title: Higher risk of mismatch repair-deficient colorectal cancer in alpha(1)-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 > 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.
authors.affiliation: Department of Health Sciences Research, Department of Laboratory Medicine and Pathology, Department of Medical Genetics, Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905, USA. yang.ping@mayo.edu
authors.forename: P
authors.initials: P
authors.lastname: Yang
authors.forename: J M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: K C
authors.initials: KC
authors.lastname: Halling
authors.forename: T G
authors.initials: TG
authors.lastname: Lesnick
authors.forename: L J
authors.initials: LJ
authors.lastname: Burgart
authors.forename: E M
authors.initials: EM
authors.lastname: Wiegert
authors.forename: E R
authors.initials: ER
authors.lastname: Christensen
authors.forename: N M
authors.initials: NM
authors.lastname: Lindor
authors.forename: J A
authors.initials: JA
authors.lastname: Katzmann
authors.forename: S N
authors.initials: SN
authors.lastname: Thibodeau
mesh_terms: D000368:Aged; D000483:Alleles; D020137:Base Pair Mismatch / Q000235:genetics*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000145:classification / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D016017:Odds Ratio; D010641:Phenotype; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D000515:alpha 1-Antitrypsin / Q000235:genetics; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics*
chemical_list: D000515:alpha 1-Antitrypsin