Non-hyperfunctioning nodules from multinodular goiters: A minor role in pathogenesis for somatic activating mutations in the TSH-receptor and Gs alpha subunit genes

Constitutive activation of the cAMP pathway stimulates thyrocyte proliferat ion. Gain-of-function mutations in Gs alpha protein have already been ident ified in thyroid nodules which have lost the ability to trap iodine. In con trast, most of the studies failed to detect somatic activating mutations in the thyrotropin receptor (TSH-R) in non-hyperfunctioning thyroid tumors. T he aim of this study was to screen for mutations TSH-R exon 10, encoding th e whole intracytoplasmic area involved in signal transduction, and Gs alpha exons 8 and 9, containing the two hot-spot codons 201 and 227, in a subset of non-hyperfunctioning nodules from multinodular goiter. Identified by ma tching ultrasonography and scintiscan, 22 eufunctioning (normal Tc-99 uptak e) and 15 nonfunctioning (decreased Tc-99 uptake) nodules from 27 non-toxic multinodular goiters were isolated. After DNA extraction, TSH-R exon 10 wa s analyzed by direct sequencing of the PCR products and Gs alpha exons 8 an d 9 by Denaturing Gradient Gel Electrophoresis. No mutation of TSH-R or Gs alpha was detected in the 37 nodules analyzed. This absence of mutation, de spite the use of two sensitive screening methods associated with the analys is of the TSH-R whole intracytoplasmic area and Gs alpha two hot-spot codon s, suggests that TSH-R and Gs alpha play a minor role in the pathogenesis o f non-toxic nodules from multinodular goiters.