Mutant MYO1F alters the mitochondrial network and induces tumor proliferation in thyroid cancer

Familial aggregation is a significant risk factor for the development of thyroid cancer and Familial Non-Medullary Thyroid Cancer (FNMTC) accounts for 5-7% of all NMTC. Whole Exome Sequencing analysis in the family affected by FNMTC with oncocytic features where our group previously identified a predisposing locus on chromosome 19p13.2, revealed a novel heterozygous mutation (c.400G>A, NM_012335; p.Gly134Ser) in exon 5 of MYO1F, mapping to the linkage locus. In the thyroid FRTL-5 cell model stably expressing the mutant MYO1F p.Gly134Ser protein we observed an altered mitochondrial network, with increased mitochondrial mass and a significant increase of both intracellular and extracellular Reactive Oxygen Species, compared to cells expressing the wild-type protein or carrying the empty vector. The mutation conferred a significant advantage in colony formation, invasion and anchorage independent growth. These data were corroborated by in vivo studies in zebrafish, since we demonstrated that the mutant MYO1F p.Gly134Ser, when overexpressed, can induce proliferation in whole vertebrate embryos, compared to the wild-type one. MYO1F screening in additional 192 FNMTC families identified another variant in exon 7, which leads to exon skipping, and is predicted to alter the ATP-binding domain in MYO1F. Our study identified for the first time a role for MYO1F in NMTC. This article is protected by copyright. All rights reserved

Molecular pathology of endocrine gland tumors: genetic alterations and clinicopathologic relevance

Tumors of the endocrine glands are common. Knowledge of their molecular pathology has greatly advanced in the recent past. This review covers the main molecular alterations of tumors of the anterior pituitary, thyroid and parathyroid glands, adrenal cortex, and adrenal medulla and paraganglia. All endocrine gland tumors enjoy a robust correlation between genotype and phenotype. High-throughput molecular analysis demonstrates that endocrine gland tumors can be grouped into molecular groups that are relevant from both pathologic and clinical point of views. In this review, genetic alterations have been discussed and tabulated with respect to their molecular pathogenetic role and clinicopathologic implications, addressing the use of molecular biomarkers for the purpose of diagnosis and prognosis and predicting response to molecular therapy. Hereditary conditions that play a key role in determining predisposition to many types of endocrine tumors are also discussed

Basal and Calcium-Stimulated Procalcitonin for the Diagnosis of Medullary Thyroid Cancers: Lights and Shadows

Background: Procalcitonin (proCt) was recently proposed as an alternative or in addition to calcitonin (Ct) in medullary thyroid cancer (MTC) diagnostics. Methods: Serum basal Ct (bCt) and proCt (bproCt) levels were measured before surgery from a consecutive series of patients with (n=43) and without (n=75) MTC, retrospectively collected in Padua. Serum bproCt, bCt and stimulated proCt and Ct (sproCt and sCt) were measured in another consecutive series of 33 patients seen at three tertiary-level institutions undergoing a calcium stimulation test prior to surgery, 20 of them with a final diagnosis of MTC, and 13 with non-MTC nodular disease. Results: Median bproCt levels were higher in MTC than in non-MTC. A positive correlation was found for bproCt with bCt (P<0.01, R2 = 0.75), and with tumor size (P<0.01, R2 = 0.39). The cut-off for bproCt differentiating between MTC and non-MTC patients was >0.07 ng/ml (sensitivity: 85.7%, specificity: 98.9%, positive predictive value [PPV]: 98.2%, negative predictive value [NPV]: 90.6%, P<0.01). While bproCt was >0.07 ng/ml in 38/39 (97.4%) patients with MTC >10 mm, it was above said cut-off only in 15/23 (65.2%) patients with tumors ≤10 mm. A sproCt >0.19 ng/ml was able to identify MTC [sensitivity: 90.0%, specificity:100.0%, PPV: 100.0%, NPV: 86.7% (P<0.01)]. Conclusions: Our data suggest that bproCt can be a good adjunct to Ct for MTC diagnostic purposes. In consideration of its high specificity, it can be used in combination with Ct in MTC diagnostics, particularly in the case of mildly elevated basal Ct levels

Minimal Extrathyroidal Extension in Predicting 1-Year Outcomes: A Longitudinal Multicenter Study of Low-to-Intermediate-Risk Papillary Thyroid Carcinoma (ITCO#4)

Background: The role of minimal extrathyroidal extension (mETE) as a risk factor for persistent papillary thyroid carcinoma (PTC) is still debated. The aim of this study was to assess the clinical impact of mETE as a predictor of worse initial treatment response in PTC patients and to verify the impact of radioiodine therapy after surgery in patients with mETE. Methods: We reviewed all records in the Italian Thyroid Cancer Observatory (ITCO) database and selected 2237 consecutive patients with PTC who satisfied the inclusion criteria (PTC with no lymph node metastases and at least 1 year of follow-up). For each case, we considered initial surgery, histological variant of PTC, tumor diameter, recurrence risk class according to the American Thyroid Association (ATA) risk stratification system, use of radioiodine therapy, and initial therapy response, as suggested by ATA guidelines. Results: At 1-year follow-up, 1831 patients (81.8%) had an excellent response, 296 (13.2%) had an indeterminate response, 55 (2.5%) had a biochemical incomplete response, and 55 (2.5%) had a structural incomplete response. Statistical analysis suggested that mETE (odds ratio [OR] 1.16, p=0.65), tumor size >2 cm (OR 1.45, p=0.34), aggressive PTC histology (OR 0.55, p=0.15), and age at diagnosis (OR 0.90, p=0.32) were not significant risk factors for a worse initial therapy response. When evaluating the combination of mETE, tumor size, and aggressive PTC histology, the presence of mETE with a >2 cm tumor was significantly associated with a worse outcome (OR 5.27, 95% CI, p=0.014). The role of radioiodine ablation in patients with mETE was also evaluated. When considering radioiodine treatment, propensity score-based matching was performed, and no significant differences were found between treated and non-treated patients (p=0.24). Conclusions: This study failed to show the prognostic value of mETE in predicting initial therapy response in a large cohort of PTC patients without lymph node metastases. The study suggests that the combination of tumor diameter and mETE can be used as a reliable prognostic factor for persistence and could be easily applied in clinical practice to manage PTC patients with low-to-intermediate risk of recurrent/persistent disease

Novel prognostic nomogram for predicting recurrence-free survival in medullary thyroid carcinoma

AimsRecently, there have been attempts to improve prognostication and therefore better guide treatment for patients with medullary thyroid carcinoma (MTC). In 2022, the International MTC Grading System (IMTCGS) was developed and validated using a multi-institutional cohort of 327 patients. The aim of the current study was to build upon the findings of the IMTCGS to develop and validate a prognostic nomogram to predict recurrence-free survival (RFS) in MTC.Methods and ResultsData from 300 patients with MTC from five centres across the USA, Europe, and Australia were used to develop a prognostic nomogram that included the following variables: age, sex, AJCC stage, tumour size, mitotic count, necrosis, Ki67 index, lymphovascular invasion, microscopic extrathyroidal extension, and margin status. A process of 10-fold cross-validation was used to optimize the model's performance. To assess discrimination and calibration, the area-under-the-curve (AUC) of a receiver operating characteristic (ROC) curve, concordance-index (C-index), and dissimilarity index (D-index) were calculated. Finally, the model was externally validated using a separate cohort of 87 MTC patients. The model demonstrated very strong performance, with an AUC of 0.94, a C-index of 0.876, and a D-index of 19.06. When applied to the external validation cohort, the model had an AUC of 0.9.ConclusionsUsing well-established clinicopathological prognostic variables, we developed and externally validated a robust multivariate prediction model for RFS in patients with resected MTC. The model demonstrates excellent predictive capability and may help guide decisions on patient management. The nomogram is freely available online at .Building upon the International Medullary Thyroid Carcinoma (MTC) Grading System (IMTCGS) developed in 2022, this study presents a prognostic nomogram to predict recurrence-free survival in MTC. The model was created using data from 300 MTC patients and was externally validated in a separate cohort. The nomogram is available at . imag

Association of the Genomic Profile of Medullary Thyroid Carcinoma with Tumor Characteristics and Clinical Outcomes in an International Multicenter Study

Purpose: The prognostic importance of RET and RAS mutations and their relationship to clinicopathologic parameters and outcomes in medullary thyroid carcinoma (MTC) need to be clarified. Experimental Design: A multicenter retrospective cohort study was performed utilizing data from 290 patients with MTC. The molecular profile was determined and associations were examined with clinicopathologic data and outcomes. Results: RET germ line mutations were detected in 40 patients (16.3%). Somatic RET and RAS mutations occurred in 135 (46.9%) and 57 (19.8%) patients, respectively. RETM918T was the most common somatic RET mutation (n = 75). RET somatic mutations were associated with male sex, larger tumor size, advanced American Joint Committee Cancer (AJCC) stage, vascular invasion, and high International Medullary Thyroid Carcinoma Grading System (IMTCGS) grade. When compared with other RET somatic mutations, RETM918T was associated with younger age, AJCC (eighth edition) IV, vascular invasion, extrathyroidal extension, and positive margins. RET somatic or germ line mutations were significantly associated with reduced distant metastasis-free survival on univariate analysis, but there were no significant independent associations on multivariable analysis, after adjusting for tumor grade and stage. There were no significant differences in outcomes between RET somatic and RET germ line mutations, or between RETM918T and other RET mutations. Other recurrent molecular alterations included TP53 (4.2%), ARID2 (2.9%), SETD2 (2.9%), KMT2A (2.9%), and KMT2C (2.9%). Among them, TP53 mutations were associated with decreased overall survival (OS) and disease-specific survival (DSS), independently of tumor grade and AJCC stage. Conclusions: RET somatic mutations were associated with high-grade, aggressive primary tumor characteristics, and decreased distant metastatic-free survival but this relationship was not significant after accounting for tumor grade and disease stage. RETM918T was associated with aggressive primary tumors but was not independently associated with clinical outcomes. TP53 mutation may represent an adverse molecular event associated with decreased OS and DSS in MTC, but its prognostic value needs to be confirmed in future studies

Ghrelin and reproductive disorders

International audienceGhrelin is an important factor involved in most of the metabolic and hormonal signals which adapt the reproductive functions in conditions of altered energy balance. Moreover, the coordinated role of leptin and ghrelin appears in fact to have a specific role in the regulation of puberty. Systemic action of ghrelin on the reproductive axis involves the control of the hypothalamic-pituitary-gondal axis. In addition, it has been shown that ghrelin may directly act at a gonadal level in both females and males. Available data also demonstrate that sex steroid hormones and gonadotropins may in turn regulate the gonadal effect of ghrelin, as documented by studies performed in females with the polycystic ovary syndrome and in hypogonadal men. Notably, recent studies also confirm a potentially important role for ghrelin in fetal and neonatal energy balance, and specifically in allowing fetal adaptation to an adverse intrauterine environment