Endocrine-related cancer最新文献

Approximately 10-20% of thyroid cancers are driven by gene fusions, which activate oncogenic signaling through aberrant overexpression, ligand-independent dimerization, or loss of inhibitory motifs. We identified 13 thyroid tumors with thyroglobulin (TG) gene fusions and aimed to assess their histopathology and the fusions' oncogenic and tumorigenic properties. Of 11 cases with surgical pathology, 82% were carcinomas and 18% noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP). TG fusions preserved exon(s) 1, 1-15, 1-35 or, most frequently, 1-47 of TG and, based on the 3' partner were grouped as (i) involving receptor tyrosine kinases (RTKs) (TG::FGFR1, TG::RET, TG::ALK, TG::NTRK1), (ii) driving aberrant DPRX and chromosome 19 microRNA cluster expression (TG::DPRX), or (iii) involving IGF2 mRNA-binding protein (TG::IGF2BP1). All 13 fusion-positive tumors exhibited strong (8.5±3.3 log2-fold) 3' partner overexpression driven by the TG promoter. Gene expression analysis revealed TG::RET- and TG::ALK-positive tumors being BRAFV600E-like and remaining tumors RAS-like. In thyroid PCCL3 cells, the TG::NTRK1 fusion demonstrated both spontaneous and ligand-associated dimerization, activated downstream MAPK, AKT, and STAT3 signaling, and drove xenograft tumorigenesis in nude mice. FDA-approved NTRK inhibitors entrectinib and larotrectinib effectively blocked TG::NTRK1 signaling in vitro and inhibited xenograft tumor growth in vivo. In summary, we report a spectrum of TG gene fusions as recurrent oncogenic events in thyroid cancer and NIFTP that drive strong overexpression of partner genes, frequently RTKs. The TG::NTRK1 fusion is prone to dimerization, activates oncogenic signaling, drives tumorigenesis in thyroid cells, and, like other fusions involving RTKs, represents a potential therapeutic target in thyroid cancer.

Gastroenteropancreatic neuroendocrine neoplasms(GEP NEN) exhibit substantial biological heterogeneity, impacting clinical management and outcomes. In 2019, the WHO introduced the neuroendocrine tumour(NET) grade 3 (G3) subgroup, characterized by Ki-67>20% and a well-differentiated morphology and poorly differentiated neuroendocrine carcinomas(NEC) (Ki-67>20%). Since this update, questions about the prognostic implications and best treatment strategies for NET G3 and NEC remain. Therefore we initiated a real-world retrospective observational cohort study, using data from 225 NEC and 58 NET G3 patients treated in Belgium. Analysis of patient and tumour characteristics and the effect of survival was conducted. Most frequent primary locations were pancreatic (32.9%) and colorectal (21.5%), and 71.8% was diagnosed with stage IV disease. Median overall survival(mOS) was higher in NET G3 (41.3 months(m)) compared to NEC (13.2m). Of those who underwent functional imaging, fluorodeoxyglucose-positron emission tomography-imaging (18F-FDG-PET) was positive in 90.6% and 95.6% of the NET G3 and NEC patients, respectively, and somatostatin receptor(SSTR) expression was seen in 97.4% and 66.0%, respectively. The latter was linked to a better mOS, suggesting the added value of performing both SSTR imaging and 18F-FDG-PET for high grade(HG) NEN to provide prognostic information and to possibly expand to therapeutic options which are currently reserved for lower-grade NEN patients. Moreover, while debated, in our population primary surgery was performed in 92% and 73.5% of locoregional NET G3 and NEC cases respectively, indicating that surgery can be considered in locoregional setting. Finally, platinum-etoposide was the predominant first-line treatment in metastatic NEC, with no significant survival difference between carboplatin and cisplatin.

This study evaluated the global burden of thyroid cancer (TC) from 1990 to 2021, analyzing its association with sociodemographic factors, sex, age, risk factors, and future projections. Using 2021 Global Burden of Disease data, we analyzed TC incidence, mortality, and disability-adjusted life years (DALYs) across populations. Risk factors were assessed, and future trends forecasted using the Bayesian age-period-cohort model. In 2021, global TC incidence was 249,538 cases (age-standardized incidence rate [ASIR]: 2.91 per 100,000). Mortality reached 44,799 cases, with a slight decrease in the age-standardized mortality rate (ASMR). DALYs increased by 92.73%, though the age-standardized DALYs rate (ASDR) declined. East Asia had the highest incidence, while South Asia led in mortality and DALYs. TC burden showed a strong negative correlation with socioeconomic development, especially in high- and medium Socio-Demographic Index countries. High body mass index (BMI) contributed significantly to DALYs and mortality, particularly in the Middle East and North Africa. Population growth emerged as the key driver of the rising global TC burden. Projections suggest ASIR will increase by 2050, while ASMR and ASDR will decline. Global TC incidence has risen markedly, particularly among males, while mortality and DALYs have decreased due to improved healthcare. High BMI increasingly contributes to the TC burden. Projections highlight a continued rise in incidence but declining mortality and DALYs, reflecting advancements in treatment and management.

The molecular biology of pituitary neuroendocrine tumors (PitNETs) revealed few recurrent mutations and extensive chromosomal alterations, with the latter being the driving force in a subset of these lesions. Addressing the need for an easily applicable diagnostic tool, we conducted a retrospective study of 61 PitNETs operated at a tertiary care center. All cases were subtyped according to the 2022 WHO Classification of Endocrine Tumors. A genome-wide next-generation sequencing panel targeting 1500 single nucleotide polymorphisms (SNPs) was used to classify chromosomal imbalances, loss of heterozygosity, and copy number variations in DNA from formalin-fixed paraffin-embedded tissues. We identified four distinct chromosomal patterns, with varying distribution among different tumor lineages. Forty-two of 61 (69%) PitNETs showed chromosomal alterations. Gonadotroph PitNETs showed mostly quiet genomes. The majority of lactotroph PitNETs (19/20, 95%) were altered, exhibiting a gained genome and a remarkably low recurrence rate. Nine of ten (90%) corticotroph PitNETs harbored chromosomal alterations, of which two aggressive corticotroph tumors and one metastatic corticotroph PitNET showed massive chromosomal losses, leading to near-haploid/near-homozygous genomes. The comparison of the molecular profile of primary and recurrent PitNETs of five patients showed no significant accumulation of alterations over time. A simple genome-wide 1500-SNP test can be used in the identification of outspoken aggressive subsets of PitNETs by the occurrence of a near-haploid/near-homozygous genome. Furthermore, the presence of neoplastic tissue in the resected material can be potentially confirmed for non-gonadotroph PitNETs under suboptimal histological assessment conditions.

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Abstract: Rearranged during transfection (RET) is a developmentally important receptor tyrosine kinase that has been identified as an oncogenic driver in a number of cancers. Activating RET point mutations gives rise to the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2), characterized by medullary thyroid carcinoma. There are two MEN2 subtypes, MEN2A and MEN2B, that differ in tumour aggressiveness and the associated constellation of other disease features, which are caused by distinct patterns of RET amino acid substitution mutations. MEN2A-RET mutations affecting extracellular cysteine residues promote ligand-independent dimerization and constitutive RET activity, while MEN2B is caused by a single amino acid change in the tyrosine kinase domain of RET, releasing autoinhibition and producing a more active MEN2B-RET kinase that can promote signalling as monomers or dimers in the absence of a ligand. These mutations cause intrinsic biochemical changes in the RET structure and activation but also trigger extrinsic effects that alter RET cellular location, interactions and mechanisms of downregulation that can prolong or mislocate RET activity, changing or enhancing functional outcomes. Furthermore, changes in specific combinations of RET-mediated effects associated with different mutations give rise to the distinct MEN2 disease phenotypes. Here, we discuss the current understanding of the intrinsic and extrinsic characteristics of RET MEN2A cysteine and MEN2B mutants and how these contribute to transforming cellular processes and to the differences in tumour progression and disease aggressiveness.

The rearranged during transfection (RET) receptor tyrosine kinase is physiologically stimulated by growth factors belonging to the glial cell line-derived neurotrophic factor family and by the growth differentiation factor-15 cytokine. RET plays a critical role in normal development as well as in various human tumors and developmental disorders. This review focuses on mechanisms of RET signaling and their alterations in human diseases.

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy characterized by diagnostic challenges, high recurrence rates, and poor prognosis. This study explored the role of miRNA processing genes in ACC and their potential role as diagnostic and prognostic biomarkers. We analyzed the mRNA expression levels of miRNA machinery components (DROSHA, DGCR8, XPO5, RAN, DICER, TARBP2, and AGO2) utilizing mRNA-Seq data from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) projects. Additionally, protein levels were quantified in tissue samples from the Kolling Institute of Medical Research's tumor bank. Our results demonstrated that among all miRNA processing components, AGO2 exhibited significant overexpression in ACC compared to the normal adrenal cortex and benign adrenal adenoma (P < 0.001). Kaplan-Meier survival analysis indicated that higher AGO2 expression correlated with significantly worse overall survival in ACC patients (HR: 7.07, P < 0.001). Among 32 cancer types in TCGA, the prognostic significance of AGO2 was most prominent in ACC. This study is the first to report AGO2's potential as a diagnostic and prognostic biomarker in ACC, emphasizing its significance in ACC pathogenesis and potential application as a non-invasive liquid biopsy biomarker.

Differentiated thyroid cancer in older adults has been linked to alterations in the mutational landscape and tumor immune cell infiltration that create a tumor-permissive microenvironment. We sought to determine the impact of age on genomic alterations and immune cell composition in papillary thyroid cancer (PTC). Genomic alterations, immune cell composition, and clinical data were obtained using The Cancer Genome Atlas and computational immunogenomic analyses. Disease severity was recoded into three groups: Group A (T1-2N0M0), Group B (T1-3N1a-1bM0), and Group C (T4NxMx or TxNxM1). Histopathologic subtypes included conventional, follicular-variant, and tall cell variant PTC. Spearman's rank correlation, ANOVA, t-test, and multivariable linear regression were performed. A total of 470 PTC samples were retrieved from the TCGA portal with genomic alteration and immune cell composition data. TERT promoter alterations were more common in patients aged ≥65 years (26% vs 4%, P < 0.0001). Tumor mutational burden increased with increasing age (r = 0.463, P < 0.0001). Increasing age was associated with decreased CD8+ T cells (r = -0.15, P = 0.01) using CIBERSORT and decreased B cells (r = -0.13), CD8+ T cells (r = -0.19), and neutrophils (r = -0.14, P < 0.05) using TIMER. Multivariate regression found that increasing age was independently associated with increased resting NK cells and resting dendritic cells, and decreased naïve B cells and CD8+ T cells (P < 0.05). PTC tumors of older adults are characterized by increased TERT promoter alterations, increased tumor mutational burden, and a decreased cytotoxic CD8+ T cells and increased resting dendritic cell immune infiltrate. Further studies are needed to determine if these changes in immune cell infiltrate are associated with compromised outcomes.