title: Relationship between glutathione S-transferase M1, P1 and T1 polymorphisms and early onset prostate cancer.
abstract: There is evidence suggesting that polymorphic variations in the glutathione S-transferases (GSTs) are associated with cancer susceptibility. Inter-individual differences in cancer susceptibility may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. The GSTs have been consistently implicated as cancer susceptibility genes in this context. The GST supergene family includes several loci with well characterized polymorphisms. Approximately 50% of the Caucasian population are homozygous for deletions in GSTM1 and approximately 20% are homozygous for deletions in GSTT1, resulting in conjugation deficiency of mutagenic electrophiles to glutathione. The GSTP1 gene has a polymorphism at codon 105 resulting in an Ile to Val substitution which consequently alters the enzymatic activity of the protein and this has been suggested as a putative high-risk genotype in various cancers. We investigated the relationship between GST polymorphisms and young onset prostate cancer in a case-control study. GSTM1, GSTT1 and GSTP1 genotypes were determined for 275 prostate cancer patients and for 280 geographically matched control subjects. We found no significant difference in the frequency of GSTM1 or GSTT1 null genotypes between cases and controls. GSTP1 genotype was, however, significantly associated with prostate cancer risk: the Ile/Ile homozygotes had the lowest risk and there was a trend in increasing the risk with the number of 105 Val alleles: Ile/Val odds ratio (OR)= 1.30 (95% FCI 0.99-1.69), Val/Val OR = 1.80 (95% FCI 1.11-2.91); Ptrend = 0.026. These results suggest that the GSTP1 polymorphism may be a risk factor for developing young onset prostate cancer. We also found that carrying more than one putative high-risk allele in the carcinogen metabolizing GST family was associated with an elevated risk for early onset prostate cancer (OR 2.48, 95% FCI 1.22-5.04, Ptrend = 0.017).
authors: Section of Cancer Genetics, The Institute of Cancer Research and Royal Marsden NHS Trust, Sutton, Surrey, UK. z.jarai@icr.ac.uk
authors: Z
authors: Z
authors: Kote-Jarai
authors: D
authors: D
authors: Easton
authors: S M
authors: SM
authors: Edwards
authors: S
authors: S
authors: Jefferies
authors: F
authors: F
authors: Durocher
authors: R A
authors: RA
authors: Jackson
authors: R
authors: R
authors: Singh
authors: A
authors: A
authors: Ardern-Jones
authors: A
authors: A
authors: Murkin
authors: D P
authors: DP
authors: Dearnaley
authors: R
authors: R
authors: Shearer
authors: R
authors: R
authors: Kirby
authors: R
authors: R
authors: Houlston
authors: R
authors: R
authors: Eeles
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D019943:Amino Acid Substitution; D001483:Base Sequence; D016022:Case-Control Studies; D017931:DNA Primers / Q000235:genetics; D005838:Genotype; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000172:deficiency / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics*; D012307:Risk Factors; D017384:Sequence Deletion
chemical_list: D017931:DNA Primers; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007527:Isoenzymes; C413545:glutathione S-transferase T1; C496556:GSTP1 protein, human