Germline mutation in the RAD51B gene confers predisposition to breast cancer

BMC Cancer

Lisa Golmard³  Virginie Caux-Moncoutier²  Grégoire Davy²  Essam Al Ageeli²  Brigitte Poirot²  Carole Tirapo²  Dorothée Michaux²  Catherine Barbaroux²  Catherine Dubois d’Enghien²  André Nicolas²  Laurent Castéra²  Xavier Sastre-Garau²  Marc-Henri Stern³  Claude Houdayer¹  Dominique Stoppa-Lyonnet¹ 

[1] Université Paris Descartes, Sorbonne Paris Cité, 12 rue de l’école de Médecine, 75270 Paris, Cedex 06, France

[2] Institut Curie, Department of Tumour Biology, 26 rue d’Ulm, 75248, Paris, Cedex 05, France

[3] Institut Curie, INSERM U830, 26 rue d’Ulm, 75248, Paris, Cedex 05, France

关键词: RAD51B;    RAD51 paralogs;    Ovarian cancer;    Breast cancer;    Genetic predisposition;   

Others  :  1079509
DOI  :  10.1186/1471-2407-13-484

 received in 2013-08-03, accepted in 2013-10-08,  发布年份 2013

【 摘 要 】

Background

Most currently known breast cancer predisposition genes play a role in DNA repair by homologous recombination. Recent studies conducted on RAD51 paralogs, involved in the same DNA repair pathway, have identified rare germline mutations conferring breast and/or ovarian cancer predisposition in the RAD51C, RAD51D and XRCC2 genes. The present study analysed the five RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3) to estimate their contribution to breast and ovarian cancer predisposition.

Methods

The study was conducted on 142 unrelated patients with breast and/or ovarian cancer either with early onset or with a breast/ovarian cancer family history. Patients were referred to a French family cancer clinic and had been previously tested negative for a BRCA1/2 mutation. Coding sequences of the five genes were analysed by EMMA (Enhanced Mismatch Mutation Analysis). Detected variants were characterized by Sanger sequencing analysis.

Results

Three splicing mutations and two likely deleterious missense variants were identified: RAD51B c.452 + 3A > G, RAD51C c.706-2A > G, RAD51C c.1026 + 5_1026 + 7del, RAD51B c.475C > T/p.Arg159Cys and XRCC3 c.448C > T/p.Arg150Cys. No RAD51D and XRCC2 gene mutations were detected. These mutations and variants were detected in families with both breast and ovarian cancers, except for the RAD51B c.475C > T/p.Arg159Cys variant that occurred in a family with 3 breast cancer cases.

Conclusions

This study identified the first RAD51B mutation in a breast and ovarian cancer family and is the first report of XRCC3 mutation analysis in breast and ovarian cancer. It confirms that RAD51 paralog mutations confer breast and ovarian cancer predisposition and are rare events. In view of the low frequency of RAD51 paralog mutations, international collaboration of family cancer clinics will be required to more accurately estimate their penetrance and establish clinical guidelines in carrier individuals.

【 授权许可】

   
2013 Golmard et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011, 61:69-90.
• [2]Claus EB, Risch N, Thompson WD: Genetic analysis of breast cancer in the cancer and steroid hormone study. Am J Hum Genet 1991, 48:232-242.
• [3]Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, Bell R, Rosenthal J, Hussey C, Tran T, McClure M, Frye C, Hattier T, Phelps R, Haugen-Strano A, Katcher H, Yakumo K, Gholami Z, Shaffer D, Stone S, Bayer S, Wray C, Bogden R, Dayananth P, Ward J, Tonin P, et al.: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994, 266:66-71.
• [4]Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G: Identification of the breast cancer susceptibility gene BRCA2. Nature 1995, 378:789-792.
• [5]Pharoah PD, Antoniou AC, Easton DF, Ponder BA: Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med 2008, 358:2796-2803.
• [6]Walsh T, King MC: Ten genes for inherited breast cancer. Cancer Cell 2007, 11:103-105.
• [7]Seal S, Thompson D, Renwick A, Elliott A, Kelly P, Barfoot R, Chagtai T, Jayatilake H, Ahmed M, Spanova K, North B, McGuffog L, Evans DG, Eccles D, Easton DF, Stratton MR, Rahman N, Breast Cancer Susceptibility Collaboration (UK): Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet 2006, 38:1239-1241.
• [8]Rahman N, Seal S, Thompson D, Kelly P, Renwick A, Elliott A, Reid S, Spanova K, Barfoot R, Chagtai T, Jayatilake H, McGuffog L, Hanks S, Evans DG, Eccles D, Easton DF, Stratton MR, Breast Cancer Susceptibility Collaboration (UK): PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 2007, 39:165-167.
• [9]Foulkes WD: Inherited susceptibility to common cancers. N Engl J Med 2008, 359:2143-2153.
• [10]Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, D’Andrea AD: Biallelic inactivation of BRCA2 in Fanconi anemia. Science 2002, 297:606-609.
• [11]Levitus M, Waisfisz Q, Godthelp BC, de Vries Y, Hussain S, Wiegant WW, Elghalbzouri-Maghrani E, Steltenpool J, Rooimans MA, Pals G, Arwert F, Mathew CG, Zdzienicka MZ, Hiom K, De Winter JP, Joenje H: The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat Genet 2005, 37:934-935.
• [12]Reid S, Schindler D, Hanenberg H, Barker K, Hanks S, Kalb R, Neveling K, Kelly P, Seal S, Freund M, Wurm M, Batish SD, Lach FP, Yetgin S, Neitzel H, Ariffin H, Tischkowitz M, Mathew CG, Auerbach AD, Rahman N: Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet 2007, 39:162-164.
• [13]Suwaki N, Klare K, Tarsounas M: RAD51 paralogs: roles in DNA damage signalling, recombinational repair and tumorigenesis. Semin Cell Dev Biol 2011, 22:898-905.
• [14]Vaz F, Hanenberg H, Schuster B, Barker K, Wiek C, Erven V, Neveling K, Endt D, Kesterton I, Autore F, Fraternali F, Freund M, Hartmann L, Grimwade D, Roberts RG, Schaal H, Mohammed S, Rahman N, Schindler D, Mathew CG: Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet 2010, 42:406-409.
• [15]Shamseldin HE, Elfaki M, Alkuraya FS: Exome sequencing reveals a novel Fanconi group defined by XRCC2 mutation. J Med Genet 2012, 49:184-186.
• [16]Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D, Freund M, Lichtner P, Hartmann L, Schaal H, Ramser J, Honisch E, Kubisch C, Wichmann HE, Kast K, Deissler H, Engel C, Müller-Myhsok B, Neveling K, Kiechle M, Mathew CG, Schindler D, Schmutzler RK, Hanenberg H: Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 2010, 42:410-414.
• [17]Loveday C, Turnbull C, Ramsay E, Hughes D, Ruark E, Frankum JR, Bowden G, Kalmyrzaev B, Warren-Perry M, Snape K, Adlard JW, Barwell J, Berg J, Brady AF, Brewer C, Brice G, Chapman C, Cook J, Davidson R, Donaldson A, Douglas F, Greenhalgh L, Henderson A, Izatt L, Kumar A, Lalloo F, Miedzybrodzka Z, Morrison PJ, Paterson J, Porteous M, et al.: Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet 2011, 43:879-882.
• [18]Park DJ, Lesueur F, Nguyen-Dumont T, Pertesi M, Odefrey F, Hammet F, Neuhausen SL, John EM, Andrulis IL, Terry MB, Daly M, Buys S, Le Calvez-Kelm F, Lonie A, Pope BJ, Tsimiklis H, Voegele C, Hilbers FM, Hoogerbrugge N, Barroso A, Osorio A, Giles GG, Devilee P, Benitez J, Hopper JL, Tavtigian SV, Goldgar DE, Southey MC, Breast Cancer Family Registry: Rare mutations in XRCC2 increase the risk of breast cancer. Am J Hum Genet 2012, 90:734-739. 13
• [19]Hilbers FS, Wijnen JT, Hoogerbrugge N, Oosterwijk JC, Collee MJ, Peterlongo P, Radice P, Manoukian S, Feroce I, Capra F, Couch FJ, Wang X, Guidugli L, Offit K, Shah S, Campbell IG, Thompson ER, James PA, Trainer AH, Gracia J, Benitez J, van Asperen CJ, Devilee P: Rare variants in XRCC2 as breast cancer susceptibility alleles. J Med Genet 2012, 49:618-620.
• [20]Johnson J, Healey S, Khanna KK, Chenevix-Trench G, kConFab: Mutation analysis of RAD51L1 (RAD51B/REC2) in multiple-case, non-BRCA1/2 breast cancer families. Breast Cancer Res Treat 2011, 129:255-263.
• [21]Caux-Moncoutier V, Castéra L, Tirapo C, Michaux D, Rémon MA, Laugé A, Rouleau E, De Pauw A, Buecher B, Gauthier-Villars M, Viovy JL, Stoppa-Lyonnet D, Houdayer C: EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients. Hum Mutat 2011, 32:325-334.
• [22]Align-GVGD http://agvgd.iarc.fr/agvgd_input.php webcite
• [23]Tavtigian SV, Deffenbaugh AM, Yin L, Judkins T, Scholl T, Samollow PB, de Silva D, Zharkikh A, Thomas A: Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J Med Genet 2006, 43:295-305.
• [24]SIFT http://sift.jcvi.org/ webcite
• [25]Kumar P, Henikoff S, Ng PC: Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009, 4:1073-1081.
• [26]Polyphen-2 http://genetics.bwh.harvard.edu/pph2/ webcite
• [27]Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR: A method and server for predicting damaging missense mutations. Nat Methods 2010, 7:248-249.
• [28]Exome Variant Server http://evs.gs.washington.edu/EVS/ webcite
• [29]1000 Genomes http://www.1000genomes.org/ webcite
• [30]Houdayer C, Caux-Moncoutier V, Krieger S, Barrois M, Bonnet F, Bourdon V, Bronner M, Buisson M, Coulet F, Gaildrat P, Lefol C, Léone M, Mazoyer S, Muller D, Remenieras A, Révillion F, Rouleau E, Sokolowska J, Vert JP, Lidereau R, Soubrier F, Sobol H, Sevenet N, Bressac-de Paillerets B, Hardouin A, Tosi M, Sinilnikova OM, Stoppa-Lyonnet D: Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. Hum Mutat 2012, 33:1228-1238.
• [31]Heim S, Nilbert M, Vanni R, Floderus UM, Mandahl N, Liedgren S, Lecca U, Mitelman F: A specific translocation, t(12;14)(q14-15;q23-24), characterizes a subgroup of uterine leiomyomas. Cancer Genet Cytogenet 1988, 32:13-17.
• [32]Schoenmakers EF, Huysmans C, van de Ven WJ: Allelic knockout of novel splice variants of human recombination repair gene RAD51B in t(12;14) uterine leiomyomas. Cancer Res 1999, 59:19-23.
• [33]Date O, Katsura M, Ishida M, Yoshihara T, Kinomura A, Sueda T, Miyagawa K: Haploinsufficiency of RAD51B causes centrosome fragmentation and aneuploidy in human cells. Cancer Res 2006, 66:6018-6024.
• [34]Thomas G, Jacobs KB, Kraft P, Yeager M, Wacholder S, Cox DG, Hankinson SE, Hutchinson A, Wang Z, Yu K, Chatterjee N, Garcia-Closas M, Gonzalez-Bosquet J, Prokunina-Olsson L, Orr N, Willett WC, Colditz GA, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Diver R, Prentice R, Jackson R, Kooperberg C, Chlebowski R, Lissowska J, et al.: A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet 2009, 41:579-584.
• [35]Orr N, Lemnrau A, Cooke R, Fletcher O, Tomczyk K, Jones M, Johnson N, Lord CJ, Mitsopoulos C, Zvelebil M, McDade SS, Buck G, Blancher C, Trainer AH, James PA, Bojesen SE, Bokmand S, Nevanlinna H, Mattson J, Friedman E, Laitman Y, Palli D, Masala G, Zanna I, Ottini L, Giannini G, Hollestelle A, Ouweland AM, Novaković S, Krajc M, KConFab Consortium, et al.: Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk. Nat Genet 2012, 44:1182-1184.
• [36]Zucchero TM, Cooper ME, Maher BS, Daack-Hirsch S, Nepomuceno B, Ribeiro L, Caprau D, Christensen K, Suzuki Y, Machida J, Natsume N, Yoshiura K, Vieira AR, Orioli IM, Castilla EE, Moreno L, Arcos-Burgos M, Lidral AC, Field LL, Liu YE, Ray A, Goldstein TH, Schultz RE, Shi M, Johnson MK, Kondo S, Schutte BC, Marazita ML, Murray JC: Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med 2004, 351:769-780.
• [37]Dickson SP, Wang K, Krantz I, Hakonarson H, Goldstein DB: Rare variants create synthetic genome-wide associations. PLoS Biol 2010, 8:e1000294.
• [38]dbSNP http://www.ncbi.nlm.nih.gov/SNP/ webcite
• [39]He XF, Wei W, Su J, Yang ZX, Liu Y, Zhang Y, Ding DP, Wang W: Association between the XRCC3 polymorphisms and breast cancer risk: meta-analysis based on case–control studies. Mol Biol Rep 2012, 39:5125-5134.
• [40]Thompson ER, Boyle SE, Johnson J, Ryland GL, Sawyer S, Choong DY, Chenevix-Trench G, Trainer AH, Lindeman GJ, Mitchell G, James PA, Campbell IG, kConFab: Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients. Hum Mutat 2012, 33:95-99.
• [41]Romero A, Pérez-Segura P, Tosar A, García-Saenz JA, Díaz-Rubio E, Caldés T, de la Hoya M: A HRM-based screening method detects RAD51C germ-line deleterious mutations in Spanish breast and ovarian cancer families. Breast Cancer Res Treat 2011, 129:939-946.
• [42]Loveday C, Turnbull C, Ruark E, Xicola RM, Ramsay E, Hughes D, Warren-Perry M, Snape K, Eccles D, Evans DG, Gore M, Renwick A, Seal S, Antoniou AC, Rahman N, Breast Cancer Susceptibility Collaboration (UK): Germline RAD51C mutations confer susceptibility to ovarian cancer. Nat Genet 2012, 44:475-476. author reply 476