Activating mutations of Gsα in kidney cancer

Purpose: Heterotrimeric G proteins are signal transduction proteins coupled to hormone receptors that activate intracellular second messenger systems, mainly cyclic adenosine monophosphate mediated protein kinase. Recent studies indicate that G proteins may have a major role in oncogenesis as well as in tumor invasiveness and cell proliferation. The involvement of G proteins was formerly thought to be limited to hormonal signal transduction. Activating Gs alpha mutations have been reported in tumors arising only from highly specialized endocrine tissue, such as pituitary adenomas, toxic thyroid adenomas and differentiated thyroid carcinomas, but never in other nonendocrine tumors. We hypothesized that a constitutive activation of this pathway, that is activated Gs alpha and inhibited Gi alpha, could be implicated in kidney cancers. We searched for alterations on the Gs alpha gene GNAS and the Gi alpha gene in renal cell carcinoma. Materials and Methods: Using nested polymerase chain reaction, enzyme digestions, laser microdissection. and direct sequencing we looked for activating mutations on GNAS codons 201 and 227, and inhibiting mutations on the Gi alpha gene in 30 consecutive patients with clear cell renal cell carcinoma between January 2003 and January 2004. Results: Somatic (tumor specific) activating mutations of Gs alpha were present in a significant proportion of human clear cell renal cell carcinomas. Activating mutations were identified in 5 of the 30 patient DNA preparations (16.6%) with a substitution of arginine 201 by cysteine in 3 and histidine in 2. Conclusions: These findings suggest the implication of this pathway in human oncogenesis. It may provide a potential therapeutic approach to these frequent and aggressive tumors.