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The discovery of RET mutations in multiple endocrine neoplasia type 2A (MEN2A) in 1993 ignited a revolution in our understanding of this versatile receptor. Since then, the influence of RET has expanded to encompass diverse organs, including the pituitary gland. This review explores the multifaceted role of RET in somatotrophs, focusing on two opposing pathways: proliferation versus differentiation and apoptosis. The binding of glial-derived neurotrophic factor (GDNF) to RET promotes pituitary cell survival and inhibits PIT1-dependent differentiation, while low levels of GDNF trigger differentiation via PIT1. Excessive PIT1, on the other hand, will lead to apoptosis through caspase-3 activation involving the adaptor protein AIP and CDKN2A-ARF/p53. Pathogenic mutations in AIP can disrupt this apoptotic pathway, contributing to somatotrophinoma or prolactinoma development. In this concise review, we highlight the potential of CDKN2A-ARF expression as a prognostic marker for therapy response and discuss the promise of novel RET tyrosine kinase inhibitors for aggressive somatotrophinomas.

Pharmacologic treatment of acromegaly is currently based upon assay-error strategy, the first-generation somatostatin receptor ligands (SRL) being the first-line treatment. However, about 50% of patients do not respond adequately to SRL. Our objective was to evaluate the potential usefulness of different molecular markers as predictors of response to SRL. We used somatotropinoma tissue obtained after surgery from a national cohort of 100 acromegalic patients. Seventy-one patients were treated with SRL during at least 6 months under maximal therapeutic doses according to IGF1 values. We analyzed the expression of SSTR2, SSTR5, AIP, CDH1 (E-cadherin), MKI67 (Ki-67), KLK10, DRD2, ARRB1, GHRL, In1-Ghrelin, PLAGL1 and PEBP1 (RKIP) by RT-qPCR and mutations in GNAS gene by Sanger sequencing. The response to SRL was categorized as complete response (CR), partial (PR) or non-response (NR) if IGF1 was normal, between >2<3 SDS or >3 SDS IGF1 at 6 months of follow-up, respectively. From the 71 patients treated, there were 27 CR (38%), 18 PR (25%) and 26 NR (37%). SSTR2, Ki-67 and E-cadherin were associated with SRL response (P < 0.03, P < 0.01 and P < 0.003, respectively). E-cadherin was the best discriminator for response prediction (AUC = 0.74, P < 0.02, PPV of 83.7%, NPV of 72.6%), which was validated at protein level. SSTR5 expression was higher in patients pre-treated with SRL before surgery. We conclude that somatotropinomas showed heterogeneity in the expression of genes associated with SRL response. E-cadherin was the best molecular predictor of response to SRL. Thus, the inclusion of E-cadherin in subsequent treatment-decision after surgical failure may be useful in acromegaly.

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.