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Background & Aims-Biomarkers are needed to identify patients at risk of tumor progression following chemoradiotherapy for localized esophageal cancer. These could improve identification of patients at risk for cancer progression and selection of therapy.

DNA repair capacity (DRC) plays an important role in genetic susceptibility to cancer. Polymorphisms of a number of DNA repair genes involved in several distinct pathways have been identified. However, their effects on repair function have not been well characterized. We demonstrated previously that DRC for removal of benzo[a]pyrene diol epoxide-induced DNA damage measured by a host-cell reactivation assay was modulated by two XPD/ERCC2 polymorphisms in lung cancer. In this report, we investigated the association between the repair phenotype of ultraviolet (UV)-induced damage and genotypes of three DNA repair genes, XPC and XPD [involved in nucleotide excision repair (NER)] and XRCC1 [involved in base excision repair (BER)]. We measured DRC for removal of UV photoproducts by the host-cell reactivation assay in cryopreserved lymphocytes from 102 healthy non-Hispanic white subjects. We also typed these subjects for five polymorphisms in these three DNA repair genes (at intron 9 of XPC; exons 6, 10 and 23 of XPD and exon 10 of XRCC1). Compared with wild-type homozygotes, subjects homozygous for polymorphisms of the two NER genes consistently had suboptimal DRC. The DRC was consistently lower in subjects homozygous for XPC, XPD or both than in subjects with other genotypes, although the difference was not statistically significant for XPD variants. In contrast, the polymorphic allele of the BER gene, XRCC1, had no consistent effect on DRC. We concluded that these NER polymorphisms may modulate DRC and may be useful biomarkers for identifying individuals at risk of developing cancer.

XPA, a DNA binding protein in the nucleotide excision repair (NER) pathway, modulates damage recognition. Recently, a common single-nucleotide polymorphism (A --> G) of unknown function was identified in the 5' non-coding region of the XPA gene. Because a deficiency in NER is associated with an increased risk of lung cancer, we evaluated the role of this polymorphism in 695 lung cancer case patients and 695 age-, sex-, ethnicity- and smoking-matched control subjects. We also studied the effect of this polymorphism on NER capacity in a subset sample for whom the host cell reactivation data were available. The presence of one or two copies of the G allele was associated with a reduced lung cancer risk for Caucasians [adjusted odds ratio (ORadj) = 0.69 [95% confidence interval (CI) = 0.53-0.90]], Mexican-Americans [ORadj = 0.32 (95% CI = 0.12-0.83)] and African-Americans [ORadj = 0.45 (95% CI = 0.16-1.22)]. In Caucasians, ever smokers with one or more copies of the G allele were observed to have a significantly reduced risk of lung cancer. Control subjects with one or two copies of the G allele demonstrated more efficient DRC than did those with the homozygous A allele. Our data suggest that the XPA 5' non-coding region polymorphism modulates NER capacity and is associated with decreased lung cancer risk, especially in the presence of exposure to tobacco carcinogens.

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