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

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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.

Authors: 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 
Citation: Hao B, etal., Oncogene. 2006 Jun 15;25(25):3613-20. doi: 10.1038/sj.onc.1209355. Epub 2006 May 1.
RGD ID: 151232296
Pubmed: PMID:16652158   (View Abstract at PubMed)
DOI: DOI:10.1038/sj.onc.1209355   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
XRCC1Humanlung cancer susceptibilityIAGP DNA:SNP and haplotype:5'utr: 77T>C (rs3213245) (human)RGD 
Xrcc1Ratlung cancer susceptibilityISOXRCC1 (Homo sapiens)DNA:SNP and haplotype:5'utr: 77T>C (rs3213245) (human)RGD 
Xrcc1Mouselung cancer susceptibilityISOXRCC1 (Homo sapiens)DNA:SNP and haplotype:5'utr: 77T>C (rs3213245) (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
XRCC1HumanNon-small cell lung carcinoma susceptibilityIAGP DNA:SNP:5'utr: 77T>C (rs3213245) (human)RGD 
Objects Annotated

Genes (Rattus norvegicus)
Xrcc1  (X-ray repair cross complementing 1)

Genes (Mus musculus)
Xrcc1  (X-ray repair complementing defective repair in Chinese hamster cells 1)

Genes (Homo sapiens)
XRCC1  (X-ray repair cross complementing 1)


Additional Information