title: Activating mutations of Gsalpha in kidney cancer.
abstract: OBJECTIVE
  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 Gsalpha 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 Gsalpha and inhibited Gialpha, could be implicated in kidney cancers. We searched for alterations on the Gsalpha gene GNAS and the Gialpha gene in renal cell carcinoma.
  
  
  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 Gialpha gene in 30 consecutive patients with clear cell renal cell carcinoma between January 2003 and January 2004.
  
  
  RESULTS
  Somatic (tumor specific) activating mutations of Gsalpha 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.
authors.affiliation: INSERM U540, Endocrinologie Moléculaire et Cellulaire des Cancers and Service d'Hormonologie du Développement et de la Reproduction, Hôpital Lapeyronie, CHU Montpellier, 34295 Montpellier, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Kalfa
authors.forename: Serge
authors.initials: S
authors.lastname: Lumbroso
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boulle
authors.forename: Jacques
authors.initials: J
authors.lastname: Guiter
authors.forename: Laurent
authors.initials: L
authors.lastname: Soustelle
authors.forename: Pierre
authors.initials: P
authors.lastname: Costa
authors.forename: Heliette
authors.initials: H
authors.lastname: Chapuis
authors.forename: Pierre
authors.initials: P
authors.lastname: Baldet
authors.forename: Charles
authors.initials: C
authors.lastname: Sultan
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation
chemical_list: D019205:GTP-Binding Protein alpha Subunits, Gs