Genetic polymorphisms in xenobiotic clearance genes and their influence on disease expression in hereditary nonpolyposis colorectal cancer patients.
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 chi(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.
Talseth
Bente A
BA
Discipline of Medical Genetic, Faculty of Health, University of Newcastle and the Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
Meldrum
Cliff
C
Suchy
Janina
J
Kurzawski
Grzegroz
G
Lubinski
Jan
J
Scott
Rodney J
RJ
D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D020137:Base Pair Mismatch; D015179:Colorectal Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D004260:DNA Repair; D015972:Gene Expression Regulation, Neoplastic; D018095:Germ-Line Mutation; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D009154:Mutation; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D015262:Xenobiotics / Q000493:pharmacokinetics*
D015262:Xenobiotics; D004247:DNA; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D005982:Glutathione Transferase