The emerging mutational landscape of G proteins and G-protein-coupled receptors in cancer

Key Points Recent cancer genome deep sequencing efforts have revealed an unanticipated high frequency of mutations in G proteins and G-protein-coupled receptors (GPCRs) in most tumour types. A striking 4.2% of all tumour sequences deposited to date show activating mutations in GNAS (a complex locus that encodes Gα s ). Transforming mutations in GNAS have been well documented in human thyroid and pituitary tumours, and recent sequencing efforts have shown these mutations to be present in a wide variety of additional tumour types, including colon cancer, hepatocellular carcinoma, and parathyroid, ovarian, endometrial, biliary tract and pancreatic tumours. Mutually exclusive activating mutations in GNAQ or GNA11 (encoding Gα q family members) occur in 5.6% of tumours, and they are present in ∼66% and ∼6% of melanomas arising in the eye and skin, respectively, where they can act as driver oncogenes. Hotspot mutations in Gα s (R201 and Q227) as well as Gα q and Gα 11 (R183 and Q209) disrupt the GTPase activity, thereby leading to constitutive activity and persistent signalling. Nearly 20% of human cancers harbour mutations in GPCRs. The most frequently mutated GPCRs include thyroid-stimulating hormone receptor (TSHR), Smoothened (SMO), glutamate metabotropic receptors (GRMs), members of the adhesion family of GPCRs and receptors for bioactive lipid mediators such as lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) that accumulate in the tumour microenvironment. Many GPCR mutations are still uncharacterized with respect to their potential contribution to tumorigenesis and cancer progression. Aberrant expression, overexpression or signal reprogramming of GPCRs and G proteins in tumour cells can contribute to cancer development and progression. These alterations may arise from cancer-specific changes in gene copy number, as well as from other genetic, epigenetic and post-translational changes resulting in higher protein expression, thereby enhancing tumour progression and metastasis. Detailed three dimensional structures of GPCRs in various activation states can now help to explain the functional impact of cancer-associated GPCR mutations, and guide the rational design of signalling-selective GPCR agonists, antagonists and allosteric modulators. G proteins, GPCRs and their linked signalling circuitry represent novel therapeutic targets for cancer prevention and treatment. Aberrant expression and activity of G proteins and G-protein-coupled receptors (