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  • Oncogenomics
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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

Oncogene volume 25, pages 3613–3620 (2006)Cite this article

Abstract

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.

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Abbreviations

R:

base excision repair

SCC:

squamous cell carcinoma

PCR-RFLP:

polymerase chain reaction-based restriction fragment length polymorphism

EMSA:

electrophoretic mobility shift assay

OR:

odds ratio

CI:

confidence interval

SNP:

single nucleotide polymorphism

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Acknowledgements

This study was supported by National ‘863’ High Technology Project grants 2004AA221100 (F He) and 2002BA711A06 (D Lin), National Natural Science Foundation grant 30128020 (D Lin), and Chinese National Natural Science Foundation grants for Creative Research Groups 30321003 (F He).

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Author notes

  1. B Hao and X Miao: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biology Sciences and Biotechnology, Tsinghua University, Beijing, China

    B Hao & F He

  2. Department of Etiology and Carcinogenesis, Cancer Institute & Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

    X Miao, X Zhang, T Sun, G Liang, Y Zhou, W Tan & D Lin

  3. Laboratory of Systems Biology, Beijing Institute of Radiation Medicine, Beijing, China

    B Hao, Y Li, Y Zhao, H Wang, X Chen, L Zhang & F He

  4. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Q Wei

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  1. B Hao
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Correspondence to D Lin or F He.

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Hao, B., Miao, X., Li, Y. 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, 3613–3620 (2006). https://doi.org/10.1038/sj.onc.1209355

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