Screening of candidate oncogenes in human thyrotroph tumors: Absence of 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 superficially resemble those of somatotroph tumors. We hypothesized that a subset of thyrotroph tumors might be caused by dominant somatic mutations that lead to inappropriate activation of the G(q)/phospholipase C beta/Ca2+/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), alpha(11), and TRHR genes. Fragments of alpha(q) and alpha(11) complementary DNA encompassing residues (Arg(183) and Gln(209)) that correspond to Arg(201) and Gln(227) of alpha(s) were amplified and sequenced. Temperature gradient gel electrophoresis was used to screen for heterozygous 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 occur infrequently, if at all, in human thyrotroph tumors. Alternative mechanisms underlying thyrotroph tumorigenesis, including changes in the expression levels of G protein alpha-subunits or TRHR, dysregulation of downstream components, inappropriate activation of other stimulatory pathways, or loss of inhibitory inputs, remain to be explored.