To the Editor: I read with interest the recent publication by Reding et al. on “Genetic polymorphisms in the catechol estrogen metabolism pathway and breast cancer risk” (CEBP 2009; 18:1461–7), which examined polymorphisms in five genes including GSTM1 and GSTT1 and found no association with the latter two genes. I was disappointed to see yet another study of GSTM1 and GSTT1 null “genotypes” using inadequate methodology from 1993 and 1995, respectively (1, 2). These methods have as a basic analytic flaw that they do not positively identify the null allele and therefore cannot distinguish homozygous wild-type +/+ from heterozygous +/− individuals (3). True genotyping is important because of the gene dosage effect associated with having two, one, or no alleles (4, 5). New methods using either long-range PCR or real-time PCR are available to definitively identify +/+, +/−, and −/− genotypes (6, 7). An example of the scientific advantage of this unambiguous genotyping is provided by an investigation published in CEBP (8), which showed that associations between colorectal adenomas and GSTM1 wild-type and GSTT1 null alleles only became apparent with a real-time PCR assay that distinguished heterozygous from wild-type individuals. Another example is a recent study (9) of GSTM1 in breast cancer, which used real-time PCR to reveal a more complicated association between GSTM1 allele numbers and risk than would be apparent by using older methods.
In view of the importance of glutathione S-transferases in cellular detoxification, the enzyme deficiency associated with the GSTM1 and GSTT1 null genotypes has attracted considerable attention with regard to cancer epidemiology. A search of the literature through 2008 listed over 600 studies of GSTM1 and GSTT1 genotypes in relation to lung, breast, colon, brain, and various other types of cancer. Nearly all these studies including the current one have used old methodology (1, 2) and, not surprisingly, obtained confusing data, which resulted in inconsistent or contradictory publications on the association of the GSTM1 and GSTT1 genotypes with various malignancies. With respect to glutathione S-transferases studies, the field of molecular epidemiology will not advance unless investigators use state-of-the-art genotyping methods such as long-range or real-time PCR.
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