Genetic polymorphisms of phase I and phase II metabolic enzymes as modulators of lung cancer susceptibility.
OBJECTIVE
Tobacco exposure remains the main etiologic factor for lung cancer (LC). Interactions between environment and individual genetic profile are particularly important for this disease. The aim of this study was to evaluate the contribution of CYP1A1*2A, CYP1A1*2C, CYP2D6*4, GSTP1, GSTM1, GSTT1 and NAT2 polymorphisms for the susceptibility to LC in a Portuguese population considering their demographic and clinical characteristics.


METHODS
A total of 200 LC and 247 controls subjects from the Centre of Portugal were studied. Clinical and demographic characteristics were collected from clinical files and by individual questionnaires. Polymorphisms of CYP1A1*2A, CYP1A1*2C, CYP2D6*4, GSTP1, GSTM1, GSTT1 and NAT2 were genotyped using PCR-RFLP, PCR multiplex, ARMS and real time.


RESULTS
Gender, family history of cancer, smoke cessation and alcohol consumption were independent risk factors (p < 0.05). Associations found between phases I and II genes and LC population reveal a sex dependent distribution. Logistic regression analysis demonstrates that enhanced activation by CYPs, associated by reduced or loss of function of phase II enzymes, can lead to a greater risk. GSTP1 and NAT2 polymorphisms studied have a significant contribution for the histological tumour types and the presence of metastases, at time of diagnosis, respectively, when males with smoking habits were considered.


CONCLUSIONS
Multiple interactions between environment and individual characteristics are clearly associated to this disease. Variants of the detoxification genes may act synergistically contributing to this disease and modifying the risk posed by smoking and sex. The GSTT1*0 and GSTP1 (Ile462Val) might contribute to the malignant phenotype through different mechanisms.
Unit of Medical Genetics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal, motapaula8@gmail.com.
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Soares
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Regateiro
D000328:Adult; D000368:Aged; D000428:Alcohol Drinking; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D016022:Case-Control Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011174:Portugal; D012307:Risk Factors; D012737:Sex Factors; D012907:Smoking / Q000009:adverse effects; D011795:Surveys and Questionnaires; D016019:Survival Analysis
D001191:Arylamine N-Acetyltransferase; D019363:Cytochrome P-450 CYP1A1; D019389:Cytochrome P-450 CYP2D6; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C569463:CYP1A1 protein, human; C478900:NAT2 protein, human; C413545:glutathione S-transferase T1; C496556:GSTP1 protein, human