Abstract
The past two decades have seen steady progress in the field of breast cancer genetics as we continually increase our understanding of how tumorigenesis results from damaged DNA. While BRCA1 and BRCA2 have taken center stage as indicators for breast cancer risk, we continue to identify other susceptibility genes and genomic regions, ever increasing our comprehension of breast cancer etiology. Through genome-wide association studies (GWAS), the 19p13 locus was found to contribute to breast and ovarian cancer risk. This region harbors a gene called C19orf62 whose protein has been reported to be a pivotal component in DNA damage repair. In this study, complete sequencing was performed to screen for deleterious mutations in the C19orf62 gene. In our cohort of 110 familial and 144 nonfamilial African-American breast cancer female patients, we identified 35 DNA sequence variants, including four missense variants, which appeared unlikely to be disease-causing. We did not detect deleterious frameshift truncating or nonsense mutations in this cohort. Our findings suggest that germline deleterious mutations in C19orf62 should be rare or absent in familial and nonfamilial breast cancer women. However, the possibility that mutations in C19orf62 contribute to breast cancer risk warrants further studies in large diverse populations.
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References
Mavaddat N, Antoniou AC, Easton DF, Garcia-Closas M (2010) Genetic susceptibility to breast cancer. Mol Oncol 4(3):174–191. doi:10.1016/j.molonc.2010.04.011
Ioannidis JP, Castaldi P, Evangelou E (2010) A compendium of genome-wide associations for cancer: critical synopsis and reappraisal. J Natl Cancer Inst 102(12):846–858. doi:10.1093/jnci/djq173
Bolton KL, Tyrer J, Song H, Ramus SJ, Notaridou M, Jones C, Sher T, Gentry-Maharaj A, Wozniak E, Tsai YY, Weidhaas J, Paik D, Van Den Berg DJ, Stram DO, Pearce CL, Wu AH, Brewster W, Anton-Culver H, Ziogas A, Narod SA, Levine DA, Kaye SB, Brown R, Paul J, Flanagan J, Sieh W, McGuire V, Whittemore AS, Campbell I, Gore ME, Lissowska J, Yang HP, Medrek K, Gronwald J, Lubinski J, Jakubowska A, Le ND, Cook LS, Kelemen LE, Brook-Wilson A, Massuger LF, Kiemeney LA, Aben KK, van Altena AM, Houlston R, Tomlinson I, Palmieri RT, Moorman PG, Schildkraut J, Iversen ES, Phelan C, Vierkant RA, Cunningham JM, Goode EL, Fridley BL, Kruger-Kjaer S, Blaeker J, Hogdall E, Hogdall C, Gross J, Karlan BY, Ness RB, Edwards RP, Odunsi K, Moyisch KB, Baker JA, Modugno F, Heikkinenen T, Butzow R, Nevanlinna H, Leminen A, Bogdanova N, Antonenkova N, Doerk T, Hillemanns P, Durst M, Runnebaum I, Thompson PJ, Carney ME, Goodman MT, Lurie G, Wang-Gohrke S, Hein R, Chang-Claude J, Rossing MA, Cushing-Haugen KL, Doherty J, Chen C, Rafnar T, Besenbacher S, Sulem P, Stefansson K, Birrer MJ, Terry KL, Hernandez D, Cramer DW, Vergote I, Amant F, Lambrechts D, Despierre E, Fasching PA, Beckmann MW, Thiel FC, Ekici AB, Chen X, Johnatty SE, Webb PM, Beesley J, Chanock S, Garcia-Closas M, Sellers T, Easton DF, Berchuck A, Chenevix-Trench G, Pharoah PD, Gayther SA (2010) Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nat Genet 42(10):880–884. doi:10.1038/ng.666
Antoniou AC, Wang X, Fredericksen ZS, McGuffog L, Tarrell R, Sinilnikova OM, Healey S, Morrison J, Kartsonaki C, Lesnick T, Ghoussaini M, Barrowdale D, Peock S, Cook M, Oliver C, Frost D, Eccles D, Evans DG, Eeles R, Izatt L, Chu C, Douglas F, Paterson J, Stoppa-Lyonnet D, Houdayer C, Mazoyer S, Giraud S, Lasset C, Remenieras A, Caron O, Hardouin A, Berthet P, Hogervorst FB, Rookus MA, Jager A, van den Ouweland A, Hoogerbrugge N, van der Luijt RB, Meijers-Heijboer H, Gomez Garcia EB, Devilee P, Vreeswijk MP, Lubinski J, Jakubowska A, Gronwald J, Huzarski T, Byrski T, Gorski B, Cybulski C, Spurdle AB, Holland H, Goldgar DE, John EM, Hopper JL, Southey M, Buys SS, Daly MB, Terry MB, Schmutzler RK, Wappenschmidt B, Engel C, Meindl A, Preisler-Adams S, Arnold N, Niederacher D, Sutter C, Domchek SM, Nathanson KL, Rebbeck T, Blum JL, Piedmonte M, Rodriguez GC, Wakeley K, Boggess JF, Basil J, Blank SV, Friedman E, Kaufman B, Laitman Y, Milgrom R, Andrulis IL, Glendon G, Ozcelik H, Kirchhoff T, Vijai J, Gaudet MM, Altshuler D, Guiducci C, Loman N, Harbst K, Rantala J, Ehrencrona H, Gerdes AM, Thomassen M, Sunde L, Peterlongo P, Manoukian S, Bonanni B, Viel A, Radice P, Caldes T, de la Hoya M, Singer CF, Fink-Retter A, Greene MH, Mai PL, Loud JT, Guidugli L, Lindor NM, Hansen TV, Nielsen FC, Blanco I, Lazaro C, Garber J, Ramus SJ, Gayther SA, Phelan C, Narod S, Szabo CI, Benitez J, Osorio A, Nevanlinna H, Heikkinen T, Caligo MA, Beattie MS, Hamann U, Godwin AK, Montagna M, Casella C, Neuhausen SL, Karlan BY, Tung N, Toland AE, Weitzel J, Olopade O, Simard J, Soucy P, Rubinstein WS, Arason A, Rennert G, Martin NG, Montgomery GW, Chang-Claude J, Flesch-Janys D, Brauch H, Severi G, Baglietto L, Cox A, Cross SS, Miron P, Gerty SM, Tapper W, Yannoukakos D, Fountzilas G, Fasching PA, Beckmann MW, Dos Santos Silva I, Peto J, Lambrechts D, Paridaens R, Rudiger T, Forsti A, Winqvist R, Pylkas K, Diasio RB, Lee AM, Eckel-Passow J, Vachon C, Blows F, Driver K, Dunning A, Pharoah PP, Offit K, Pankratz VS, Hakonarson H, Chenevix-Trench G, Easton DF, Couch FJ (2010) A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nat Genet 42(10):885–892. doi:10.1038/ng.669
Shao G, Patterson-Fortin J, Messick TE, Feng D, Shanbhag N, Wang Y, Greenberg RA (2009) MERIT40 controls BRCA1-RAP80 complex integrity and recruitment to DNA double-strand breaks. Genes Dev 23(6):740–754. doi:10.1101/gad.1739609
Feng L, Huang J, Chen J (2009) MERIT40 facilitates BRCA1 localization and DNA damage repair. Genes Dev 23(6):719–728. doi:10.1101/gad.1770609
Wang B, Hurov K, Hofmann K, Elledge SJ (2009) NBA1, a new player in the BRCA1 a complex, is required for DNA damage resistance and checkpoint control. Genes Dev 23(6):729–739. doi:10.1101/gad.1770309
Huen MS, Sy SM, Chen J (2010) BRCA1 and its toolbox for the maintenance of genome integrity. Nat Rev Mol Cell Biol 11(2):138–148. doi:10.1038/nrm2831
Hu X, Kim J, Castillo A, Huang M, Liu J, Wang B (2011) Nba1/merit40 and bre interaction is required for the integrity of two distinct deubiqutinating enzyme BRCC36 containing complexes. J Biol Chem (in press). doi:10.1074/jbc.M110.200857
Turnbull C, Rahman N (2008) Genetic predisposition to breast cancer: Past, present, and future. Annu Rev Genomics Hum Genet 9:321–345. doi:10.1146/annurev.genom.9.081307.164339
Olopade OI, Grushko TA, Nanda R, Huo D (2008) Advances in breast cancer: pathways to personalized medicine. Clin Cancer Res 14(24):7988–7999. doi:10.1158/1078-0432.CCR-08-1211
Solyom S, Patterson-Fortin J, Pylkas K, Greenberg RA, Winqvist R (2010) Mutation screening of the MERIT40 gene encoding a novel BRCA1 and RAP80 interacting protein in breast cancer families. Breast Cancer Res Treat 120(1):165–168. doi:10.1007/s10549-009-0453-7
Acknowledgments
We thank all the subjects for providing samples voluntarily. This study was supported by the National Cancer Institute at the National Institutes of Health (R01 CA141712 and R01 CA142996-01) and the Entertainment Industry Foundation.
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Zheng, Y., Zhang, J., Niu, Q. et al. Germline mutational analysis of the C19orf62 gene in African-American women with breast cancer. Breast Cancer Res Treat 127, 871–877 (2011). https://doi.org/10.1007/s10549-011-1445-y
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DOI: https://doi.org/10.1007/s10549-011-1445-y