Purpose: In previous studies, we have shown that theTallele of a specific single-nucleotide polymorphism (SNP) in the Gas gene (T393C) correlates with increased Gas expression and hence apoptosis. The T allele was associated with a favorable outcome in a variety of human cancers, e.g., carcinoma of the urinary bladder, kidney, and colorectum. Experimental Design: The prognostic value of theT393C SNP was evaluated in an unselected series of patients treated with curative intent for oropharyngeal and hypopharyngeal squamous cell carcinomas, including all tumor stages with different therapeutic regimens. Genotype analysis was done using DNA from paraffin-embedded tissue samples from 202 patients (162 men, 40 women) with a median follow-up of 38 months (1-133 months). The various genotypes were correlated with relapse-free and overall survival. Results: GNAS1 393C homozygous patients displayed a higher risk for disease progression than T393 homozygous patients (hazard ratio CC versus TT, 1.9; 95% confidence interval, 1.1-3.2; P = 0.019). The same genotype effect was observed for overall survival with CC genotypes at higher risk for death compared with TT genotypes (hazard ratio, 1.7; 95% confidence interval, 1.1-2.9; P = 0.015). Multivariate analysis showed that, besides American Joint Committee on Cancer stage, tumor localization, and gender, the T393C polymorphism was an independent prognostic factor for disease progression and death. Conclusion: The T393C SNP could be considered as a genetic marker to predict the clinical course of patients suffering from oropharyngeal and hypopharyngeal cancer.Head and neck cancer comprises f6% to 7% of all human malignancies (1). Among head and neck cancer, squamous cell carcinoma (SCC) is the most common histologic subgroup, overall (80-85% of oropharyngeal and 97% of hypopharyngeal carcinomas; ref.2) representing the sixth most frequent cancer worldwide (3). Annually, about 400,000 head and neck SCC (HNSCC) are diagnosed worldwide, most of which are locally advanced at presentation. Some tumor sites, like the hypopharynx (4), imply a particularly bad prognosis among HNSCC due to the lack of obvious symptoms in the early disease stage. Surgery and/or radiochemotherapy are the mainstay of locoregional treatment in these patients (5). For previously untreated advanced stage resectable cancers in the oral cavity, oropharynx, and hypopharynx, the standard therapy regimens of surgery and postoperative radiation therapy result in a 5-year survival rate of only 40% to 50% (6). Because of an already extensive locoregional involvement upon admission, one third of patients with HNSCC have nonresectable tumors (7). Nonresectable advanced tumors are currently treated by combined radiochemotherapy with a 5-year overall survival rate of almost 30% (8). Chemotherapy alone has a modest favorable effect upon outcome; patients with recurrent or metastatic disease receiving chemotherapy show a median survival ranging from 6 to 9 months (9). Poor distant disease control rates in this par...