Higher risk of mismatch repair-deficient colorectal cancer in alpha(1)-antitrypsin deficiency carriers and cigarette smokers

Mol Genet Metab. 2000 Dec;71(4):639-45. doi: 10.1006/mgme.2000.3089.


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 > or =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 alpha(1)-antitrypsin deficiency carrier (alpha(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 alpha(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 alpha(1)ATD-ht rate was 9.4% (MSI-H vs controls, P = 0.02). The estimated relative risk of having MSI-H CRC among alpha(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 alpha(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 alpha(1)ATD locus. Our findings suggest an etiologic link between alpha(1)ATD alleles and development of CRC with defective MMR, and a synergistic effect between smoking and alpha(1)ATD allele in the development of MSI-H CRC.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Alleles
  • Base Pair Mismatch / genetics*
  • Case-Control Studies
  • Colorectal Neoplasms / classification
  • Colorectal Neoplasms / genetics*
  • DNA Repair / genetics*
  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Immunohistochemistry
  • Logistic Models
  • Male
  • Microsatellite Repeats / genetics
  • Odds Ratio
  • Phenotype
  • Risk Factors
  • Smoking / adverse effects*
  • Trinucleotide Repeat Expansion / genetics
  • alpha 1-Antitrypsin / genetics
  • alpha 1-Antitrypsin Deficiency / genetics*


  • alpha 1-Antitrypsin