| Abstract |
Carcinogenesis is a multi-stage process and the exposure to environmental chemicals plays an important role in it. A cornerstone of human chemical carcinogenesis is the concept of gene–environment interactions. Potential interindividual susceptibility to chemical carcinogenesis may well be defined by genetic variations in the host elements of this compound system. The functional polymorphisms of proteins, which have, or could have, a role in the chemical carcinogenesis, include the enzymes that metabolize (activate and detoxify) xenobiotics, the DNA-damage repair enzymes, the cell cycle control genes (ongogenes and tumor-suppressor genes). Maintenance of an appropriate balance between the phase I and II detoxification enzymes is required to ensure optimal cellular protection. Metabolic activity of both phase detoxification enzymes may be altered by genetic polymorphisms. P450s, phase I enzymes, metabolizing activate carcinogens in highly reactive intermediates, while GSTs, phase II enzymes, catalyze the conversion of reactive intermediates to inactive conjugates which are more water soluble and more readily excreted. The aim of this study was the determination and the comparison of the genetic polymorphisms frequencies of detoxification genes among greek lung cancer and breast cancer cases. It was observed that the frequencies of the genetic polymorphisms of detoxification genes, CYP1A1 MspI, GSTM1 and GSTT1 null deletions, in the Greek population are found in agreement with those that correspond in the Caucasian race. Genotyping analysis did not show any correlation to breast cancer risk. Expression of mRNA levels of CYP1A1, GSTM1, GSTP1, GSTT1 and AhR genes in 31 breast cancer patients, revealed inter-individual variation in an independent manner to patient age, genotype, or tumour stage. 87% of the tumour specimens tested was deregulated, compared to their normal counterparts, in at least one locus. Up regulation of CYP1A1 was observed only when one of the GSTM1 or GSTP1 was down regulated while the other remained constant. No alterations in gene copy number were observed which suggest that the deregulations of mRNA levels observed are due to transcriptional apparatus modifications. CYP1A1 was not correlated to AhR expression. Up regulation of CYP1A1 was observed only when one of the GSTM1 or GSTP1 was down regulated while the other remained constant. Considering their functional significance in the metabolism of a series of chemotherapeutic compounds and the variety of transcriptional patterns exhibited by different breast tumours in an independent manner to age, stage or grade, CYP1A1, AhR, GSTM1, GSTP1 and GSTP1 mRNA levels could be useful molecular biomarkers. Individuals with CYP1A1m1 genotype were at a higher risk for lung cancer, which is enhanced for the carriers of GSTM1(-) genotype, but with no association with GSTT1 genotype. Older individuals with two combined mutant genotypes were at high risk for lung cancer compared to younger ages and this is a result of the high exposure to toxic factors lifetime. Individuals with GSTT1(-) genotype and high exposure to occupational carcinogens were at an elevated risk for lung cancer. The frequency of GSTT(-) genotype was increased among heavy smokers, although the possible substrates of GSTT1 among components of tobacco smoke have not been totally identified. The high percentage of mutant CYP1A1 genotypes among heavy smokers is associated with its role as metabolic enzyme of aromatic hydrocarbons, while the frequency of CYP1A1m1 among non smokers shows that it participate in the metabolism of other toxic substances, where even low exposure to them could lead to increased susceptibility for lung cancer. When the cases stratified by histological type, different combined genotypes were at higher risk for each type. There was not observed association between the genotypes and the familial history. Individuals with COPD and GSTM1(-) genotype were at higher risk for lung cancer than those with old lung inflammation. Also patients with CYP1A1wt/m1 or m1 genotype presented higher sensitivity in the development of metastases. This differentiation that is observed in the frequencies of genetic polymorphisms is of a clinical importance with respect to treatment management of lung cancer patients.
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Προσδιορισμός και σύγκριση γενετικών συχνοτήτων των πολυμορφισμών των γονιδίων αποτοξίνωσης του κυττάρου στον καρκίνο του πνεύμονα
