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Activating mutations of Gsalpha in kidney cancer

Nicolas Kalfa1, Serge Lumbroso, Nathalie Boulle

  • 1INSERM U540, Endocrinologie Moléculaire et Cellulaire des Cancers and Service d'Hormonologie du Développement et de la Reproduction, Hôpital Lapeyronie, CHU Montpellier, 34295 Montpellier, France.

The Journal of Urology
|August 8, 2006
PubMed
Abstract

Insights

Activating Gsalpha mutations were found in 16.6% of clear cell renal cell carcinomas, suggesting a role for G protein signaling in kidney cancer development and potential therapeutic targets.

Area of Science:

  • Molecular Biology
  • Oncology
  • Signal Transduction

Background:

  • Heterotrimeric G proteins are key signal transducers linking hormone receptors to intracellular pathways.
  • Recent evidence suggests G protein involvement in oncogenesis, tumor invasiveness, and cell proliferation.
  • Previously, Gsalpha mutations were confined to endocrine tumors; this study investigates their role in nonendocrine cancers.

Purpose of the Study:

  • To investigate the hypothesis that constitutive activation of G protein signaling (activated Gsalpha, inhibited Gialpha) is implicated in kidney cancers.
  • To search for alterations in the GNAS (Gsalpha) and Gialpha genes in renal cell carcinoma.

Main Methods:

  • Nested polymerase chain reaction, enzyme digestions, laser microdissection, and direct sequencing were employed.
  • Analysis focused on activating mutations in GNAS codons 201 and 227, and inhibiting mutations in the Gialpha gene.
  • The study included 30 consecutive patients with clear cell renal cell carcinoma.

Main Results:

  • Somatic activating mutations of Gsalpha were identified in a significant proportion (16.6%) of clear cell renal cell carcinomas.
  • Activating mutations were found in 5 out of 30 patient DNA samples.
  • Specific mutations involved substitution of arginine 201 by cysteine (3 patients) or histidine (2 patients).

Conclusions:

  • The findings indicate the involvement of the G protein signaling pathway in human oncogenesis, specifically in kidney cancers.
  • This pathway may represent a potential therapeutic target for treating frequent and aggressive kidney tumors.
  • Further research into G protein signaling in renal cell carcinoma is warranted.

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