Association of Rad51 polymorphism with DNA repair in BRCA1 mutation carriers and sporadic breast cancer risk

BMC Cancer

Luisel J Ricks-Santi²  Lara E Sucheston¹  Yang Yang³  Jo L Freudenheim⁴  Claudine J Isaacs³  Marc D Schwartz³  Ramona G Dumitrescu³  Catalin Marian³  Jing Nie⁴  Dominica Vito⁴  Stephen B Edge⁵  Peter G Shields³ 

[1] Department of Biostatistics, University at Buffalo, State University of New York, Buffalo, NY 14214, USA

[2] National Human Genome Center at Howard University, 2041 Georgia Ave, NW #615, Washington, DC 20059, USA

[3] Lombardi Comprehensive Cancer Center, Georgetown University Medical Cancer, 3800 Reservoir Rd, NW, Washington, DC 20057, USA

[4] Department of Social and Preventive Medicine, University at Buffalo, State University of New York, Buffalo, NY 14214, USA

[5] Department of Surgery, University at Buffalo, State University of New York, Buffalo, NY 14214, USA

Others  :  1080857
DOI  :  10.1186/1471-2407-11-278

 received in 2011-01-06, accepted in 2011-06-27,  发布年份 2011

【 摘 要 】

Background

Inter-individual variation in DNA repair capacity is thought to modulate breast cancer risk. The phenotypic mutagen sensitivity assay (MSA) measures DNA strand breaks in lymphocytes; women with familial and sporadic breast cancers have a higher mean number of breaks per cell (MBPC) then women without breast cancer. Here, we explore the relationships between the MSA and the Rad51 gene, which encodes a DNA repair enzyme that interacts with BRCA1 and BRCA2, in BRCA1 mutation carriers and women with sporadic breast cancer.

Methods

Peripheral blood lymphoblasts from women with known BRCA1 mutations underwent the MSA (n = 138 among 20 families). BRCA1 and Rad51 genotyping and sequencing were performed to identify SNPs and haplotypes associated with the MSA. Positive associations from the study in high-risk families were subsequently examined in a population-based case-control study of breast cancer (n = 1170 cases and 2115 controls).

Results

Breast cancer diagnosis was significantly associated with the MSA among women from BRCA1 families (OR = 3.2 95%CI: 1.5-6.7; p = 0.004). The Rad51 5'UTR 135 C>G genotype (OR = 3.64; 95% CI: 1.38, 9.54; p = 0.02), one BRCA1 haplotype (p = 0.03) and in a polygenic model, the E1038G and Q356R BRCA1 SNPs were significantly associated with MBPC (p = 0.009 and 0.002, respectively). The Rad51 5'UTR 135C genotype was not associated with breast cancer risk in the population-based study.

Conclusions

Mutagen sensitivity might be a useful biomarker of penetrance among women with BRCA1 mutations because the MSA phenotype is partially explained by genetic variants in BRCA1 and Rad51.

【 授权许可】

   
2011 Ricks-Santi et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Chen S, Parmigiani G: Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 2007, 25:1329-1333.
• [2]Kadouri L, Easton DF, Edwards S, Hubert A, Kote-Jarai Z, Glaser B, et al.: CAG and GGC repeat polymorphisms in the androgen receptor gene and breast cancer susceptibility in BRCA1/2 carriers and non-carriers. Br J Cancer 2001, 85:36-40.
• [3]Rebbeck TR, Kantoff PW, Krithivas K, Neuhausen S, Blackwood MA, Godwin AK, et al.: Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat. Am J Hum Genet 1999, 64:1371-1377.
• [4]Kadouri L, Kote-Jarai Z, Easton DF, Hubert A, Hamoudi R, Glaser B, et al.: Polyglutamine repeat length in the AIB1 gene modifies breast cancer susceptibility in BRCA1 carriers. Int J Cancer 2004, 108:399-403.
• [5]Wacholder S, Chanock S, Garcia-Closas M, El GL, Rothman N: Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst 2004, 96:434-442.
• [6]Helzlsouer KJ, Harris EL, Parshad R, Perry HR, Price FM, Sanford KK: DNA repair proficiency: potential susceptiblity factor for breast cancer. J Natl Cancer Inst 1996, 88:754-755.
• [7]Parshad R, Price FM, Bohr VA, Cowans KH, Zujewski JA, Sanford KK: Deficient DNA repair capacity, a predisposing factor in breast cancer. Br J Cancer 1996, 74:1-5.
• [8]Patel RK, Trivedi AH, Arora DC, Bhatavdekar JM, Patel DD: DNA repair proficiency in breast cancer patients and their first-degree relatives. Int J Cancer 1997, 73:20-24.
• [9]Scott D, Spreadborough AR, Jones LA, Roberts SA, Moore CJ: Chromosomal radiosensitivity in G2-phase lymphocytes as an indicator of cancer predisposition. Radiat Res 1996, 145:3-16.
• [10]Natarajan TG, Ganesan N, Carter-Nolan P, Tucker CA, Shields PG, ms-Campbell LL: gamma-Radiation-induced chromosomal mutagen sensitivity is associated with breast cancer risk in African-American women: caffeine modulates the outcome of mutagen sensitivity assay. Cancer Epidemiol Biomarkers Prev 2006, 15:437-442.
• [11]Parshad R, Sanford KK: Radiation-induced chromatid breaks and deficient DNA repair in cancer predisposition. Crit Rev Oncol Hematol 2001, 37:87-96.
• [12]Moynahan ME, Cui TY, Jasin M: Homology-directed dna repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res 2001, 61:4842-4850.
• [13]Scully R, Xie A, Nagaraju G: Molecular functions of BRCA1 in the DNA damage response. Cancer Biol Ther 2004, 3:521-527.
• [14]Tibbetts RS, Cortez D, Brumbaugh KM, Scully R, Livingston D, Elledge SJ, et al.: Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Genes Dev 2000, 14:2989-3002.
• [15]The international HapMap Project [http://hapmap.ncbi.nlm.nih.gov/] webcite
• [16]Durocher F, Shattuck-Eidens D, McClure M, Labrie F, Skolnick MH, Goldgar DE, et al.: Comparison of BRCA1 polymorphisms, rare sequence variants and/or missense mutations in unaffected and breast/ovarian cancer populations. Hum Mol Genet 1996, 5:835-842.
• [17]Dunning AM, Chiano M, Smith NR, Dearden J, Gore M, Oakes S, et al.: Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population. Hum Mol Genet 1997, 6:285-289.
• [18]Tommasi S, Crapolicchio A, Lacalamita R, Bruno M, Monaco A, Petroni S, et al.: BRCA1 mutations and polymorphisms in a hospital-based consecutive series of breast cancer patients from Apulia, Italy. Mutat Res 2005, 578:395-405.
• [19]Dombernowsky SL, Weischer M, Freiberg JJ, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG: Missense polymorphisms in BRCA1 and BRCA2 and risk of breast and ovarian cancer. Cancer Epidemiol Biomarkers Prev 2009, 18:2339-2342.
• [20]Sehl ME, Langer LR, Papp JC, Kwan L, Seldon JL, Arellano G, et al.: Associations between single nucleotide polymorphisms in double-stranded DNA repair pathway genes and familial breast cancer. Clin Cancer Res 2009, 15:2192-2203.
• [21]The MARIE-GENICA Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk: Polymorphisms in the BRCA1 and ABCB1 genes modulate menopausal hormone therapy associated breast cancer risk in postmenopausal women. Breast Cancer Res Treat 2009.
• [22]Freedman ML, Penney KL, Stram DO, Riley S, Kean-Cowdin R, Le ML, et al.: A haplotype-based case-control study of BRCA1 and sporadic breast cancer risk. Cancer Res 2005, 65:7516-7522.
• [23]Soucek P, Borovanova T, Pohlreich P, Kleibl Z, Novotny J: Role of single nucleotide polymorphisms and haplotypes in BRCA1 in breast cancer: Czech case-control study. Breast Cancer Res Treat 2007, 103:219-224.
• [24]Cox DG, Kraft P, Hankinson SE, Hunter DJ: Haplotype analysis of common variants in the BRCA1 gene and risk of sporadic breast cancer. Breast Cancer Res 2005, 7:R171-R175. BioMed Central Full Text
• [25]Tommasi S, Pilato B, Pinto R, Monaco A, Bruno M, Campana M, et al.: Molecular and in silico analysis of BRCA1 and BRCA2 variants. Mutat Res 2008, 644:64-70.
• [26]Davies AA, Masson JY, McIlwraith MJ, Stasiak AZ, Stasiak A, Venkitaraman AR, et al.: Role of BRCA2 in control of the RAD51 recombination and DNA repair protein. Mol Cell 2001, 7:273-282.
• [27]Galkin VE, Wu Y, Zhang XP, Qian X, He Y, Yu X, et al.: The Rad51/RadA N-terminal domain activates nucleoprotein filament ATPase activity. Structure 2006, 14:983-992.
• [28]Wang WW, Spurdle AB, Kolachana P, Bove B, Modan B, Ebbers SM, et al.: A single nucleotide polymorphism in the 5' untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers. Cancer Epidemiol Biomarkers Prev 2001, 10:955-960.
• [29]Jakubowska A, Narod SA, Goldgar DE, Mierzejewski M, Masojc B, Nej K, et al.: Breast cancer risk reduction associated with the RAD51 polymorphism among carriers of the BRCA1 5382insC mutation in Poland. Cancer Epidemiol Biomarkers Prev 2003, 12:457-459.
• [30]Jakubowska A, Gronwald J, Menkiszak J, Gorski B, Huzarski T, Byrski T, et al.: The RAD51 135 G>C polymorphism modifies breast cancer and ovarian cancer risk in Polish BRCA1 mutation carriers. Cancer Epidemiol Biomarkers Prev 2007, 16:270-275.
• [31]Gal I, Kimmel G, Gershoni-Baruch R, Papa MZ, Dagan E, Shamir R, et al.: A specific RAD51 haplotype increases breast cancer risk in Jewish non-Ashkenazi high-risk women. Eur J Cancer 2006, 42:1129-1134.
• [32]Sehl ME, Langer LR, Papp JC, Kwan L, Seldon JL, Arellano G, et al.: Associations between single nucleotide polymorphisms in double-stranded DNA repair pathway genes and familial breast cancer. Clin Cancer Res 2009, 15:2192-2203.
• [33]Xia F, Taghian DG, DeFrank JS, Zeng ZC, Willers H, Iliakis G, et al.: Deficiency of human BRCA2 leads to impaired homologous recombination but maintains normal nonhomologous end joining. Proc Natl Acad Sci USA 2001, 98:8644-8649.
• [34]Richardson C: RAD51, genomic stability, and tumorigenesis. Cancer Lett 2005, 218:127-139.
• [35]Sonoda E, Sasaki MS, Buerstedde JM, Bezzubova O, Shinohara A, Ogawa H, et al.: Rad51-deficient vertebrate cells accumulate chromosomal breaks prior to cell death. EMBO J 1998, 17:598-608.
• [36]Thacker J: The RAD51 gene family, genetic instability and cancer. Cancer Lett 2005, 219:125-135.
• [37]Martin RW, Orelli BJ, Yamazoe M, Minn AJ, Takeda S, Bishop DK: RAD51 Up-regulation Bypasses BRCA1 Function and Is a Common Feature of BRCA1-Deficient Breast Tumors. Cancer Res 2007, 67:9658-9665.
• [38]Blasiak J, Przybylowska K, Czechowska A, Zadrozny M, Pertynski T, Rykala J, et al.: Analysis of the G/C polymorphism in the 5'-untranslated region of the RAD51 gene in breast cancer. Acta Biochim Pol 2003, 50:249-253.
• [39]Loizidou MA, Michael T, Neuhausen SL, Newbold RF, Marcou Y, Kakouri E, et al.: DNA-repair genetic polymorphisms and risk of breast cancer in Cyprus. Breast Cancer Res Treat 2009, 115:623-627.
• [40]Antoniou AC, Sinilnikova OM, Simard J, Leone M, Dumont M, Neuhausen SL, et al.: RAD51 135G>C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies. Am J Hum Genet 2007, 81:1186-1200.
• [41]Hasselbach L, Haase S, Fischer D, Kolberg HC, Sturzbecher HW: Characterisation of the promoter region of the human DNA-repair gene Rad51. Eur J Gynaecol Oncol 2005, 26:589-598.
• [42]Antoniou AntonisC, Sinilnikova OlgaM, Simard Jacques, Léoné Mélanie: RAD51 135G>C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies. The American Journal of Human Genetics 2007, in press.
• [43]Ding SL, Yu JC, Chen ST, Hsu GC, Kuo SJ, Lin YH, et al.: Genetic variants of BLM interact with RAD51 to increase breast cancer susceptibility. Carcinogenesis 2009, 30:43-49.
• [44]Rebbeck TR, Mitra N, Domchek SM, Wan F, Chuai S, Friebel TM, et al.: Modification of ovarian cancer risk by BRCA1/2-interacting genes in a multicenter cohort of BRCA1/2 mutation carriers. Cancer Res 2009, 69:5801-5810.
• [45]Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, et al.: The human genome browser at UCSC. Genome Res 2002, 12:996-1006.
• [46]McCann SE, Ip C, Ip MM, McGuire MK, Muti P, Edge SB, et al.: Dietary intake of conjugated linoleic acids and risk of premenopausal and postmenopausal breast cancer, Western New York Exposures and Breast Cancer Study (WEB Study). Cancer Epidemiol Biomarkers Prev 2004, 13:1480-1484.
• [47]Boyum A: Separation of White Blood Cells. Nature 1964, 204:793-794.
• [48]walls EV, Crawford DH: Generation of Human B lymphoblatoid cell lines using Epstein-Barr virus. Klaus GGB. In Lymphocytes - A practical Approach. IRL Press, Oxford; 1987:149-162.
• [49]Parshad R, Sanford KK, Jones GM: Chromatid damage after G2 phase x-irradiation of cells from cancer-prone individuals implicates deficiency in DNA repair. Proc Natl Acad Sci USA 1983, 80:5612-5616.
• [50]Sanford KK, Parshad R, Price FM, Jones GM, Tarone RE, Eierman L, et al.: Enhanced chromatid damage in blood lymphocytes after G2 phase x irradiation, a marker of the ataxia-telangiectasia gene. J Natl Cancer Inst 1990, 82:1050-1054.
• [51]Tennis M, Krishnan S, Bonner M, Ambrosone CB, Vena JE, Moysich K, et al.: p53 Mutation analysis in breast tumors by a DNA microarray method. Cancer Epidemiol Biomarkers Prev 2006, 15:80-85.
• [52]Kadouri L, Kote-Jarai Z, Hubert A, Durocher F, Abeliovich D, Glaser B, et al.: A single-nucleotide polymorphism in the RAD51 gene modifies breast cancer risk in BRCA2 carriers, but not in BRCA1 carriers or noncarriers. Br J Cancer 2004, 90:2002-2005.
• [53]Barrett JC, Fry B, Maller J, Daly MJ: Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005, 21:263-265.
• [54]Haploview [http:/ / www.broadinstitute.org/ scientific-community/ science/ programs/ medical-and-population-genetics/ haploview/ haploview] webcite
• [55]S.A.G.E. Statistical Analysis for Genetic Epidemiology 2009. Release 6.0.1
• [56]George VT, Elston RC: Generalized modulus power transformations. Commun Statist - TheoryMeth 1988, 17:2933-2952.
• [57]Elston RC, George VT, Severtson F: The Elston-Stewart algorithm for continuous genotypes and environmental factors. Hum Hered 1992, 42:16-27.
• [58]George VT, Elston RC: Testing the association between polymorphic markers and quantitative traits in pedigrees. Genet Epidemiol 1987, 4:193-201.
• [59]Gray-McGuire C, Sinha R, Iyengar S, Millard C, Rybicki BA, Elston RC, et al.: Genetic characterization and fine mapping of susceptibility loci for sarcoidosis in African Americans on chromosome 5. Hum Genet 2006, 120:420-430.
• [60]GraphPad Software [http://www.graphpad.com/quickcalcs/index.cfm] webcite
• [61]Stephens M, Smith NJ, Donnelly P: A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001, 68:978-989.
• [62]Stephens M, Donnelly P: A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003, 73:1162-1169.
• [63]Wu X, Gu J, Spitz MR: Mutagen sensitivity: a genetic predisposition factor for cancer. Cancer Res 2007, 67:3493-3495.
• [64]Wu X, Spitz MR, Amos CI, Lin J, Shao L, Gu J, et al.: Mutagen sensitivity has high heritability: evidence from a twin study. Cancer Res 2006, 66:5993-5996.
• [65]Spielman RS, McGinnis RE, Ewens WJ: Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993, 52:506-516.
• [66]Mangia A, Chiriatti A, Tommasi S, Menolascina F, Petroni S, Zito FA, et al.: BRCA1 expression and molecular alterations in familial breast cancer. Histol Histopathol 2009, 24:69-76.
• [67]Lee SE, Pellicioli A, Vaze MB, Sugawara N, Malkova A, Foiani M, et al.: Yeast Rad52 and Rad51 recombination proteins define a second pathway of DNA damage assessment in response to a single double-strand break. Mol Cell Biol 2003, 23:8913-8923.
• [68]Palanca SS, Esteban CE, Barragan GE, de JJI, Chirivella GI, Segura HA, et al.: CASP8 D302H polymorphism delays the age of onset of breast cancer in BRCA1 and BRCA2 carriers. Breast Cancer Res Treat 2009.
• [69]Jyothish B, Ankathil R, Chandini R, Vinodkumar B, Nayar GS, Roy DD, et al.: DNA repair proficiency: a potential marker for identification of high risk members in breast cancer families. Cancer Lett 1998, 124:9-13.
• [70]Knight RD, Parshad R, Price FM, Tarone RE, Sanford KK: X-ray-induced chromatid damage in relation to DNA repair and cancer incidence in family members. Int J Cancer 1993, 54:589-593.
• [71]Riches AC, Bryant PE, Steel CM, Gleig A, Robertson AJ, Preece PE, et al.: Chromosomal radiosensitivity in G2-phase lymphocytes identifies breast cancer patients with distinctive tumour characteristics. Br J Cancer 2001, 85:1157-1161.