High prevalence of TSHR/Gsα mutation-negative clonal hot thyroid nodules (HNs) in a Turkish cohort.

Whereas the majority of hot thyroid nodules are caused by somatic TSH-receptor mutations, the percentage of TSH-receptor mutation negative clonal hot nodules (HN) and thus the percentage of hot nodules likely caused by other somatic mutations are still debated. This is especially the case for toxic multinodular goiter (TMNG). 35 HNs [12 solitary hot nodules (SHN), 23 TMNG] were screened for somatic TSHR mutations in the exons 9 and 10 and for Gsα mutations in the exons 7 and 8 using DGGE. Determination of X-chromosome inactivation was used for clonality analysis. Overall TSHR mutations were detected in 14 out of 35 (40%) HNs. A nonrandom X-chromosome inactivation pattern was detected in 18 out of 25 (72%) HNs suggesting a clonal origin. Of 15 TSHR or Gsα mutation negative cases 13 (86.6%) showed nonrandom X-chromosome inactivation, indicating clonal origin. The frequency of activating TSHR and/or Gsα mutations was higher in SHNs (9 of 12) than in TMNGs (6 of 23). There was no significant difference for the incidence of clonality for HNs between TMNGs or SHNs (p: 0.6396). Activating TSHR and/or Gsα mutations were more frequent in SHNs than in TMNG. However, the frequency of clonality is similar for SHN and TMNG and there is no significant difference for the presence or absence of TSHR and/or Gsα mutations of clonal or polyclonal HNs. The high percentage of clonal mutation-negative HNs in SHN and TMNG suggests alternative molecular aberrations leading to the development of TSHR mutation negative nodules.