CHROMOSOME-8 ALLELIC LOSS AND THE OUTCOME OF PATIENTS WITH SQUAMOUS-CELL CARCINOMA OF THE SUPRAGLOTTIC LARYNX

Background: Loss of genetic heterogeneity (allelic loss or loss of het erozygosity) on chromosome arm 8p is frequent in squamous cell carcino mas of the head and neck and has been associated with poor prognosis. We have previously demonstrated that there are three minimal regions o f allelic loss on this chromosome arm. The location of each region is marked by a microsatellite locus: D8S264 (8p23), D8S552 (8p23-p22), an d D8S133 (8p21). These findings imply the existence of at least three putative tumor suppressor genes on this chromosome arm that may become inactivated during the progression of squamous cell carcinoma. Purpos e: We used allelic loss data from these three loci to determine if ina ctivation of these putative suppressors is associated with poor progno sis for patients with squamous cell carcinoma of the supraglottic lary nx. We also used multivariate statistics to compare the prognostic pow er of allelic loss at these genetic markers with that of demographic, clinical, and histopathologic parameters. Methods: the D8S264, D8S552, microsatellites in tumors from a retrospective population of 59 patie nts. All patients had histologically confirmed squamous cell carcinoma of the supraglottic larynx and had been treated surgically. DNA was e xtracted from matched sets of normal and microdissected tumor tissue a nd used for polymerase chain reaction amplification of the microsatell ite markers. Reaction products were separated by denaturing gel electr ophoresis and visualized by autoradiography. Patient data were obtaine d from the original pathology report and from the tumor registry of th e Department of Otolaryngology-Head and Neck Surgery, Washington Medic ine, St. pathologic data were obtained by reviewing the portion of the resection specimen used for DNA extraction. Parameters whose associat ion with reduced disease-free interval and reduced disease-specific su rvival was statistically significant were identified by use of the Kap lan-Meier method and the logrank statistic. Multivariate Cox proportio nal hazards models were used to identify independent predictors of poo r prognosis. All statistical tests were two-sided. Results: In this pa tient population, allelic loss at the D8S264 locus was associated with both shorter disease-free interval (logrank P = .028) and reduced dis ease-specific survival (logrank P = .004). Allelic loss at the next mo st centromeric locus, D8S552, had a statistically significant associat ion with only reduced disease-specific survival (logrank P = .034), wh ereas allelic loss at the most centromeric region, D8S133, showed no s tatistically significant association with reductions in either interva l. Multivariate Cox models suggested that D85264 was the only 8p marke r of the three microsatellites with a statistically significant and in dependent association with shortened disease-free interval (relative r isk [RR] = 3.38; P = .0107) and reduced disease-specific survival (RR = 3.41; P = .0105). Conclusions: Allelic loss in the p23 region of chr omosome 8 appears to be a statistically significant, independent predi ctor of poor prognosis in patients with supraglottic squamous cell car cinoma.