Higher Risk of Mismatch Repair-Deficient Colorectal Cancer in α1-Antitrypsin Deficiency Carriers and Cigarette Smokers

Abstract Microsatellite instability (MSI) is a genomic alteration observed in 15–30% of colorectal cancer (CRC). Two MSI phenotypes have been defined for CRC: MSI-H is characterized by MSI at ≥30% of the examined loci and MSI-L by MSI at 1–30% of the loci. An absence of MSI at any examined loci has been defined as a microsatellite stable (MSS) phenotype. Current data suggest the majority of MSI tumors are the result of defective DNA mismatch repair (MMR). In this study, we have determined the α 1 -antitrypsin deficiency carrier (α 1 ATD-ht) status of 161 CRC patients whose MSI phenotype and protein expression states had previously been determined. Cases were selected to enrich a larger number of MSI-H cases. Among 51 CRC patients with MSI-H tumors, the α 1 ATD-ht rate was 21.6%; among 110 patients with MSI-L/MSS tumors, the rate was 9.1% (MSI-H vs MSI-L/MSS, P = 0.02); and among the 191 population-based controls the α 1 ATD-ht rate was 9.4% (MSI-H vs controls, P = 0.02). The estimated relative risk of having MSI-H CRC among α 1 ATD-ht was 3.1 after adjusting for age, gender, and smoking history. The risk of having MSI-H CRC among current and past smokers was 6.6 and 2.7, respectively. Patients who were α 1 ATD-ht and smoked had a 20-fold increased risk of developing an MSI-H CRC compared to nonsmokers who were homozygous normal at the α 1 ATD locus. Our findings suggest an etiologic link between α 1 ATD alleles and development of CRC with defective MMR, and a synergistic effect between smoking and α 1 ATD allele in the development of MSI-H CRC.