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A novel T-77C polymorphism in DNA repair gene XRCC1 contributes to diminished promoter activity and increased risk of non-small cell lung cancer.

Publication ,  Journal Article
Hao, B; Miao, X; Li, Y; Zhang, X; Sun, T; Liang, G; Zhao, Y; Zhou, Y; Wang, H; Chen, X; Zhang, L; Tan, W; Wei, Q; Lin, D; He, F
Published in: Oncogene
June 15, 2006

X-ray repair cross-complementing 1 (XRCC1) plays a key role in DNA base excision repair and cells lacking its activity are hypersensitive to DNA damage. Recently, we reported a SNP (rs3213245, -77T>C) in the XRCC1 gene 5' untranslated region (UTR) was significantly associated with the risk of developing esophageal squamous-cell carcinoma. Computer analysis predicted that this SNP was in the core of Sp1-binding motif, which suggested its functional significance. Gel shift and super shift assays confirmed that -77T>C polymorphic site in the XRCC1 promoter was within the Sp1-binding motif and the T>C substitution greatly enhanced the binding affinity of Sp1 to this region. Luciferase assays indicated that the Sp1-high-affinity C-allelic XRCC1 promoter was associated with a reduced transcriptional activity. The association between -77T>C and three other amino-acid substitution-causing polymorphisms in XRCC1 and risk of lung cancer was examined in 1024 patients and 1118 controls and the results showed that only the -77T>C polymorphism was significantly associated with an increased risk of developing lung cancer. Multivariate logistic regression analysis found that an increased risk of lung cancer was associated with the variant XRCC1 -77 genotypes (TC and CC) compared with the TT genotype (OR=1.46, 95% CI=1.18-1.82; P=0.001) and the increased risk was more pronounced in smokers (OR=1.63, 95% CI=1.20-2.21) than in non-smokers (OR=1.28, 95% CI=0.94-1.76). Taken together, these results showed that the functional SNP -77T>C in XRCC1 5'UTR was associated with cancer development owing to the decreased transcriptional activity of C-allele-containing promoter with higher affinity to Sp1 binding.

Duke Scholars

Published In

Oncogene

DOI

ISSN

0950-9232

Publication Date

June 15, 2006

Volume

25

Issue

25

Start / End Page

3613 / 3620

Location

England

Related Subject Headings

  • X-ray Repair Cross Complementing Protein 1
  • Risk Factors
  • Promoter Regions, Genetic
  • Polymorphism, Genetic
  • Oncology & Carcinogenesis
  • Middle Aged
  • Male
  • Lung Neoplasms
  • Humans
  • Genotype
 

Citation

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Hao, B., Miao, X., Li, Y., Zhang, X., Sun, T., Liang, G., … He, F. (2006). A novel T-77C polymorphism in DNA repair gene XRCC1 contributes to diminished promoter activity and increased risk of non-small cell lung cancer. Oncogene, 25(25), 3613–3620. https://doi.org/10.1038/sj.onc.1209355
Hao, B., X. Miao, Y. Li, X. Zhang, T. Sun, G. Liang, Y. Zhao, et al. “A novel T-77C polymorphism in DNA repair gene XRCC1 contributes to diminished promoter activity and increased risk of non-small cell lung cancer.Oncogene 25, no. 25 (June 15, 2006): 3613–20. https://doi.org/10.1038/sj.onc.1209355.
Hao, B., et al. “A novel T-77C polymorphism in DNA repair gene XRCC1 contributes to diminished promoter activity and increased risk of non-small cell lung cancer.Oncogene, vol. 25, no. 25, June 2006, pp. 3613–20. Pubmed, doi:10.1038/sj.onc.1209355.
Hao B, Miao X, Li Y, Zhang X, Sun T, Liang G, Zhao Y, Zhou Y, Wang H, Chen X, Zhang L, Tan W, Wei Q, Lin D, He F. A novel T-77C polymorphism in DNA repair gene XRCC1 contributes to diminished promoter activity and increased risk of non-small cell lung cancer. Oncogene. 2006 Jun 15;25(25):3613–3620.

Published In

Oncogene

DOI

ISSN

0950-9232

Publication Date

June 15, 2006

Volume

25

Issue

25

Start / End Page

3613 / 3620

Location

England

Related Subject Headings

  • X-ray Repair Cross Complementing Protein 1
  • Risk Factors
  • Promoter Regions, Genetic
  • Polymorphism, Genetic
  • Oncology & Carcinogenesis
  • Middle Aged
  • Male
  • Lung Neoplasms
  • Humans
  • Genotype