2019年 / 5卷 / 1期

基金：

美国国家卫生研究院; 英国医学研究理事会; 加拿大健康研究院; 芬兰科学院; 欧洲研究理事会; 澳大利亚国家健康与医学研究理事会; 瑞典研究理事会; 俄罗斯基础研究基金会; 欧盟地平线“2020”;

关键词：

FANCONI-ANEMIA; GENE; C.5791C-GREATER-THAN-T; MUTATIONS;

D O I：

10.1038/s41523-019-0127-5

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页数：14

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