Polymorphism in glutathione S -transferase P1 is associated with susceptibility to chemotherapy-induced leukemia

Abstract

Glutathione S -transferases (GSTs) detoxify potentially mutagenic and toxic DNA-reactive electrophiles, including metabolites of several chemotherapeutic agents, some of which are suspected human carcinogens. Functional polymorphisms exist in at least three genes that encode GSTs, including GSTM1, GSTT1, and GSTP1. We hypothesize, therefore, that polymorphisms in genes that encode GSTs alter susceptibility to chemotherapy-induced carcinogenesis, specifically to therapy-related acute myeloid leukemia (t-AML), a devastating complication of long-term cancer survival. Elucidation of genetic determinants may help to identify individuals at increased risk of developing t-AML. To this end, we have examined 89 cases of t-AML, 420 cases of de novo AML, and 1,022 controls for polymorphisms in GSTM1, GSTT1, and GSTP1 . Gene deletion of GSTM1 or GSTT1 was not specifically associated with susceptibility to t-AML. Individuals with at least one GSTP1 codon 105 Val allele were significantly over-represented in t-AML cases compared with de novo AML cases [odds ratio (OR), 1.81; 95% confidence interval (CI), 1.11–2.94]. Moreover, relative to de novo AML, the GSTP1 codon 105 Val allele occurred more often among t-AML patients with prior exposure to chemotherapy (OR, 2.66; 95% CI, 1.39–5.09), particularly among those with prior exposure to known GSTP1 substrates (OR, 4.34; 95% CI, 1.43–13.20), and not among those t-AML patients with prior exposure to radiotherapy alone (OR,1.01; 95% CI, 0.50–2.07). These data suggest that inheritance of at least one Val allele at GSTP1 codon 105 confers a significantly increased risk of developing t-AML after cytotoxic chemotherapy, but not after radiotherapy.

Secondary hematopoietic malignancies in survivors of childhood cancer

“…were related to secondary leukemia. 13,27 Also, the presence of germ line mutations such as those of p53 (Li-Fraumeni syndrome) may underlie the occurrence of primary cancers and secondary ALL, 28 whereas those of ataxia-telangiectasia gene are specifically associated with T-cell lineage ALL. 29 Likewise, somatic PTPN11 mutations, similar to those present in Noonan syndrome, underlie the risk of lymphoid malignancies.…”

“…For example, the presence of certain polymorphisms in detoxifying enzymes is associated with increased risk of secondary AML. 12,13 Most previous studies have analyzed all types of secondary malignancies, 14,15 but there are few comprehensive large-scale studies specifically on secondary hematological malignancies. Furthermore, most reports on secondary hematological malignancies focus on second leukemias only.…”

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Subsequent Neoplasms Working Group Report

“…Initial studies on inter-individual variability in risk of tMDS/AML using a candidate gene approach have identified common polymorphisms in low penetrance genes that regulate the availability of active drug metabolite or those responsible for DNA repair. Associations have been observed for glutathione S-transferase genes ( GSTM1 , GSTT1 and GSTP1 ), particularly among those with prior exposure to chemotherapeutic agents that are known GSTP1 substrates, 144 and for P-glycoprotein (encoded by MDR1 ), a cell membrane protein that impacts response to numerous chemotherapeutic agents. 145 A number of studies also have evaluated key DNA repair genes, including mismatch repair family members MLH1 146,147 and MSH2 , 148,149 RAD51 , 150 and XRCC3 .…”

Association between GSTP1 Genotypes and Hormone Receptor Phenotype in Invasive Ductal Carcinomas of Breast

“…The coding gene of glutathione S-transferase pi-class (GSTP1) is located on chromosome 11q13. GSTP1 polymorphism may affect the function of enzymes and decreased enzyme activity (Allan et al, 2001). Since a broad panel of organs including placenta, prostate, colon, breast, esophagus, brain, spleen and lung express GSTP1 consistently in their tissues (Welfare et al, 1999), and a wide range of precancerous and neoplastic growths have been shown to overexpress GSTP1, which propose a conceivable GSTP1 polymorphism association in breast cancer etiology (Joanne et al, 2000).…”