Cancer Res Treat.  2016 Apr;48(2):708-714. 10.4143/crt.2015.098.

Nucleotide Excision Repair Gene ERCC2 and ERCC5 Variants Increase Risk of Uterine Cervical Cancer

• Joo J
• Yoon KA
• Hayashi T
• Kong SY
• Shin HJ
• Park B
• Kim YM
• Hwang SH
• Kim J
• Shin A
• Kim JY

• KMID: 2454349
• DOI: http://doi.org/10.4143/crt.2015.098

Abstract

PURPOSE
Defects in the DNA damage repair process can cause genomic instability and play an important role in cervical carcinogenesis. The purpose of this study was to analyze the association of 29 candidate single nucleotide polymorphisms (SNPs) in genes in the DNA repair pathway, TP53, and TP53BP1 with the risk of cervical cancer.
MATERIALS AND METHODS
Twenty-nine SNPs in four genes in the DNA repair pathway (ERCC2, ERCC5, NBS1, and XRCC1), TP53, and TP53BP1 were genotyped for 478 cervical cancer patients and 922 healthy control subjects, and their effects on cervical carcinogenesis were analyzed.
RESULTS
The most significant association was found for rs17655 in ERCC5, with an age-adjusted p-value < 0.0001, for which a strong additive effect of the risk allele C was observed (odds ratio, 2.01 for CC to GG). On the other hand, another significant polymorphism rs454421 in ERCC2 showed a dominant effect (odds ratio, 1.68 for GA+AA to GG) with an age-adjusted p-value of 0.0009. The association of these polymorphisms remained significant regardless of the age of onset. The significant result for rs17655 was also consistent for subgroups of patients defined by histology and human papillomavirus (HPV) types. However, for rs454421, the association was observed only in patients with squamous cell carcinoma and non-HPV 18 type.
CONCLUSION
The results of this study show a novel association of cervical cancer and the genes involved in the nucleotide excision pathway in the Korean population.

Keyword

ERCC; Single nucleotide polymorphism; Uterine cervical neoplasms

MeSH Terms

Age of Onset
Alleles
Carcinogenesis
Carcinoma, Squamous Cell
DNA Damage
DNA Repair*
Genomic Instability
Hand
Humans
Polymorphism, Single Nucleotide
Uterine Cervical Neoplasms*

Reference

References

1. Oh CM, Jung KW, Won YJ, Shin A, Kong HJ, Jun JK, et al. Trends in the incidence of in situ and invasive cervical cancer by age group and histological type in Korea from 1993 to 2009. PLoS One. 2013; 8:e72012.

2. Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998; 338:423–8.

3. Jensen KE, Schmiedel S, Frederiksen K, Norrild B, Iftner T, Kjaer SK. Risk for cervical intraepithelial neoplasia grade 3 or worse in relation to smoking among women with persistent human papillomavirus infection. Cancer Epidemiol Biomarkers Prev. 2012; 21:1949–55.

4. Thomsen LS, Jochumsen KM, Mogensen O. Carcinoma in situ cervicis uteri and inheritance: a Danish twin study. Gynecol Oncol. 2006; 103:688–91.

5. Weber W, De Sabata MS, Paredes RM, Rodriguez G, Santos C, Sabillon JU, et al. Cancer in first degree relatives of Latin American women with cervical cancer: a pilot study. Anticancer Res. 2005; 25:1219–23.

6. Kadaja M, Isok-Paas H, Laos T, Ustav E, Ustav M. Mechanism of genomic instability in cells infected with the high-risk human papillomaviruses. PLoS Pathog. 2009; 5:e1000397.

7. Wood RD, Mitchell M, Lindahl T. Human DNA repair genes, 2005. Mutat Res. 2005; 577:275–83.

8. Rouissi K, Bahria IB, Bougatef K, Marrakchi R, Stambouli N, Hamdi K, et al. The effect of tobacco, XPC, ERCC2 and ERCC5 genetic variants in bladder cancer development. BMC Cancer. 2011; 11:101.

9. Gillespie KA, Mehta KP, Laimins LA, Moody CA. Human papillomaviruses recruit cellular DNA repair and homologous recombination factors to viral replication centers. J Virol. 2012; 86:9520–6.

10. Chen K, Hu Z, Wang LE, Zhang W, El-Naggar AK, Sturgis EM, et al. Polymorphic TP53BP1 and TP53 gene interactions associated with risk of squamous cell carcinoma of the head and neck. Clin Cancer Res. 2007; 13:4300–5.

11. Koshiol J, Hildesheim A, Gonzalez P, Bratti MC, Porras C, Schiffman M, et al. Common genetic variation in TP53 and risk of human papillomavirus persistence and progression to CIN3/cancer revisited. Cancer Epidemiol Biomarkers Prev. 2009; 18:1631–7.

12. Livak KJ. Allelic discrimination using fluorogenic probes and the 5' nuclease assay. Genet Anal. 1999; 14:143–9.

13. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007; 447:661–78.

14. Joo J, Kwak M, Ahn K, Zheng G. A robust genome-wide scan statistic of the Wellcome Trust Case-Control Consortium. Biometrics. 2009; 65:1115–22.

15. Kim JY, Park S, Nam BH, Roh JW, Lee CH, Kim YH, et al. Low initial human papilloma viral load implicates worse prognosis in patients with uterine cervical cancer treated with radiotherapy. J Clin Oncol. 2009; 27:5088–93.

16. Yu J, Mallon MA, Zhang W, Freimuth RR, Marsh S, Watson MA, et al. DNA repair pathway profiling and microsatellite instability in colorectal cancer. Clin Cancer Res. 2006; 12:5104–11.

17. Dabholkar M, Bostick-Bruton F, Weber C, Bohr VA, Egwuagu C, Reed E. ERCC1 and ERCC2 expression in malignant tissues from ovarian cancer patients. J Natl Cancer Inst. 1992; 84:1512–7.

18. Huang MY, Tsai HL, Lin CH, Huang CW, Ma CJ, Huang CM, et al. Predictive value of ERCC1, ERCC2, and XRCC1 overexpression for stage III colorectal cancer patients receiving FOLFOX-4 adjuvant chemotherapy. J Surg Oncol. 2013; 108:457–64.

19. Zhang W, Guo N, Yu C, Wang H, Zhang Y, Xia H, et al. Differential expression of ERCC-1 in the primary tumors and metastatic lymph nodes of patients with non-small cell lung cancer adenocarcinoma. Tumour Biol. 2012; 33:2209–16.

20. Yin M, Yan J, Martinez-Balibrea E, Graziano F, Lenz HJ, Kim HJ, et al. ERCC1 and ERCC2 polymorphisms predict clinical outcomes of oxaliplatin-based chemotherapies in gastric and colorectal cancer: a systemic review and meta-analysis. Clin Cancer Res. 2011; 17:1632–40.

21. Rajaraman P, Bhatti P, Doody MM, Simon SL, Weinstock RM, Linet MS, et al. Nucleotide excision repair polymorphisms may modify ionizing radiation-related breast cancer risk in US radiologic technologists. Int J Cancer. 2008; 123:2713–6.

22. Ma H, Hu Z, Zhai X, Wang S, Wang X, Qin J, et al. Joint effects of single nucleotide polymorphisms in P53BP1 and p53 on breast cancer risk in a Chinese population. Carcinogenesis. 2006; 27:766–71.

23. Thomas M, Kalita A, Labrecque S, Pim D, Banks L, Matlashewski G, et al. Two polymorphic variants of wild-type p53 differ biochemically and biologically. Mol Cell Biol. 1999; 19:1092–100.

24. Storey A, Thomas M, Kalita A, Harwood C, Gardiol D, Mantovani F, et al. Role of a p53 polymorphism in the development of human papillomavirus-associated cancer. Nature. 1998; 393:229–34.

25. Han JY, Yoon KA, Park JH, Lee YJ, Lee GK, Han JH, et al. DNA repair gene polymorphisms and benefit from gefitinib in never-smokers with lung adenocarcinoma. Cancer. 2011; 117:3201–8.