Two G Protein Oncogenes in Human Endocrine Tumors

Somatic mutations in a subset of growth hormone (GH)-secreting pituitary tumors convert the gene for the α polypeptide chain ($\alpha_s$) of G$_s$ into a putative oncogene, termed gsp. These mutations, which activate $\alpha_s$ by inhibiting its guanosine triphosphatase (GTPase) activity, are found in codons for either of two amino acids, each of which is completely conserved in all known G protein α chains. The likelihood that similar mutations would activate other G proteins prompted a survey of human tumors for mutations that replace either of these two amino acids in other G protein α chain genes. The first gene so far tested, which encodes the α chain of G$_{i2}$, showed mutations that replaced arginine-179 with either cysteine or histidine in 3 of 11 tumors of the adrenal cortex and 3 of 10 endocrine tumors of the ovary. The mutant $\alpha_{i2}$ gene is a putative oncogene, referred to as gip2. In addition, gsp mutations were found in 18 of 42 GH-secreting pituitary tumors and in an autonomously functioning thyroid adenoma. These findings suggest that human tumors may harbor oncogenic mutations in various G protein α chain genes.