Exon capture analysis of G-protein coupled receptors reveals activating mutations in GRM3 in melanoma

Monday, October 24, 2011 — Poster Session I
Noon – 2:00 p.m.	Natcher Conference Center	NHGRI	CANCER-19

Authors

• T Prickett
• X Wei
• I Cardenas-Navia
• J Teer
• J Lin
• V Walia
• J Gartner
• J Jiang
• P Cherukuri
• A Molino
• M Davies
• J Gershenwald
• K Stemke-Hale
• E Margulies
• S Rosenberg
• Y Samuels

Abstract

G protein-coupled receptors (GPCRs), the largest human gene family, are known to be important regulators of signaling pathways. However, knowledge of their genetic alterations is limited. In this study, we used exon capture and illumina sequencing methods to analyze the mutational status of all the GPCRs in melanoma. This investigation revealed that one family member, GRM3 was frequently mutated in melanoma and that one of its mutations clustered within one position. Biochemical analysis of GRM3 alterations revealed that mutant GRM3 selectively regulated the phosphorylation of MEK leading to increased anchorage-independent growth and migration. Melanoma cells expressing mutant GRM3 had reduced cell growth and cellular migration after shRNA-mediated knockdown of GRM3 or treatment with a selective MEK inhibitor, AZD-6244, which is currently being used in phase II clinical trials. Our study yields a comprehensive map of genetic alterations in the GPCR gene family and suggests a potential target for therapy for melanoma patients.

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