SCREENING OF CANDIDATE ONCOGENES IN HUMAN THYROTROPH TUMORS - ABSENCEOF ACTIVATING MUTATIONS OF THE G-ALPHA(Q), G-ALPHA(11), G-ALPHA(S), OR THYROTROPIN-RELEASING-HORMONE RECEPTOR GENES

Activating mutations encoding substitutions at positions Arg(201) and Gln(227) of the alpha-subunit of the stimulatory C protein, G(s), have been found in about 40% of pituitary somatotroph tumors. Although the etiology of thyrotroph adenomas is unknown, their autonomous behavior and blunted response to stimulatory hypothalamic hormone superficiall y resemble those of somatotroph tumors. We hypothesized that a subset of thyrotroph tumors might be caused by dominant somatic mutations tha t lead to inappropriate activation of the G(q)/phospholipase C beta/Ca 2+/protein kinase C pathway normally triggered by occupancy of the TRH receptor (TRHR). We, therefore, screened samples from nine thyrotroph tumors for the presence of activating mutations of the alpha(q), alph a(11), and TRHR genes. Fragments of alpha(q) and alpha(11) complementa ry DNA encompassing residues (Arg(183) and Gln(209)) that correspond t o Arg(201) and Gln(227) of alpha(s) were amplified and sequenced. Temp erature gradient gel electrophoresis was used to screen for heterozygo us mutations in the TRHR coding sequence as well as for known alpha(s) mutations. No mutations were detected. We conclude that mutations in these regions of the alpha(q), alpha(11), alpha(s), and TRHR genes occ ur infrequently, if at all, in human thyrotroph tumors. Alternative me chanisms underlying thyrotroph tumorigenesis, including changes in the expression levels of G protein alpha-subunits or TRHR, dysregulation of downstream components, inappropriate activation of other stimulator y pathways, or loss of inhibitory inputs, remain to be explored.