In 2000, some 40,000 new patients are 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 that some of the anatomic structures at risk from these tumors, the larynx and the tongue, are vital to the normal mechanisms of human speech and swallowing. These patients are at a significant risk of recurrence of the original tumor as well as the eventual development of a second primary cancer. Identifying patients who require aggressive but potentially morbid new therapies requires an accurate means of predicting tumor behavior, something the current assessment tools cannot do. One solution to this problem is to develop molecular probes, which by detecting genetic changes in tumor cell DNA, can make these predictions. A combination of allelic loss and homozygous deletion mapping has led to a less than 190 kb interval of chromosomal band 8p23.2 that appears to contain a tumor suppressor or progression gene whose inactivation is correlated with a poor clinical course. Allelic losses in this region are associated with early recurrence of the index tumor and an increased frequency of cancer related death. Work from other labs suggests that this putative suppressor is also inactivated in prostatic adenocarcinomas and possible ovarian and hepatocellular cancers. The applicant has built a transcript map from his BAC contig and found that there is only 1 gene within this region expressed in upper aerodigestive tract epithelium. This gene is expressed as a large low abundance message in epithelium, 8.5 kb of which we have now cloned. The gene is also expressed in the brain and possibly the testis and the liver/spleen. The Principal Investigator now proposes to bring these studies to fruition by demonstrating that the candidate gene is mutated or otherwise inactivated in tumors at a frequency commensurate with the frequency of allelic loss in this region of 8p. This will involve completing the cloning of the full length cDNA, examining its expression in tumor cell lines, and screening cell lines and primary human head and neck tumors for mutations. This gene will then form the basis for future studies investigating its utility as a predictor of clinical outcome and characterizing the mechanisms by which its inactivation increases the growth or aggressiveness of squamous cell carcinomas of the head and neck.
