P. Yang et al., Higher risk of mismatch repair-deficient colorectal cancer in alpha(1)-antitrypsin deficiency carriers and cigarette smokers, MOL GEN MET, 71(4), 2000, pp. 639-645
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 greater than or equal to 30% of the examin
ed loci and MSI-L by MSI at 1-30% of the loci. An absence of MSI at any exa
mined loci has been defined as a microsatellite stable (MSS) phenotype. Cur
rent data suggest the majority of MSI tumors are the result of defective DN
A mismatch repair (MMR), In this study, we have determined the alpha (1)-an
titrypsin deficiency carrier (alpha (1)ATD-ht) status of 161 CRC patients w
hose MSI phenotype and protein expression states had previously been determ
ined. Cases were selected to enrich a larger number of MSI-H cases. Among 5
1 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 o
f having MSI-H CRC among alpha (1)ATD-ht was 3.1 after adjusting for age, g
ender, 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 compa
red to nonsmokers who were homozygous normal at the alpha (1)ATD locus. Our
findings suggest an etiologic link between alpha (1)ATD alleles and develo
pment of CRC with defective MMR, and a synergistic effect between smoking a
nd alpha (1)ATD allele in the development of MSI-H CRC. (C) 2000 Academic P
ress.