Abstract: Described herein is a G-protein coupled receptor (GPCR)-directed mutational analysis of tumor DNA obtained from melanoma tissue samples. The GPCR gene glutamate receptor, metabotropic 3 (GRM3) was identified as the most highly mutated GPCR gene in this screen. Functional characterization of GRM3 mutants revealed that these mutants promote activation of MEK, anchorage-independent cell growth and metastasis. Thus, provided herein are methods of diagnosing a subject as having melanoma, or susceptible to developing melanoma, by detecting the presence of at least one mutation in GRM3. Also provided are methods of treating a subject with melanoma by detecting the presence of at least one mutation in GRM3 and administering an appropriate therapy. Further provided are methods of selecting a subject diagnosed with melanoma as a candidate for treatment with a GRM3 inhibitor, an MEK inhibitor, or both, by detecting the presence of at least one mutation in GRM3.

Abstract: Members of the protein tyrosine kinase (PTK) family are highly mutated in patients with melanoma. Described herein are novel somatic mutations in the ERBB4 gene that result in increased kinase activity, transformation ability and anchorage-independent growth. These ERBB4 mutations contribute to the tumorogenicity of melanoma. Provided is a method of predicting the prognosis of a patient with melanoma by detecting the presence or absence of a mutation in the ERBB4 gene. In some examples, the ERBB4 mutation is selected from G949A, G1354A, G1624A, C1630T, G1687A, G2506A and G2614A (numbering based on SEQ ID NO: 1). Also provided are methods of selecting a patient as a candidate for treatment with an ERBB4 and/or PI3K/AKT pathway inhibitor, and a method of identifying a therapeutic agent for the treatment of a subject diagnosed with melanoma. Oligonucleotides that specifically hybridize with an ERBB4 nucleic acid molecule comprising a novel mutation are also provided.

Abstract: It is disclosed herein that members of the protein tyrosine kinase (PTK) family are highly mutated in patients with melanoma. Described herein are novel somatic mutations in the ERBB4 gene that result in increased kinase activity, transformation ability and anchorage-independent growth. These ERBB4 mutations contribute to the tumorogenicity of melanoma. Thus, provided herein is a method of predicting the prognosis of a patient with melanoma by detecting the presence or absence of a mutation in the ERBB4 gene. In some examples, the ERBB4 mutation is selected from G949A, G1354A, G1624A, C1630T, G1687A, G2506A and G2614A (numbering based on SEQ ID NO: 1). Also provided are methods of selecting a patient as a candidate for treatment with an ERBB4 and/or PI3K/AKT pathway inhibitor, and a method of identifying a therapeutic agent for the treatment of a subject diagnosed with melanoma.

Abstract: Described herein is a G-protein coupled receptor (GPCR)-directed mutational analysis of tumor DNA obtained from melanoma tissue samples. The GPCR gene glutamate receptor, metabotropic 3 (GRM3) was identified as the most highly mutated GPCR gene in this screen. Functional characterization of GRM3 mutants revealed that these mutants promote activation of MEK, anchorage-independent cell growth and metastasis. Thus, provided herein are methods of diagnosing a subject as having melanoma, or susceptible to developing melanoma, by detecting the presence of at least one mutation in GRM3. Also provided are methods of treating a subject with melanoma by detecting the presence of at least one mutation in GRM3 and administering an appropriate therapy. Further provided are methods of selecting a subject diagnosed with melanoma as a candidate for treatment with a GRM3 inhibitor, an MEK inhibitor, or both, by detecting the presence of at least one mutation in GRM3.

Abstract: It is disclosed herein that members of the protein tyrosine kinase (PTK) family are highly mutated in patients with melanoma. Described herein are novel somatic mutations in the ERBB4 gene that result in increased kinase activity, transformation ability and anchorage-independent growth. These ERBB4 mutations contribute to the tumorogenicity of melanoma. Thus, provided herein is a method of predicting the prognosis of a patient with melanoma by detecting the presence or absence of a mutation in the ERBB4 gene. In some examples, the ERBB4 mutation is selected from G949A, G1354A, G1624A, C1630T, G1687A, G2506A and G2614A (numbering based on SEQ ID NO: 1). Also provided are methods of selecting a patient as a candidate for treatment with an ERBB4 and/or PI3K/AKT pathway inhibitor, and a method of identifying a therapeutic agent for the treatment of a subject diagnosed with melanoma.