2 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 (αs) of Gs into a putative oncogene, termed gsp. These mutations, which activate αs 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 Gi2, 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 αi2 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.