Selection of appropriate anticancer therapy is critically dependent on an accurate prediction of the clinical behavior of individual neoplasms. In squamous cell carcinoma of the head and neck, this assessment is based largely on 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, this staging system cannot predict likely responses to adjuvant treatments such as radiation or chemotherapy. The importance of more powerful biologic diagnostic tools becomes obvious given that 50,000-60,000 patients present with head, neck and upper esophageal cancer each year, and that 40% of these patients will die of their disease within 5 years. Despite the significant morbidity and mortality caused by these tumors, relatively little is known about their progression at the molecular level. This study will provide molecular biological data needed to develop more accurate diagnostic and prognostic tools. We will identify tumor suppressor genes whose mutation contributes to the disease process by detecting chromosomal deletions and rearrangements that result in the loss of the remaining wildtype allele of that gene. These chromosomal alterations manifest themselves through the use of heterozygosity for highly polymorphic genetic marker loci. We will detect these losses through the use of a relatively new molecular genetic mapping technique: polymerase chain reaction-based analysis of simple sequence repeat polymorphisms. Our findings will be correlated with patient outcome data to determine which chromosome losses have significant prognostic and diagnostic power. These findings will, in turn, form the basis for two longer term projects: 1) the high resolution mapping and eventual cloning of genes involved in squamous cell carcinoma progression, and 2) the development of molecular probes useable in clinical pathology laboratories. 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.
