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

Citation
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
Citations number
29
Categorie Soggetti
Molecular Biology & Genetics
Journal title
MOLECULAR GENETICS AND METABOLISM
ISSN journal
10967192 → ACNP
Volume
71
Issue
4
Year of publication
2000
Pages
639 - 645
Database
ISI
SICI code
1096-7192(200012)71:4<639:HROMRC>2.0.ZU;2-9
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 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.