It has been recently demonstrated that papillary thyroid carcinomas (PTCs) that develop distant metastases are characterized by three genetic alterations: Chr1qamp, TERT_locusamp, TERT_promotermut. This signature, named THYT1, holds the potential as an early prognostic predictor to identify patients at risk for disease progression. To implement the use of this signature in clinical practice we first developed a droplet digital PCR approach for a faster and cost-effective detection of the THYT1 in PTCs, then we validated its performance in a retrospective monocentric case–control training cohort (N = 90) of PTCs and in a separated multicentric validation cohort (N = 143) of PTCs. We also investigated THYT1 feasibility in cytological pre-surgical thyroid smears. In the training set, THYT1 evaluation by ddPCR showed 93
Thymic and pulmonary neuroendocrine neoplasms (NEN) are morphologically similar but arise from different embryonic tissues. Whether this similarity extends to shared molecular programs is unclear. We compared 45 thymic and 37 pulmonary NEN by immunohistochemistry, targeted and exome sequencing, NanoString RNA profiling and mass spectrometry-based proteomics. The RNA and proteomic profiles of pulmonary and thymic neuroendocrine tumors (LuNET and TNET) were clearly different, while the profiles of neuroendocrine carcinomas of both organs (LuNEC and TNEC) were largely overlapping. A subgroup of TNET corresponding to NET G3 clustered with lower-grade thymic NET rather than NEC. NET of both organs showed a low mutational burden and were proliferatively quiescent but diverged metabolically: LuNET showed broad metabolic and stress signaling and TNET a quiescent phenotype with PI3K/AKT/mTOR as the only enriched pathway. NEC of both organs converged on cell cycle activation and metabolic depletion with frequent TP53 and RB1 co-inactivation, but diverged immunologically: LuNEC were immune-hot, whereas TNEC showed epithelial–mesenchymal transition and a markedly lower mutational burden. CD44 stood out in both the transcriptomic and the proteomic analysis and was therefore immunohistochemically validated in an independent, larger cohort that included also gastrointestinal and pancreatic tumors. CD44 was high in pulmonary NET and low in every other subgroup (p = 2.1 × 10⁻¹³), identifying it as a new complementary marker of pulmonary origin. In summary, thoracic NEN segregate by anatomical origin as well as by differentiation grade. Wether these differences require treatments adapted to the organ of origin remains to be established.
Non-functioning pancreatic neuroendocrine tumors (NF-pNETs) show a variable prognosis. Despite 40–60
A substantial fraction (60-85%) of hereditary primary hyperparathyroidism (hPHPT) lacks an identifiable genetic etiology. We describe fumarate hydratase (FH) mutations as a potential cause of hPHPT, expanding the phenotypic spectrum of FH deficiency tumor predisposition syndromes. In an index patient who presented with asymptomatic hypercalcemia and a chief-to-transitional cell-dominant parathyroid adenoma, whole-exome sequencing revealed two unique heterozygous FH variants (germline p.Gln376fs*2; somatic p.Pro503_Lys504dup). Functional inactivation of FH was supported by diffuse nuclear and cytoplasmic 2-succinocysteine immunoreactivity and elevated fumarate/malate ratio in tumor tissue. This individual did not show classic HLRCC manifestations. Preserved FH protein expression suggested residual enzymatic activity, which may account for an attenuated phenotype. To assess broader relevance, no additional patients with bona fide FH-deficient parathyroid adenoma were identified among 130 individuals with suspected hPHPT of unknown etiology evaluated at our institute. In a complementary cohort of 11 patients with pheochromocytoma/paraganglioma syndrome harboring pathogenic germline heterozygous FH variants, one female (FH p.Thr234Ala) presented with multi-gland disease requiring parathyroidectomy at age 40 years, features suspicious for hPHPT. These findings support fumarate hydratase deficiency as a plausible etiology for a subset of parathyroid adenomatous disease. Thus, consideration of parathyroid function surveillance in patients with fumarate hydratase deficiency tumor predisposition syndromes may be warranted. CLINICAL TRIAL NUMBER: NCT04969926.
