Global Study on Genomic Instability of Male Oral Cancer in Taiwan (I)

Oral cancer (ICD 140141, 143146, 148149) is a very important cancer in Taiwan. According to 「Cancer Registry Annual Report Republic of China, 2001」 by Department of Health, the Executive Yuan, oral cancer is the fourth and fifth most common malignant neoplasm for males in incidence and mortality rate, respectively. After age adjustment, the incidence is much higher in males than in females with a sex ratio at 8.79. This difference could be attributed to the different prevalence of cigarette smoking, alcohol drinking and areca quid (AQ) chewing. The AQ used in Taiwan is different from that used in other countries. The AQ used in Taiwan contains areca (betel) nut, slaked lime, catechu, Piper betle inflorescence or Piper betle leaves. This combination is different from that consumed in other countries. Consequently, the mechanisms behind the AQ related oral cancer in Taiwan remains elusive. In Taiwan, about 90% of oral cancer cases were both AQ chewer and cigarette smoker. Therefore, it is not easy to discriminate the molecular mechanisms and the contributions of cigarette smoking and AQ chewing in the development of OSCC. With longlasting efforts to collect about 1000 male OSCCs from Chang Gung Memorial Hospital, it is possible for us to explore this aspect now. Recently, we reported an important contributive role for tobacco carcinogens in p53 mutation for a series of Taiwanese patients with oral squamous cell carcinomas (OSCCs) and OSCC patients with a Gln/Gln genotype exhibited a significantly higher frequency of p53 mutation than those with an Arg/Gln and an Arg/Arg genotype. In addition, we found that different p53 haplotypes of exon 4 intron 3 intron 6 affected the frequency of mutations and loss of heterozygosity (LOH) of the p53 gene in male OSCCs in Taiwan. In the genomic era, the one gene by one gene approach may not efficient enough to explore the complexity of tumor formation. Instead, a global view on tumor progression is necessary. Genomewide analysis techniques such as chromosome painting, comparative genomic hybridization (CGH), representational difference analysis, restriction landmark genome scanning and highthroughput analysis of LOH are now accelerating highresolution genome aberration localization in human tumors. These largescale genomic studies could identify the chromosomal locations of tumor suppressor genes and oncogenes for a specific human cancer type. We recently carried out a pilot study on the LOH of 30 male OSCCs associated with cigarette smoking and AQ chewing by a genomewide allelotyping approach and found that genomewide highthroughput analysis of LOH is a valuable approach for searching important tumor suppressor genes associated with the development of AQ and cigarette smokingassociated oral cancer (please refer to the progress report). Therefore, the specific aim of the present project is to globally search loci associated with male OSCCs independently contributed by exposure to cigarette smoking, AQ chewing or alcohol drinking in Taiwan by genomewide genotyping. By setting up the base for fine mapping region, we can further search the most probable candidate genes and then with large sample size to confirm the relationship between the frequency and patterns of some of the candidate genes and known environmental risk factors for oral cancer (including cigarette smoking, AQ chewing and alcohol drinking) in the future. Hopefully, the results obtained from this project will provide some global clues to the mechanisms of chemical carcinogenesis associated with oral cancer development in Taiwan.

Project ID:PC9706-0152
External Project ID:NSC95-2314-B182-049-MY3