Genomic Profiles in Tobacco Related Metastatic Oral Cancer
Initial Award Abstract
People who smoke tobacco are at risk for developing cancer of the mouth, including cancers of the tongue, gums and floor of mouth. Non-smokers can also get oral cancers; however smokers are six times more likely to develop these cancers. The five year survival rate at 40% is among the worst of all sites in the body and has not improved over the past 40 years. Cancers of the mouth or oral squamous cell carcinomas (oral SCC) typically spread to the lymph nodes in the neck, and at this stage survival is reduced further to as low as 25%. Therefore metastasis to the lymph nodes is the most important factor affecting survival of oral cancer patients. At present people with metastatic cancer are treated with major surgery where the cancer in the mouth and lymph nodes from the neck are removed. This is followed up with radiation and chemotherapy to try to prevent the cancer from recurring or developing in the neck. All these treatments are themselves associated with serious side effects that reduce the quality of life of oral cancer patients. There are currently no methods to predict oral cancer metastasis. Head and neck imaging have poor accuracy. Our goal, therefore, is to identify differences between cancers that can metastasize and those that do not in order develop tests to predict the behavior of the cancers and guide therapy.
To develop such markers of metastasis, we are studying the DNA of cancers using a technique called array comparative genomic hybridization (CGH). Cancer occurs due to the accumulation of genetic and genomic changes in tumor cells. We believe that the DNA of cancers that metastasize is different from the DNA of cancers that do not metastasize, and that these differences can help predict metastasis in a tumor. We also believe that DNA of smokers undergoes genomic changes that are different from those in non smokers. In addition, mutations in the gene TP53, a tumor suppressor gene that normally acts to restrain growth of cells, are more frequent in cancers from patients who smoke. The cancers with TP53 mutations also display different types of genomic alterations. These observations together suggest that oral cancers may acquire different genomic alterations during their development, which further suggests that the route to cancer may be different in smokers and non-smokers. To pursue our goal of identifying markers that distinguish between metastatic and non-metastatic cancers we have carefully assembled cancers from patients for whom we have extensive clinical and behavioral information, such as tobacco use. We will compare the genomic alterations in cancers from patients with metastasis to those without. Similarly, we will look for differences in the DNA of cancers from smokers and non-smokers. Finally, we will investigate whether different DNA markers distinguish metastatic cancers in smokers versus non-smokers. Because TP53 mutations are reported more often in the cancers of smokers, we will sequence the gene to identify mutations and determine whether tobacco smoking increases oral cancer mutations and metastasis.
Our study is important because it is proposing the use of genomic markers to detect metastasis, changes associated with smoking as well as TP53 mutations in the tumor DNA of oral cancer patients. This will help in establishing new and more accurate techniques of detecting metastasis, diagnosis and treatment planning and will eventually impact survival and prognosis. This study will also aid in better understanding the effect of smoking on the behavior of oral cancer. Ultimately the improved understanding and control of oral cancer and metastasis will help in reducing the burden of oral cancer and improve overall survival for its patients. |