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

Our main objective was to search for mutations in candidate genes and for paired box gene 8-peroxisome proliferator-activated receptor gamma (PAX8-PPARgamma) 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-PPARgamma 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 1-8+10)-PPARgamma was found in all tested patient's tissues. A second rearrangement, PAX8 (exons 1-8)-PPARgamma, was detected in the patient's normal thyroid tissue. Under deprived medium condition, co-transfection of PAX8-PPARgamma 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-PPARgamma 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-PPARgamma rearrangements. PAX8-PPARgamma was present as a mosaicism affecting tissues from endodermal and mesodermal origin. PAX8-PPARgamma and TSHR-M453T inhibited or promoted thyrocyte proliferation depending on medium conditions. The activating TSHR mutation could promote in vivo FTC development in PAX8-PPARgamma-positive thyrocytes under poor blood supply with deprivation of growth factors but restraint the tumor growth when growth factors are supplied.