In 1995 some 40,000 new patients were expected to develop oral or laryngeal squamous cell carcinomas; over 12,000 of them will succumb to that disease. The impact of these cancers becomes even more apparent when one considers the anatomic structures at risk from these tumors, for example, the larynx and the tongue. In addition, these patients are at a significant risk of developing a second head and neck tumor if they are cured of the first. Although aggressive new combinations of surgery and radio- or chemotherapy are being developed in response to this challenge, these new therapies have their own risk of morbidity. Accurate treatment planning is predicated on being able to identify those patients whose cancers will require such aggressive treatment and those who do not. At present, this assessment is based largely on traditional clinical parameters such as the anatomic location, size of the primary tumor, and the presence or absence of metastasis. These parameters do not address the biological properties of individual tumors, and consequently cannot readily distinguish between indolent and aggressive tumors with a given clinical stage. Furthermore, they cannot predict likely responses to adjuvant treatments such as radiation or chemotherapy. One possible solution to this problem is to develop molecular probes which, by detecting genetic changes in tumor cell DNA, can make these predictions. Much attention has been focused on tumor suppressor genes which restrain the growth of normal cells. Work in their laboratory demonstrates that patients whose supraglottic laryngeal tumors have inactivated putative tumor suppressor genes on chromosomes 8p or 13q have a significantly elevated risk of dying of cancer than patients without genetic lesions in these chromosomal regions. This is exemplified by the fact that half of the patients whose tumors have these genetic alterations die within 2.5 years of presentation, a period 4 times shorter than patients whose tumors do not. The proposed experiments will rigorously test the predictive power of these genetic markers by analyzing a new and larger population of laryngeal cancer patients. Additional experiments will refine the current localization of the 3 putative tumor suppressor genes on 8p and begin to map the location of the 13q suppressor as well as investigating when these alterations occur during progression. These probes will provide an essential part of a tumor staging system based on the biological as well as clinical properties of tumors, and the genes identified by the mapping studies may have eventual therapeutic value.
