Overall and Relapse-Free Survival in Oropharyngeal and Hypopharyngeal Squamous Cell Carcinoma Are Associated with Genotypes of T393C Polymorphism of the GNAS1 Gene

Abstract

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...

Extra-long Gαs Variant XLαs Protein Escapes Activation-induced Subcellular Redistribution and Is Able to Provide Sustained Signaling

“…6). Thus, XL␣s extended the duration of the cAMP response induced by the typically short acting agonist M-PTH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Although this finding was consistent with the absence of XL␣s internalization upon activation, a similar effect was not observed when the same cells were stimulated by isoproterenol.…”

“…We addressed this hypothesis by using a Förster resonance energy transfer (FRET)-based reporter that permits real time recording of cAMP production in live cells (46). As an agonist, we chose a PTH analog, M-PTH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), which has been shown to induce a short lived cAMP response (41). As expected, a rapid change in the FRET signal was observed upon the addition of 100 nM M-PTH (1-14) onto HEK293 cells expressing the PTHR alone or in combination with XL␣s and G␤ 1 ␥ 2 (Fig.…”

Association of the GNAS1 T393C polymorphism with tumorstage and survival in gastric cancer

“…Oro-and hypopharyngeal squamous cell carcinoma [16] 2008 202 C homozygous patients displayed a higher risk for disease progression than T homozygous patients (P = 0.019) and a higher risk for death (P = 0.015). In multivariate analysis, besides cancer stage and tumor localization, the T393C polymorphism was an independent prognostic factor for disease progression and death…”

“…Previous studies indicate that increased expression of Gαs enhances apoptosis [7,8] and that Gαs mRNA expression is different between T393C genotypes [9] . For various solid tumors, previous studies demonstrated that patient survival and tumor progression depended on T393C genotype [10][11][12][13][14][15][16][17] . Until now, nothing has been published about the impact of the GNAS1 T393C polymorphism on gastric cancer.…”

The allelic distribution of a single nucleotide polymorphism in the PDCD5 gene locus of Japanese non-small cell lung cancer patients

“…Several genetic polymorphisms are considered to be molecular markers that predict the risk, progression and prognosis of various cancers (3)(4)(5)(6)(7). Indeed, single nucleotide polymorphisms (SNPs) in several genes are reported to be associated with the risk of lung cancer (8)(9)(10), for example SNPs in the caspase-3 and vascular endothelial growth factor genes (11,12).…”