Associations between null mutations in GSTT1 and GSTM1, the GSTP1 Ile105Val polymorphism, and mortality in breast cancer survivors

Catherine Duggan,Kathy B Baumgartner,Leslie Bernstein,Anne Mctiernan,Richard N Baumgartner,Rachel Ballard-Barbash

doi:10.1186/2193-1801-2-450

Abstract

PurposeHere we assessed associations between null mutations in glutathione-S-transferase (GST)T1 and GSTM1 genes, and the rs1695 polymorphism in GSTP1 (Ile105Val), and risk of breast cancer-specific (n=45) and all-cause (n=99) mortality in a multiethnic, prospective cohort of 533 women diagnosed with stage I-IIIA breast cancer in 1995–1999, enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study.MethodsWe measured the presence of the null mutation in GSTT1 and GSTM1, and the rs1695 polymorphism in GSTP1 by polymerase chain reaction. We assessed associations between breast-cancer specific and all-cause mortality using Cox proportional hazards models.ResultsParticipants with ER-negative tumors were more likely to be GSTT1 null (χ2=4.52; P=0.03), and African American women were more likely to be GSTM1 null (χ2=34.36; P<0.0001). Neither GSTM1 nor GSTT1 null mutations were associated with breast cancer-specific or all-cause mortality. In a model adjusted for body mass index, race/ethnicity, tumor stage and treatment received at diagnosis, the variant Val allele of rs1695 was associated with increased risk of all-cause (HR=1.81, 95% CI 1.16-2.82, P=0.008), but not breast cancer-specific mortality. The GSTT1 null mutation was associated with significantly higher levels of C-reactive protein.ConclusionsGSTM1 and GSTT1 null genotypes had no effect on outcome; however the variant allele of rs1695 appears to confer increased risk for all-cause mortality in breast-cancer survivors.Given the limited sample size of most studies examining associations between GST polymorphisms with breast cancer survival, and the lack of women undergoing more contemporary treatment protocols (treated prior to 1999), it may be helpful to re-examine this issue among larger samples of women diagnosed after the late 1990s, who all received some form of chemotherapy or radiotherapy.

Highlights

The Glutathione-S Transferases (GST) are a phase II superfamily of cytosolic, mitochondrial and microsomal enzymes that catalyze the conjugation of reduced glutathione to electrophilic centers on a variety of substrates (Strange et al 2001)
In two reports based on the same sample, women with breast cancer with null mutations for GSTM1 and GSTT1 had reduced risk of death compared to women with alleles present, (Ambrosone et al 2001) and a reduction in mortality risk for women homozygous for the variant GSTP1 Val allele compared to those homozygous for the Ile allele (Sweeney et al 2000; Yang et al 2005)
We extend prior research by examining the association between three different GST isoenzymes, and all-cause and breast-cancer specific mortality in a multi-ethnic cohort of breast cancer survivors drawn from population-based cancer registries

Summary

Introduction

The Glutathione-S Transferases (GST) are a phase II superfamily of cytosolic, mitochondrial and microsomal enzymes that catalyze the conjugation of reduced glutathione to electrophilic centers on a variety of substrates (Strange et al 2001). A limited number of studies with conflicting results have investigated the association between polymorphisms in GST genes and mortality in breast cancer patients. One other large study of 1034 women from Shanghai, China, all treated with adjuvant chemotherapy, found a reduction in risk with the variant GSTP1 Val allele but no association with either GSTT1 or GSTM1 and risk of death (Yang et al 2005). In two reports based on the same sample, women with breast cancer with null mutations for GSTM1 and GSTT1 had reduced risk of death compared to women with alleles present, (Ambrosone et al 2001) and a reduction in mortality risk for women homozygous for the variant GSTP1 Val allele compared to those homozygous for the Ile allele (Sweeney et al 2000; Yang et al 2005). 2 other small studies examined associations between one GST polymorphism among women treated with high dose chemotherapy, one reported no association between survival and GSTM1 null; (Lizard-Nacol et al 1999) another, that the GSTP1 Val/Val polymorphism was non-significantly associated with worse overall survival (Bewick et al 2008)

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