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Genetic Polymorphisms in Xenobiotic Clearance Genes and Their Influence on Disease Expression in Hereditary Nonpolyposis Colorectal Cancer Patients

¹ Discipline of Medical Genetic, Faculty of Health, University of Newcastle and the Hunter Medical Research Institute; ² Division of Genetics, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, New South Wales Australia; and ³ Department of Genetics and Pathology, International Hereditary Cancer Center, Szczecin, Poland

Requests for reprints: Rodney J. Scott, Hunter Area Pathology Service, John Hunter Hospital, Lookout Road, New Lambton Heights, Newcastle, New South Wales 2305, Australia. Phone: 61-2-4921-4974; Fax: 61-2-4921-4253. E-mail: rodney.scott{at}newcastle.edu.au

Background: Hereditary nonpolyposis colorectal cancer (HNPCC) is associated with germ-line mutations in DNA mismatch repair genes. There is considerable variation in disease expression that cannot be explained by genotype/phenotype correlation, which is likely to be the result of polymorphic modifier genes. One candidate group of modifiers is the xenobiotic clearance enzyme genes that encode CYP1A1, GSTM1, GSTT1, GSTP1, and NAT2. Alterations in these xenobiotic clearance genes can potentially influence the host response to carcinogen exposure and thereby alter cancer risk. We have investigated eight polymorphisms in xenobiotic clearance genes to assess the effect on the risk of disease in mutation positive HNPCC patients.

Methods: DNA samples from 220 mutation-positive HNPCC participants (86 Australian and 134 Polish) were genotyped for single nucleotide polymorphisms (SNP) in CYP1A1, GSTM1, GSTT1, GSTP1, and NAT2. The association between the SNPs and disease characteristics, disease expression and age of diagnosis of colorectal cancer (CRC), was tested with Pearson's ² and Kaplan-Meier survival analysis.

Results: The HNPCC population displays a significant difference in the genotype frequency distribution between CRC patients and unaffected mismatch repair gene mutation carriers for the CYP1A1 SNP where the CRC patients harbor more of the mutant genotype.

Conclusions: Evidence from this study is not conclusive, but our data suggest that the CYP1A1 influences disease expression in individuals with HNPCC. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2307–10)