Identification of a paired box gene 8–peroxisome proliferator-activated receptor gamma (PAX8–PPARγ) rearrangement mosaicism in a patient with an autonomous functioning follicular thyroid carcinoma bearing an activating mutation in the TSH receptor

Abstract

Our main objective was to search for mutations in candidate genes and for paired box gene 8-peroxisome proliferator-activated receptor gamma (PAX8-PPARg) rearrangement in a well-differentiated angioinvasive follicular thyroid carcinoma (FTC) causing hyperthyroidism. DNA and RNA were extracted from the patient's thyroid tumor, as well as 'normal' thyroid tissue, and from peripheral blood lymphocytes (PBLs) of the patient, her daughter, and two siblings. Nuclear isolation was extracted from the patient's tumor, 'normal' thyroid tissue, PBLs, and uterine leiomyoma tissue. TSH receptor (TSHR ), RAS, and BRAF genes were sequenced. We searched for PAX8-PPARg in thyroid, PBL, and uterine leiomyoma samples from the patient and family members. Proliferative effects of detected mutants on non-transformed human thyrocytes cultures. An activating TSHR mutation, M453T, was detected in the tumor. PAX8 (exons 1-8C10 )-PPARg was found in all tested patient's tissues. A second rearrangement, PAX8 (exons 1-8 )-PPARg, was detected in the patient's normal thyroid tissue. Under deprived medium condition, co-transfection of PAX8-PPARg and TSHR-M453T dramatically increased the number of thyrocytes, an effect that it was not observed with TSHR wild-type (WT); under complete medium conditions, co-transfection of PAX8-PPARg with either TSHR-M453T or TSHR-WT inhibited cell proliferation. We report a patient with hyperthyroidism due to a FTC bearing an activating TSHR mutation and PAX8-PPARg rearrangements. PAX8-PPARg was present as a mosaicism affecting tissues from endodermal and mesodermal origin. PAX8-PPARg and TSHR-M453T inhibited or promoted thyrocyte proliferation depending on medium conditions. The activating TSHR mutation could promote in vivo FTC development in PAX8-PPARg-positive thyrocytes under poor blood supply with deprivation of growth factors but restraint the tumor growth when growth factors are supplied.

Diagnostic value and lymph node metastasis prediction of a custom‑made panel (thyroline) in thyroid cancer

“…We found many gene mutations in particular tumor subtypes that are seldom reported, such as CTNNB1 and TSHR in PTC; NRAS and TSHR in ATC; CTNNB1 in MTC; and PIK3CA and CTNNB1 in FTC. Interestingly, TSHR was traditionally reported in FTC ( 27 ), but found in all subtypes by our gene spectrum. Thus, we hypothesize that TSHR may be a common driver gene for TC.…”

“…Thus, we hypothesize that TSHR may be a common driver gene for TC. Due to sample size limitations, our gene spectrum results may vary from previous studies ( 27 – 29 ), and some mutations in our panel were negative among TC patients.…”

Cancer risk and clinicopathological characteristics of thyroid nodules harboring thyroid‐stimulating hormone receptor gene mutations

“…8 At least 13 functional and 2 nonfunctional malignant thyroid nodules with confirmed TSHR mutations have been reported in multiple small case series. [9][10][11][12][13][14][15][16][17][18][19] These include 7 follicular thyroid cancer (FTC), 4 papillary thyroid cancer (PTC), 1 oncocytic (Hurthle cell) carcinoma, and 1 insular thyroid carcinoma. 1 toxic FTC nodule harbored TSHR mutations at two different codons 631 and 633 and it was associated with lung metastasis.…”

“…11 The presence of simultaneous mutations of RAS, RET/PTC, TP53, PAX8/PPARG, TRK, GNAS, and BRAF has been selectively evaluated in some of these cases. [11][12][13][14][16][17][18] This has identified a single confirmed coincident mutation in PAX8/PPARG in a follicular thyroid cancer also harboring a TSHR mutation, 19 as well as 3 other cases with confirmed simultaneous mutations in RAS and TSHR genes. 12,16,20 Despite these findings, how detection of TSHR mutations in FNA specimens impacts cancer risk, and whether TSHR mutations cooccur with other known thyroid cancer driver mutations has not been systematically studied.…”

Clinical Significance of Thyroid-Stimulating Hormone Receptor Gene Mutations and/or Sodium-Iodine Symporter Gene Overexpression in Indeterminate Thyroid Fine Needle Biopsies

“…Given the critical roles of TSHR and NIS in maintaining normal thyroid cell function and proliferation, it is expected that alterations of genes coding these two proteins ( TSHR and NIS genes) will be implicated, at least in part, in a variety of thyroid disorders including thyroid nodules In fact, since the 1990s, germline and somatic activating mutations of TSHR have been reported in familial nonautoimmune hyperthyroidism (FNAH), sporadic congenital nonautoimmune hyperthyroidism (SCNAH), and autonomously functioning thyroid nodules (AFTNs) ( 10 ); loss-of-function mutations of TSHR have been found to cause hypothyroidism and euthyroidism with elevated serum TSH (so-called “compensated hypothyroidism”) ( 11 , 12 ). TSHR mutations have also been found occasionally in functional and rarely in non-functional malignant thyroid nodules ( 1 , 13 – 21 ). It was suggested that a TSHR mutation concurrent with other thyroid cancer-related genetic alterations such as BRAF, GNAS, RAS, TP53, TRK, PAX8 / PPARr , and RET / PTC , or TSHR mutations occurring with very high allelic frequency (allelic frequency >30%) may have a high probability of thyroid cancer ( 22 – 25 ).…”