DNA repair polymorphisms, smoking, and microsatellite instability in colon cancer.

B195

Genetic variation in DNA repair genes may contribute to higher risk of sporadic colon cancer with microsatellite instability (MSI), particularly in combination with DNA damaging agents such as tobacco smoke. Using data from sporadic colon cancer cases (n=503) in a population-based study, we examined the association between mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER) gene polymorphisms and MSI. We also assessed whether this association was modified by smoking. Methods: Study participants were case subjects enrolled in the North Carolina Colon Cancer Study (NCCCS) who were identified through the NC cancer registry. Consenting subjects provided information about lifestyle and diet during in-home interviews, blood specimens and tumor blocks. Genotyping for four MMR genes, eight BER genes and five NER genes was performed using a multiplex PCR assay. Homozygous variants and heterozygotes were grouped together [dominant model] and compared with the homozygous wildtype . DNA from normal and tumor tissue sections was used to determine microsatellite status. Tumors were classified as MSI-H if 2 or more markers from the NIH reference panel (BAT25, BAT26, D5S346, D2S123 and D17S250) contained changes in the number of DNA sequence repeats compared to matched non-tumor tissue. Tumors with one positive marker (MSI-low) or no positive markers (MSS) were grouped together as non-MSI tumors. Smokers were classified as ever smokers or never smokers. Logistic regression was used to calculate odds ratio (OR) and 95% confidence intervals (CI). Results: The frequency of MSI-H tumors was ten percent (n=49). Smoking was positively associated with microsatellite instability (OR=3.2, 95% CI=1.5, 6.7). Four of the five NER genes showed a positive association with MSI-H status with one of them (RAD23B A249V) being statistically significant (OR=2.5, 95% CI=1.3, 4.9). There was a significant positive dose-response relationship between the number of variant alleles in the NER genes and MSI high status (P trend = 0.04). We found non-significant inverse associations between MMR and BER gene polymorphisms and MSI. Overall, there was no significant additive interaction between the DNA repair genes and smoking on MSI status. Conclusions: Smoking strongly predicts elevated risk of MSI tumors. Our results suggest that MMR and BER gene polymorphisms may not be associated with MSI but NER gene polymorphisms may increase the risk of MSI tumors.