Relationship between glutathione S-transferase M1, T1, and P1 polymorphisms and chronic lymphocytic leukemia

Abstract

Interindividual differences in susceptibility to hematologic malignancies may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. The glutathione S-transferases (GSTs) have been implicated as susceptibility genes in this context for a number of cancers. The aim of this study was to examine whether polymorphic variation in GSTs confers susceptibility to chronic lymphocytic leukemia (CLL). GSTM1, GSTT1, and GSTP1 genotypes were determined in 138 patients and 280 healthy individuals. The frequency of both GSTM1 and GSTT1 null genotypes and the GSTP1-Ile allele was higher in cases than in controls. There was evidence of a trend in increasing risk with the number of putative "high-risk" alleles of the GST family carried (P ‫؍‬ .04). The risk of CLL associated with possession of all 3 "high-risk" genotypes was increased 2.8-fold (OR ‫؍‬ 2.8, 95% confidence interval: 1.1-6.9). Our findings suggest that heritable GST status may influence the risk of developing CLL. IntroductionB-cell chronic lymphocytic leukemia (CLL) is the most common form of leukemia, accounting for around 30% of all cases. 1 There is increasing evidence that predisposition to CLL involves both inherited and environmental factors. 2,3 It is likely that part of the inherited susceptibility to CLL may be determined by interindividual differences in the bioactivation of procarcinogens and detoxification of carcinogens.The glutathione S-transferases (GSTs) are a superfamily of genes whose products are phase II enzymes, catalyzing the conjugation of reactive intermediates to soluble glutathione. 4 GSTM1 and GSTP1 detoxify carcinogenic polycyclic aromatic hydrocarbons such as benzo-(a)pyrene, whereas GSTT1 is responsible for the detoxification of smaller reactive hydrocarbons, such as ethylene oxide. 4 Differences in the activities of some GSTs are determined by genetic polymorphisms. 4 GSTM1 activity is absent in ϳ50% of whites as a consequence of the inheritance of 2 null alleles (deletion of the gene). Similarly, GSTT1 activity is deficient in ϳ20% of whites, resulting from homozygous deletion. The GSTP subfamily comprises only GSTP1. The 1578AϾG substitution in GSTP1 creates the Ile105Val polymorphism that leads to expression of an enzyme with reduced activity. 4 There is epidemiologic evidence that exposure to aliphatic hydrocarbons and chlorinated hydrocarbons plays a role in the etiology of CLL. 3,[5][6][7][8] This, coupled with the proposed role of GSTs in the etiology of a number of common cancers 9 provides a strong rationale for evaluating GSTM1, GSTT1, and GSTP1 polymorphisms as risk factors for CLL. Study design PatientsBlood samples were obtained from 138 white patients (62% male; 38% female; mean age at presentation 54 years, SD: 12) with B-cell CLL referred to the Royal Marsden Hospital NHS Trust. The diagnosis of CLL was based on standard hematologic and immunologic criteria. The proportion of patients with Binet stages A, B, and C were 58%, 14%, and 28%, respectively. Median white c...

Cigarette Smoking and Risk of Non-Hodgkin's Lymphoma—A Population-Based Case-Control Study

“…A potential etiologic role of the polymorphism has also been suggested for non-Hodgkin's lymphoma in some studies (50)(51)(52)(53). Furthermore, it is noteworthy that GST polymorphisms have been identified as a prognostic factor in pediatric non-Hodgkin's lymphoma (54) and as a risk factor for chronic lymphocytic leukemia (55). The latter association is interesting as several epidemiologic studies have shown that patients with chronic lymphocytic leukemia have an increased risk of smoking-related malignancies such as cancers of the lung, urinary bladder, and larynx (56-58).…”

Nullity of GSTT1/GSTM1 related to pesticides is associated with Parkinson's disease

“…GST detoxified agents are, for example, polycyclic aromatic hydrocarbons, which may be found in pesticides 11 . Therefore, individuals with null genotype for GSTM1 and GSTT1 have a higher risk for oxidative stress associated diseases 12,29 , including PD 10,16 . However, there is little research on this matter, and even less on Brazilian individuals.…”

Polymorphisms in xenobiotic‐metabolizing genes and the risk of chronic lymphocytic leukemia and non‐Hodgkin's lymphoma in adult Russian patients

“…For instance, Yuille et al [30] tested 138 adult B-CLL patients and 280 normal controls to demonstrate a 1.3 times higher frequency of the GSTM1 null genotype in the former group than in the latter (95% CI 5 0.8-1.9).…”

“…Thus, it would be interesting to investigate associations between polymorphous variants of xenobiotic-metabolizing genes and risk of development of other lymphoproliferative diseases. The data concerning B-CLL and NHL susceptibility regarding xenobiotic-metabolizing genes status are limited and sometimes contradictory [26][27][28][29][30][31][32]. There might be gender-specific and subtype-specific associations that require further investigations.…”