Higher risk of mismatch repair-deficient colorectal cancer in α1-antitrypsin deficiency carriers and cigarette smokers

Ping Yang, Julie M. Cunningham, Kevin C. Halling, Timothy G. Lesnick, Lawrence J. Burgart, Elaine M. Wiegert, Eric R. Christensen, Noralane M. Lindor, Jerry A. Katzmann, Stephen N. Thibodeau

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


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 α1-antitrypsin deficiency carrier (α1ATD-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 α1ATD-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 α1ATD-ht rate was 9.4.% (MSI-H vs controls, P = 0.02). The estimated relative risk of having MSI-H CRC among α1ATD-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 α1ATD-ht and smoked had a 20-fold increased risk of developing an MSI-H CRC compared to nonsmokers who were homozygous normal at the α1ATD locus. Our findings suggest an etiologic link between α1ATD alleles and development of CRC with defective MMR, and a synergistic effect between smoking and α1ATD allele in the development of MSI-H CRC.

Original languageEnglish (US)
Pages (from-to)639-645
Number of pages7
JournalMolecular genetics and metabolism
Issue number4
StatePublished - 2000


  • Case-control study
  • Cigarette smoking
  • Colorectal cancer
  • Microsatellite instability
  • Mismatch repair
  • α-antitrypsin deficiency

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology


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