Frequency of glutathione S-transferase M1 deletion in smokers with emphysema and lung cancer.

1. Genetic variation at the glutathione S-transferase M1 locus (GSTM1) has been associated with a number of apparently unrelated cancers, including lung cancer. Emphysema is a common lung disease often found concomitant with lung cancer. Both emphysema and lung cancer may result from chemical and oxidative damage caused by reactive species present in cigarette smoke or released from neutrophils recruited following cigarette smoke induced injury. GSTM1 may protect against such damage through detoxification of cigarette smoke components. Polymorphism of this gene may thus influence susceptibility not just to lung cancer, but to other forms of lung disease. 2. Resection specimens from a group of 168 lung cancer patients were assessed for the presence of macroscopic centriacinar and panacinar emphysema. DNA was extracted from archival material and genotyped for the GSTM1 polymorphism using the polymerase chain reaction. A control group of 384 anonymous blood donations was used to determine the frequency of the GSTM1 gene deletion in a random control population. Reverse transcription on lung tissue was performed to investigate mRNA expression of GSTM1 and GSTM4. 3. In 57 lung cancer cases with no emphysema there was no association with homozygous deletion of the GSTM1 gene (51% null in cancer and 53% null in control groups). However in 111 patients with emphysema and lung cancer there was an increase in the frequency of deletion (65%, P = 0.032) giving an odds ratio of 1.36(0.32-2.40). In 43 cases there was evidence of both centriacinar and panacinar emphysema. The frequency of GSTM1 deletion was 70% (Odds ratio 2.11, 0.97-3.25). Both GSTM1 and GSTM4 mRNAs were expressed in lung tissue. 4 These findings suggest that GSTM1 has a general but rather small protective effect against toxicological injury in the lung which is not specific to cancer. This is of relevance in considering the health effects of exposure to a wide range of reactive chemicals in the environment.

Association between the CYP1A1 gene polymorphism and susceptibility to emphysema and lung cancer.

Aim-To investigate cytochrome P4501A1 (CYP1A1) polymorphism and susceptibility to emphysema and lung cancer.Methods-A novel polymerase chain reaction (PCR) for genotyping the CYP1A1 polymorphism, corresponding to putative low or high enzyme activity, was developed to genotype lung cancer resection samples which had been assessed macroscopically for the presence of centriacinar and panacinar emphysema. Samples were collected and genotyped from a group of patients with chronic obstructive airways disease. A control group of anonymous blood donations was genotyped to determine the basal levels of the polymorphism in the Scottish population.Results-The high activity allele of the CYP1A1 gene is associated with susceptibility to centriacinar emphysema and lung cancer but not panacinar emphysema. CYP1A1 polymorphism is not linked to lung cancer in the absence of emphysema, nor to chronic obstructive airways disease which is the clinical manifestation of emphysema, particularly of the panacinar type.Conclusions-Susceptibility to emphysema and lung cancer is associated with polymorphism of the P4501A1 gene. A trend towards damage of centriacinar pattern has been detected, which supports the theory that centriacinar emphysema results from local, direct damage to the respiratory bronchioles from exposure to cigarette smoke.

Heterogeneous expression and polymorphic genotype of glutathione S-transferases in human lung.

BACKGROUND: Glutathione S-transferases (GSTs) are involved in the detoxification of xenobiotics by conjugation with glutathione. One of the mu class genes of this superfamily of enzymes, GSTM1, is polymorphic because of a partial gene deletion. This results in a failure to express GSTM1 in approximately 50% of individuals. Several studies have linked GSTM1 null status to an increased risk of lung carcinoma. This study investigated the expression and distribution of GST isoenzymes in human lung, and developed a polymerase chain reaction (PCR) assay which would allow genotyping of archival, paraffin embedded lung tissue. METHODS: Distribution was examined using a panel of polyclonal anti-GST antibodies for immunohistochemistry in normal tissue of 21 tumour-bearing lungs. DNA for PCR was extracted from paraffin blocks and a control group of 350 blood lysates. As a positive control each assay amplified part of GSTM4, a mu class gene which is not polymorphic but which shows strong sequence homology to GSTM1. The presence of GST in bronchoalveolar lavage fluid was sought by Western analysis. RESULTS: Proximal airways contained pi class GST, alpha class GST, and mu class GST with expression concentrated in the brush border. In distal airspaces no alpha GST was expressed but pi GST and mu GST were present in alveolar cells and also alveolar macrophages. Pi class GST was present in bronchoalveolar lavage fluid. The PCR assay enabled genotypic determination using DNA extracted from archival material. Of the control group 56% were null at the GSTM1 locus. CONCLUSIONS: The distribution of GST isoenzymes in the lung is heterogeneous with an apparent decrease in GST in distal lung. Since GSTM1 status has already been associated with susceptibility to disease, the PCR assay developed will allow further studies of the relation between genotype and structural disorders in the lung using archival pathological material.