| Summary: | 碩士 === 國立臺灣大學 === 臨床醫學研究所 === 99 === Background
Squamous cell carcinoma of the upper aerodigestive tract (UADT), including the malignancies of the oral cavity, pharynx, larynx and esophagus, is one of the most common cancers worldwide. Such malignancies are associated with the behaviors of alcohol consumption, cigarette smoking and betel quid chewing. They are with grave prognosis despite multidisciplinary therapies. Elucidation of carcinogenesis and development of novel strategies for cancer prevention and early detection are crucial for reducing the disease burden of these devastating diseases.
Aims
We aim to investigate the effects of genetic polymorphisms in alcohol-metabolizing enzymes on UADT cancer risk by haplotype tag single nucleotide polymorphisms (SNPs) approaching method, and to evaluate the gene-environmental interaction in Taiwanese population.
Methods
In this hospital-based case-control candidate gene study, 138 esophageal and 120 head and neck squamous cell carcinoma patients, and 276 controls without these malignancies after endoscopy evaluation were enrolled for study. Demographic and the status of carcinogen consumption were recorded by questionnaires. All study subjects received image-enhanced endoscopy for the evaluation of UADT cancers and blood sampling from peripheral veins. Utilizing the databases of the International HapMap Project and the National Center for Biotechnology Information, haplotype tag SNPs of the population Han Chinese in the three genes, alcohol dehydrogenase (ADH)-1B, ADH-1C, and aldehyde dehydrogenase(ALDH)-2 which have aggressive taggingγ2≧0.8 were selected for analysis. Screened SNPs were genotyped by the high throughput method, Sequenom MassARRAY system, with high resolution.
Results:
Lower body mass index, alcohol drinking, cigarette smoking, and betel quid chewing were independent risk factors for UADT cancers with the odds ratios (ORs) of 0.78 (95% confidence interval (CI) 0.70-0.86), 7.04 (95% CI 3.34-14.83), 5.56 (95% CI 2.70-11.47), and 12.46 (95% CI 4.65-33.39), respectively. Common haplotype GAGC (OR 1.61, 95% CI 1.08-2.41) of ADH1B and ADH1C genes on chromosome 4, and CCAATG (OR 1.69, 95% CI 1.24-2.30) of ALDH2 gene on chromosome 12 were found to increase UADT cancer risk. Risk alleles of ADH1B (rs1229984) and ALDH2 (rs671) were closely associated with UADT cancers. Similar effects were observed for both head and neck and esophageal cancers. Alcohol drinkers with risk alleles of ADH1B and ALDH2 had increased risk for UADT cancers with the ORs of 53.44 (95% CI 25.21-113.29) and 70.08 (95% CI 33.65-145.95) when compared with non-users without genetic risk factors. Without carcinogen exposure, carrying risk alleles were not associated with increased risk. Compared with subjects carrying ancestral alleles with carcinogens use, those carrying both risk alleles of ADH1B and ALDH2 with alcohol and/or cigarette and/or betel quid use had 10.36-fold (95% confidence interval (CI) 3.46-31.00, p <0.001) and 3.32-fold (95%CI 1.07-10.32, p= 0.038) increased risk for esophageal and head and neck cancers, respectively.
Conclusions:
Certain haplotypes in alcohol-metabolizing enzymes of ADH1B, ADH1C and ALDH2 were identified to be associated with increased risk of UADT cancers in Taiwanese. ADH1B and ALDH2 genotypes can modify the carcinogenesis effect among subjects with alcohol consumption. In this study, we efficiently screened the risk alleles in candidate genes by haplotype tag SNPs approaching method, and these findings, supported the concept of field cancerization in this cancer region.
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