Abstract
PurposeDeletion of Glutathione S-Transferase Theta 1 (GSTT1) encoding gene is implicated in breast cancer susceptibility, clinical outcomes, and survival. Contradictory results have been reported in different studies. The present investigation based on a representative Pakistani population evaluated the GSTT1-absent genotype in breast cancer risk and prognosis.MethodsA prospective study comprising case-control analysis and case series analysis components was designed. Peripheral blood samples were collected from enrolled participants. After DNA extraction, GSTT1 genotyping was carried out by a multiplex PCR with β-globin as an amplification control. Association evaluation of GSTT1 genotypes with breast cancer risk, specific tumor characteristics, and survival were the primary endpoints.ResultsA total of 264 participants were enrolled in the molecular investigation (3 institutions). The study included 121 primary breast cancer patients as cases and 143 age-matched female subjects, with no history of any cancer, as controls. A significant genetic association between GSTT1-absent genotype and breast cancer susceptibility (p-value: 0.03; OR: 2.13; 95% CI: 1.08-4.29) was reported. The case-series analysis showed lack of association of GSTT1 genotypes with menopause (p-value: 0.86), tumor stage (p-value: 0.12), grade (p-value: 0.32), and size (p-value: 0.07). The survival analysis revealed that GSTT1-absent genotype cases had a statistically significant shorter overall survival (OS) than those with the GSTT1-present genotype cases (mean OS: 23 months vs 33 months). The HR (95% CI) for OS in patients carrying GSTT1-absent genotype was 8.13 (2.91-22.96) when compared with the GSTT1-present genotype.ConclusionsThe present study is the first report of an independent significant genetic association between GSTT1-absent genotype and breast cancer susceptibility in a Pakistani population. It is also the foremost report of the association of this genotype with OS in breast cancer cases. Upon further validation, GSTT1 variation may serve as a marker for devising better population-specific strategies. The information may have translational implications in the screening and treatment of breast cancers.
Highlights
Glutathione is present in all living cells
We report a significant association of GSTT1-absent genotype with increased breast cancer risk in a representative sample from a Pakistani population
We report a significant difference in the survival duration between GSTT1-present and GSTT1-absent carriers: mean OSGSTT1-present: 33 months vs mean OSGSTT1-absent: 23 months
Summary
Glutathione is present in all living cells It performs three important functions: protection of thiol groups in proteins from oxidation, intracellular redox buffering, storage for sulphur-containing cysteine. These functions are dependent upon the catalysis by Glutathione S-Transferases (GSTs), E.C. 2.5.1.18. GSTs play a major role in the detoxification of potent endogenous and exogenous carcinogens [1] These enzymes constitute a superfamily of isoenzymes including GST- theta 1. GSTT1 gene is located on chromosome 22q11.2 It encodes the enzyme, which is involved in the conjugation of reduced glutathione to certain electrophiles and hydrophobic compounds [2]. Such toxic substrates may be removed from the body
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