DOI QR코드

DOI QR Code

Association of a Newly Identified Variant of DNA Polymerase Beta (polβΔ63-123, 208-304) with the Risk Factor of Ovarian Carcinoma in India

  • Khanra, Kalyani (Department of Biotechnology, Haldia Institute of Technology, Regional Research Station) ;
  • Bhattacharya, Chandan (Bidhan Chandra Krishi Vishyavidyalaya, Regional Research Station) ;
  • Bhattacharyya, Nandan (Department of Biotechnology, Haldia Institute of Technology, Regional Research Station)
  • 발행 : 2012.05.30

초록

Background: DNA polymerase is a single-copy gene that is considered to be part of the DNA repair machinery in mammalian cells. The encoded enzyme is a key to the base excision repair (BER) pathway. It is evident that pol beta has mutations in various cancer samples, but little is known about ovarian cancer. Aim: Identification of any variant form of $pol{\beta}$ cDNA in ovarian carcinoma and determination of association between the polymorphism and ovarian cancer risk in Indian patients. We used 152 samples to isolate and perform RT-PCR and sequencing. Results: A variant of polymerase beta (deletion of exon 4-6 and 11-13, comprising of amino acid 63-123, and 208-304) is detected in heterozygous condition. The product size of this variant is 532 bp while wild type pol beta is 1 kb. Our study of association between the variant and the endometrioid type shows that it is a statistically significant factor for ovarian cancer [OR=31.9 (4.12-246.25) with p<0.001]. The association between variant and stage IV patients further indicated risk (${\chi}^2$ value of 29.7, and OR value 6.77 with 95% CI values 3.3-13.86). The correlation study also confirms the association data (Pearson correlation values for variant/stage IV and variant/endometrioid of 0.44 and 0.39). Conclusion: Individuals from this part of India with this type of variant may be at risk of stage IV, endometrioid type ovarian carcinoma.

키워드

참고문헌

  1. American Cancer Society. Cancer Facts and Figures 2012. Atlanta, GA: American Cancer Society; 2012
  2. Bhattacharyya N, Banerjee S (1997). A variant of DNA polymerase b acts as a dominant negative mutant. Proc Natl Acad Sci USA, 94, 10324-9. https://doi.org/10.1073/pnas.94.19.10324
  3. Bhattacharyya N, Banerjee T, Patel U, et al (2001). Impaired repair activity of a truncated DNA polymerase beta protein. Life Sci, 69, 271-80. https://doi.org/10.1016/S0024-3205(01)01120-1
  4. Bhattacharyya N, Chen HC, Comhair S, Erzurum SC, et al (1999a). Variant forms of DNA polymerase beta in primary lung carcinomas. DNA Cell Biol, 18, 549-54. https://doi.org/10.1089/104454999315097
  5. Bhattacharyya N, Chen HC, Grundfest-Broniatowski S, Banerjee S (1999). Alteration of hMSH2 and DNA polymerase b genes in Breast Carcinomas and Fibroadenomas. Biochem Biophys Res Comm, 259, 429-35. https://doi.org/10.1006/bbrc.1999.0791
  6. Bulgar, AD, Snell M, Donze JR, et al (2010). Targeting base excision repair suggests a new therapeutic strategy of fludarabine for the treatment of chronic lymphocytic leukemia. Leukemia, 24, 1795-9. https://doi.org/10.1038/leu.2010.166
  7. Buys SS, Partridge E, Black A, et al (2011). Effect of screening on ovarian cancer mortality; the prostate, lung, colorectal and ovarian (PLCO) cancer screening randomized controlled trial. JAMA, 305, 2295-303. https://doi.org/10.1001/jama.2011.766
  8. Canitrot Y, Cazaux C, Chet MF, et al (1998). Overexpression of DNA polymerase b in cell results in a mutator phenotype and a decreased sensitivity to anticancer drugs. Proc Natl Acad Sci USA, 95, 12586-90. https://doi.org/10.1073/pnas.95.21.12586
  9. Chen HC, Bhattacharyya N, Wang L, et al (2000) Defective DNA repair genes in a primary culture of human renal cell carcinoma. Cancer Res Clinic Oncol, 126, 185-90. https://doi.org/10.1007/s004320050031
  10. Chen HC, Wang L, Banerjee S (2002). Heterogeneity in expression and functional analysis of DNA polymerase b in human tumor cell lines. Gene Expression, 10, 115-23.
  11. Chyan YJ, Ackerman S, Shepherd NS, et al (1994). The human DNA polymerase gene structure. Evidenceof alternative splicing in gene expression. Nucleic Acids Res, 22, 2719-25. https://doi.org/10.1093/nar/22.14.2719
  12. Dalal S, Daniela S, Joachim J, et al (2008). The Leu22Pro tumor-associated variant of DNA polymerase beta is dRP lyase deficient. Nucleic Acids Res, 36, 2411-22.
  13. Dalal S, S Hile, K A Eckert, et al (2005). Prostate-cancerassociated I260M variant of DNA polymerase beta is a sequence-specific mutator. Biochemistry, 44, 15664-73. https://doi.org/10.1021/bi051179z
  14. Huang GL, Guo HQ, Yu CY, et al (2011). XRCC1 Polymorphisms and Risk of Nasopharyngeal Carcinoma: a Meta-analysis. Asian Pac J Cancer Prev, 12, 2329-33.
  15. Idris H, Al-Assar O, Wilson SH (2002). DNA polymerase $\beta$. Int J Bio Cell Biology, 34, 321-4. https://doi.org/10.1016/S1357-2725(01)00131-5
  16. Khanra K, Panda P, Bhattacharya C, et al (2012). Association of two polymorphisms of DNA polymerase Beta in exon-9 and exon-11 with ovarian carcinoma in India. Asian Pac J Cancer Prev, 13, 1321-4. https://doi.org/10.7314/APJCP.2012.13.4.1321
  17. Kigawa J, Minagawa Y, Ishihara H, Kanamori Y, Terakwa N (1993). Tumor DNA ploidy and prognosis of patients with serous cystadenocarcinoma of the ovary. Cancer, 72, 804-8. https://doi.org/10.1002/1097-0142(19930801)72:3<804::AID-CNCR2820720328>3.0.CO;2-N
  18. Kigawa J, Takahashi M, Minagawa Y, et al (1999). Topoisomerase-I activity and response to second-line chemotherapy consisting of camptothecin-11 and cisplatin in patients with ovarian cancer. Int J Cancer, 84, 521-4. https://doi.org/10.1002/(SICI)1097-0215(19991022)84:5<521::AID-IJC13>3.0.CO;2-X
  19. Lang T, Dalal S, Chikova A, et al (2007). The E295K DNA polymerase beta gastric cancer-associated variant interferes with base excision repair and induces cellular transformation. Mol Cell Biol, 27, 5587-96. https://doi.org/10.1128/MCB.01883-06
  20. Lang T, Maitra M, Starcevic D, et al (2003). A DNA polymerase beta mutant from colon cancer cells induces mutations. Proc Natl Acad Sci USA, 101, 6074-9.
  21. Liu L, Gerson SL (2004). Therapeutic impact of methoxyamine: blocking repair of abasic sites in the base excision repair pathway. Curr Opin Investig Drugs, 5, 623-7.
  22. Pan HZ, Liang J, Yu Z, et al (2011). Polymorphism of DNA repair gene XRCC1 and hepatocellular carcinoma risk in Chinese population. Asian Pac J Cancer Prev, 12, 2947-50.
  23. Starcevic D, Dalal S, Sweasy JB (2004). Is there a link between DNA polymerase beta and cancer? Cell Cycle, 3, 998-1001.
  24. Trivedi RN, Wang XN, Jelezcova E, et al (2008). Human methyl purine DNA glycosylase and DNA polymerase beta expression collectively predict sensitivity to temozolomide. Mol Pharmacol, 74, 505-16. https://doi.org/10.1124/mol.108.045112
  25. Vijayaraman KP, Veluchamy M, Murugesan P, Shanmugiah KP, Kasi PD (2012) p53 exon 4 (codon 72) polymorphism and exon 7 (codon 249) mutation in breast cancer patients in southern region (Madurai) of Tamil Nadu. Asian Pac J Cancer Prev, 13, 511-6. https://doi.org/10.7314/APJCP.2012.13.2.511
  26. Wang Y-G, Zheng TY (2012). XRCC1-77T>C Polymorphism and Cancer Risk: A Meta-analysis. Asian Pac J Cancer Prev, 13, 111-5. https://doi.org/10.7314/APJCP.2012.13.1.111
  27. Yang L, Beard WA, Wilson SH, et al (2004). Highly organized but pliant active site of DNA polymerase beta. Compensatory mechanisms in mutant enzymes revealed by dynamics simulations and energy analyses. Bio J, 86, 3392-408
  28. Zhao Y, Deng X, Wang Z, Wang Q, Liu Y (2012). Genetic polymorphisms of DNA repair genes XRCC1 and XRCC3 and risk of colorectal cancer in Chinese population. Asian Pac J Cancer Prev, 13, 665-9. https://doi.org/10.7314/APJCP.2012.13.2.665

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