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


G protein-coupled receptors (GPCRs), the largest human gene family, are important regulators of signaling pathways. However, knowledge of their genetic alterations is limited. In this study, we used exon capture and massively parallel sequencing methods to analyze the mutational status of 734 GPCRs in melanoma. This investigation revealed that one family member, GRM3, was frequently mutated 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 short hairpin RNA–mediated knockdown of GRM3 or treatment with a selective MEK inhibitor, AZD-6244, which is currently being used in phase 2 clinical trials. Our study yields the most comprehensive map of genetic alterations in the GPCR gene family.

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Figure 1: Effects of GRM3 alterations on cell growth and MEK phosphorylation.
Figure 2: GRM3 mutations increase migration in vitro and in vivo.
Figure 3: Expression of mutant GRM3 provides cell proliferation and survival signals in melanoma.
Figure 4: Melanoma cell lines expressing GRM3 mutants show increased sensitivity to inhibition of MEK by AZD-6244.

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We thank S. Gutkind, J. Cronin, H. Abaan, P. Cruz, J. Mullikin, N. Hansen and members of the US National Institutes of Health Intramural Sequencing Center Comparative Sequencing Program for generating the sequence data analyzed here. We thank S. Hoogstraten-Miller and I. Ginty for assistance with the mouse experiments and S. Anderson for assistance with FACS analysis. This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and National Cancer Institute, US National Institutes of Health, USA. Grant support was also provided by the University of Texas MD Anderson Cancer Center Melanoma Informatics, Tissue Resource and Pathology Core and the Melanoma Specialized Programs of Research Excellence (P50 CA93459). M.A.D. is supported by funding from the Melanoma Research Alliance, the American Society of Clinical Oncology and the MD Anderson Physician-Scientist Program. A.M. is supported by the Intramural Research program of the National Institute of Dental and Craniofacial Research, NIH.

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T.D.P., I.C.-N., X.W., E.H.M. and Y.S. designed the study. K.S.-H., M.A.D., J.E.G. and S.A.R. collected and analyzed the melanoma samples. X.W., I.C.-N., J.K.T., J.G., P.F.C. and J.C.L. analyzed the genetic data. T.D.P., A.M., J.J. and V.W. produced and analyzed the functional data. All authors contributed to the final version of the paper.

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Correspondence to Yardena Samuels.

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The authors declare no competing financial interests.

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Supplementary Text and Figures

Supplementary Figures 1–6, 8 and 9, Supplementary Tables 1–11 and Supplementary Note. (PDF 2481 kb)

Supplementary Table 7

MIP probes used for GPCR capture (XLS 1346 kb)

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Prickett, T., Wei, X., Cardenas-Navia, I. et al. Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma. Nat Genet 43, 1119–1126 (2011).

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