Abstract
The DNA double strand break repair gene XRCC4, an important caretaker of genome stability and XRCC3 are suggested to play an imperative role in the development of carcinogenesis. However, no evidence has been provided showing that these genes are associated with risk of urinary bladder cancer (UBC). The study was designed to examine the polymorphisms associated with two genes namely XRCC4 G1394T (rs6869366), intron 3 (rs28360317), intron 7 rs1805377 and rs2836007 and XRCC3 (rs861539 and rs1799796), respectively and investigate their role as susceptible markers for UBC risk in North Indian cohort. In this hospital-based case–control study histologically confirmed 211 UBC patients and 244 age and gender matched controls of similar ethnicity were genotyped by means of PCR-RFLP. Significant different distributions in the frequency of the XRCC4 intron 3 genotype, but not the XRCC4 G1394T or intron 7 genotypes, between the UBC and control groups were observed. XRCC4 intron 7 Del/Del conferred enhanced risk (OR 1.94; P 0.017) in UBC. Interestingly, XRCC −1394 G>T variant genotype GG was associated with reduced risk (OR 0.27; P 0.020). However, none of the four polymorphisms in XRCC4 were associated with tobacco smoking and risk of recurrence in patients treated with BCG immunotherapy. Similarly, none of the XRCC3 polymorphisms were associated with UBC susceptibility. Our results suggested that the XRCC4 intron 3 rs6869366 genotype and intron 7 rs28360317 may be associated with UBC risk and may be a novel useful marker for primary prevention and anticancer intervention.
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Sinha R, Anderson DE, McDonald SS, Greenwald P (2003) Cancer risk and diet in India. J Postgrad Med 49:222–228
Merz VW, Marth D, Kraft R, Ackermann DK, Zingg EJ, Studer UE (1995) Analysis of early failures after intravesical instillation therapy with bacilli Calmette-Guérin for carcinoma in situ of the bladder. Br J Urol 75:180–184
Gao Y, Sun Y, Frank KM, Dikkes P, Fujiwara Y, Seidl KJ et al (1998) A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell 95:891–902
Gao Y, Ferguson DO, Xie W, Manis JP, Sekiguchi J, Frank KM et al (2000) Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature 404:897–900
Griffin CS, Simpson PJ, Wilson CR, Thacker J (2000) Mammalian recombination-repair genes XRCC2 and XRCC3 promote correct chromosome segregation. Nat Cell Biol 2:757–761
Griffin CS (2002) Aneuploidy, centrosome activity and chromosome instability in cells deficient in homologous recombination repair. Mutat Res 504:149–155
Sobin LH, Fleming ID (1997) TNM classification of malignant tumors, fifth edition. Union international contre le cancer and the American joint committee on cancer. Cancer 80:1803–1804
Miller SA, Dykes DD, Polesky HF (1998) A simple salting out procedure for extracting DNA from human nucleated cells. Nucl Acids Res 16:1215
Chiu CF, Tsai MH, Tseng HC, Wang CL, Tsai FJ, Lin CC et al (2008) A novel single nucleotide polymorphism in ERCC6 gene is associated with oral cancer susceptibility in Taiwanese patients. Oral Oncol 44:582–586
López-Cima MF, González-Arriaga P, García-Castro L, Pascual T, Marrón MG, Puente XS et al (2007) Polymorphisms in XPC, XPD, XRCC1, and XRCC3 DNA repair genes and lung cancer risk in a population of northern Spain. BMC Cancer 7:162
Werbrouck J, De Ruyck K, Duprez F, Van Eijkeren M, Rietzschel E, Bekaert S et al (2008) Single-nucleotide polymorphisms in DNA double-strand break repair genes: association with head and neck cancer and interaction with tobacco use and alcohol consumption. Mutat Res 656:74–81
Chang CH, Chang CL, Tsai CW, Wu HC, Chiu CF, Wang RF et al (2009) Significant association of an XRCC4 single nucleotide polymorphism with bladder cancer susceptibility in Taiwan. Anticancer Res 29:1777–1782
Broberg K, Björk J, Paulsson K, Höglund M, Albin M (2005) Constitutional short telomeres are strong genetic susceptibility markers for bladder cancer. Carcinogenesis 26:1263–1271
Wu X, Gu J, Grossman HB, Amos CI, Etzel C, Huang M et al (2006) Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cycle-control genes. Am J Hum Genet 78:464–479
Figueroa JD, Malats N, Rothman N, Real FX, Silverman D, Kogevinas M et al (2007) Evaluation of genetic variation in the double-strand break repair pathway and bladder cancer risk. Carcinogenesis 28:1788–1793
Tseng HC, Tsai MH, Chiu CF, Wang CH, Chang NW, Huang CY et al (2008) Association of XRCC4 codon 247 polymorphism with oral cancer susceptibility in Taiwan. Anticancer Res 28:1687–1691
Chiu CF, Wang HC, Wang CH, Wang CL, Lin CC, Shen CY et al (2008) A new single nucleotide polymorphism in XRCC4 gene is associated with breast cancer susceptibility in Taiwanese patients. Anticancer Res 28:267–270
Chiu CF, Wang CH, Wang CL, Lin CC, Hsu NY, Weng JR et al (2008) A novel single nucleotide polymorphism in XRCC4 gene is associated with gastric cancer susceptibility in Taiwan. Ann Surg Oncol 15:514–518
Chiu CF, Tsai MH, Tseng HC, Wang CL, Wang CH, Wu CN et al (2008) A novel single nucleotide polymorphism in XRCC4 gene is associated with oral cancer susceptibility in Taiwanese patients. Oral Oncol 44:898–902
Doré AS, Furnham N, Davies OR, Sibanda BL, Chirgadze DY, Jackson SP et al (2006) Structure of an XRCC4-DNA ligase IV yeast ortholog complex reveals a novel BRCT interaction mode. DNA Repair (Amst) 5:362–368
Fontana L, Bosviel R, Delort L, Guy L, Chalabi N, Kwiatkowski F et al (2008) DNA repair gene ERCC2, XPC, XRCC1, XRCC3 polymorphisms and associations with bladder cancer risk in a French cohort. Anticancer Res 28:1853–1856
Stern MC, Umbach DM, Lunn RM, Taylor JA (2002) DNA repair gene XRCC3 codon 241 polymorphism, its interaction with smoking and XRCC1 polymorphisms, and bladder cancer risk. Cancer Epidemiol Biomarkers Prev 11:939–943
Han S, Zhang HT, Wang Z, Xie Y, Tang R, Mao Y et al (2006) DNA repair gene XRCC3 polymorphisms and cancer risk: a meta-analysis of 48 case-control studies. Eur J Hum Genet 14:1136–1144
Winsey SL, Haldar NA, Marsh HP, Bunce M, Marshall SE, Harris AL et al (2000) A variant within the DNA repair gene XRCC3 is associated with the development of melanoma skin cancer. Cancer Res 60:5612–5616
Matullo G, Guarrera S, Carturan S, Peluso M, Malaveille C, Davico L et al (2001) DNA repair gene polymorphisms, bulky DNA adducts in white blood cells and bladder cancer in a case–control study. Int J Cancer 92:562–567
Jacobsen NR, Raaschou-Nielsen O, Nexø B, Wallin H, Overvad K, Tjønneland A et al (2004) XRCC3 polymorphisms and risk of lung cancer. Cancer Lett 213:67–72
Qiu LX, Mao C, Yao L, Yu KD, Zhan P, Chen B et al (2010) XRCC3 5′-UTR and IVS5–14 polymorphisms and breast cancer susceptibility: a meta-analysis. Breast Cancer Res Treat 122:489–493
Böhle A, Suttmann H, Brandau S (2006) Effect mechanism of intravesical BCG immunotherapy of superficial bladder cancer. Urologe A 45:629–633
Acknowledgments
The authors are grateful to Division of Science and Technology (DST), New Delhi, India for funding. We are thankful to Dr. Mandhani and the senior residents for recruitment of patients and organizing health check-up camps from time to time which was helpful in collecting healthy control blood samples. RG and RKM are thankful to Council of Scientific and Industrial Research (CSIR), New Delhi for Senior Research Fellowship and Junior Research Fellowship.
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Mittal, R.D., Gangwar, R., Mandal, R.K. et al. Gene variants of XRCC4 and XRCC3 and their association with risk for urothelial bladder cancer. Mol Biol Rep 39, 1667–1675 (2012). https://doi.org/10.1007/s11033-011-0906-z
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DOI: https://doi.org/10.1007/s11033-011-0906-z