Defining the Sketchy Blueprints of Nuclear and Mitochondrial Cancer Genome in Taiwanese Male Oral Squamous Cell Carcinoma

Oral squamous cell carcinoma (OSCC) is the most rapidly raising male cancer in Taiwan. The incidence rate has increased 18% from 2001 to 2005. In 2005, OSCCs was the fourth most common cancer in males. In spite of improvements in surgical and radiotherapy treatment, the 5-year survival rate for oral cancer has remained almost unchanged at about 50% for the past 30 years. The most important determinant of a poor outcome within the first 2 years after treatment of the primary tumor is a high recurrence rate for primary tumors or the presence of a second primary tumor; these are often difficult cases involving radical surgical resectioning and resistance to radiotherapy or chemo-radiotherapy. Prediction of tumor behavior, such as metastatic potential and response to different treatments, would enable a more individualized approach by selecting the optimal treatment. To date, the most important factors predicting outcome of OSCC are tumor volume, grade and TNM stage. However, neither biologic behavior nor response to therapy can be fully explained by these factors. Thus, there remains an urgent need to find better ways to predict outcome and aid treatment choice for individual patients. It is widely accepted that cancer is a genetic disease caused by accumulation of alterations in specific genes. With improvements in technologies, there are several means to study DNA alterations on a genome-wide scale, including array CGH with very high genome resolution, transcriptome analysis, new methylation detection systems, and single-molecule sequencing technologies. The Johns Hopkins group and The Cancer Genome Atlas (TCGA) group had initiated these integrated genomic analyses to discover major cancer-causing genome alterations in pancreatic and brain tumors. Besides nuclear genome, defects in mitochondrial function have long been suspected to contribute to the development and possibly progression of cancer. Recently, several cancer-related mitochondrial alterations have been identified and mutant mitochondria have been further shown to be positively and directly contribute to tumorigenesis. Taken together, nuclear and mitochondrial cancer genome profiling will have important applications in pinpointing new targets, discovering resistance mutations to existing therapies, and discovering both positive and negative genomic predictors of response to specific therapies. Although the high-throughput integrated genomic analyses are fascinating, it is not possible for a laboratory with low financial resource and limited personnel to carry out these comprehensive analyses simultaneously. Thus, a stepwise genome-wide approach to define sketchy blueprints of nuclear and mitochondrial cancer genome in Taiwanese OSCC is adopted. The specific aims of this 3-year project are: 1) characterization of mitochondrial genomic mutations by OSCC phenotype (including TNM stage, tumor size, clinical outcome and status of p53 mutation), 2) validation of amplified region 8q based on the preliminary findings from the copy number analysis, and 3) fine mapping of MDR region c01r1, c02r1, c04r2 and c19r2 based on the preliminary findings from the LOH analysis using microsatellite MD10 markers. We expect that the results obtained from this project will define some global clues to the mechanisms of chemical carcinogenesis associated with oral cancer development in Taiwan. In addition, these systematic genomic studies will provide a road map for the long-term management of OSCC in Taiwan.

Project ID:PC9808-1027
External Project ID:NSC98-2314-B182-046-MY3