Activating mutations of Gsalpha in kidney cancer.
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.
Kalfa
Nicolas
N
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.
Lumbroso
Serge
S
Boulle
Nathalie
N
Guiter
Jacques
J
Soustelle
Laurent
L
Costa
Pierre
P
Chapuis
Heliette
H
Baldet
Pierre
P
Sultan
Charles
C
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
D019205:GTP-Binding Protein alpha Subunits, Gs