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Introduction: Paragangliomas (PGL), a type of neuroendocrine tumor, pose a significant diagnostic challenge due to their potential for unpredictable locations and asymptomatic presentation. Misdiagnosis of peripancreatic PGLs, particularly as pancreatic neuroendocrine tumors (PANNETs), is a pressing issue as it can negatively impact both pre- and post-treatment decisionmaking. The aim of our study was to identify microRNA markers for the reliable differential diagnosis of peripancreatic PGLs and PANNETs, addressing a crucial unmet need in the field and advancing the standard of care for these patients. Methods: Morphing projections tool was used to analyze miRNA data from PGL and PANNET tumors present in the TCGA database. The findings were validated using two additional databases: GSE29742 and GSE73367. Results: Our research uncovered substantial differences in the miRNA expression profiles of PGL and PANNET, leading to the identification of 6 key miRNAs (miR-10b-3p, miR-10b-5p, and the miRNA families miR-200c/141 and miR-194/192) that can effectively differentiate between the two types of tumors. Discussion: These miRNA levels hold potential as biomarkers for improved diagnosis, offering a solution to the diagnostic challenge posed by these tumors and potentially improving the standard of care for patients. [ABSTRACT FROM AUTHOR]

Metastatic pheochromocytoma and paraganglioma (PPGL) have poor prognosis and limited therapeutic options. The recent advent of immunotherapies showing remarkable clinical efficacies against various cancer types offers the possibility of novel opportunities also for metastatic PPGL. Most PPGLs are pathogenically linked to inactivating mutations in genes encoding different succinate dehydrogenase (SDH) subunits. This causes activation of the hypoxia‐inducible factor 2 (HIF2)‐mediated transcriptional program in the absence of decreased intratumoral oxygen levels, a phenomenon known as pseudohypoxia. Genuine hypoxia in a tumor creates an immunosuppressive tumor microenvironment. However, the impact of pseudohypoxia in the immune landscape of tumors remains largely unexplored. In this study, tumoral expression of programmed death‐ligand 1 (PD‐L1) and HIF2α and tumor infiltration of CD8 T lymphocytes (CTLs) were examined in PPGL specimens from 102 patients. We assessed associations between PD‐L1, CTL infiltration, HIF2α expression, and the mutational status of SDH genes. Our results show that high PD‐L1 expression levels in tumor cells and CTL tumor infiltration were more frequent in metastatic than nonmetastatic PPGL. However, this phenotype was negatively associated with SDH mutations and high HIF2α protein expression. These data were validated by analysis of mRNA levels of genes expressing PD‐L1, CD8, and HIF2α in PPGL included in The Cancer Genome Atlas database. Further, PD‐L1 and CD8 expression was lower in norepinephrine than epinephrine‐secreting PPGL. This in silico analysis also revealed the low PD‐L1 or CD8 expression levels in tumors with inactivating mutations in VHL or activating mutations in the HIF2α‐coding gene, EPAS1, which, together with SDH‐mutated tumors, comprise the pseudohypoxic molecular subtype of PPGL. These findings suggest that pseudohypoxic tumor cells induce extrinsic signaling toward the immune cells promoting the development of an immunosuppressive environment. It also provides compelling support to explore the differential response of metastatic PPGL to immune checkpoint inhibitors. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Background: Succinate dehydrogenase subunit B (SDHB) immunohistochemistry was considered a valuable tool to identify patients with inherited paraganglioma/pheochromocytoma (PGL/PCC). However, previous studies jointly analyzed 2 related but clinically distinct entities, parasympathetic head and neck paragangliomas (HNPGLs) and sympathetic PCCs/PGLs. Additionally, a role for hypoxia inducible factor‐1α (HIF‐1α) as a biomarker for succinate dehydrogenase (SDHx)‐mutated tumors has not been studied. Here, we evaluated the utility of SDHB/HIF‐1α proteins in HNPGLs and PCCs/PGLs as clinically useful biomarkers. Methods: The SDHB/succinate dehydrogenase subunit A (SDHA)/HIF‐1α immunohistochemistry analysis was performed in 158 genetically defined patients. Results: Similarly to PCCs/PGLs, SDHB immune‐negativity correlated with SDHx‐mutations in HNPGLs (P <.0001). The HIF‐1α stabilization was associated with SDHx‐mutations in HNPGLs (P =.020), not in PCCs/PGLs (P =.319). However, 25% of SDHx‐HNPGLs lacked HIF‐1α positive cells. Conclusion: As in PCCs/PGLs, SDHB immunohistochemistry in HNPGLs is a valuable method for identification of candidates for SDHx‐genetic testing. On the contrary, although SDHx mutations may favor HIF‐1α stabilization in HNPGLs, this is not a clinically useful biomarker. [ABSTRACT FROM AUTHOR]

Background: Cytogenetic and gene expression analyses in head and neck squamous cell carcinomas (HNSCC) have allowed identification of genomic aberrations that may contribute to cancer pathophysiology. Nevertheless, the molecular consequences of numerous genetic alterations still remain unclear. Methods: To identify novel genes implicated in HNSCC pathogenesis, we analyzed the genomic alterations present in five HNSCC-derived cell lines by array CGH, and compared high level focal gene amplifications with gene expression levels to identify genes whose expression is directly impacted by these genetic events. Next, we knocked down TRPC6, one of the most highly amplified and over-expressed genes, to characterize the biological roles of TRPC6 in carcinogenesis. Finally, real time PCR was performed to determine TRPC6 gene dosage and mRNA levels in normal mucosa and human HNSCC tissues. Results: The data showed that the HNSCC-derived cell lines carry most of the recurrent genomic abnormalities previously described in primary tumors. High-level genomic amplifications were found at four chromosomal sites (11q21-q22.2, 18p11.31-p11.21, 19p13.2-p13.13, and 21q11) with associated gene expression changes in selective candidate genes suggesting that they may play an important role in the malignant behavior of HNSCC. One of the most dramatic alterations of gene transcription involved the TRPC6 gene (located at 11q21-q22.2) which has been recently implicated in tumour invasiveness. siRNA-induced knockdown of TRPC6 expression in HNSCC-derived cells dramatically inhibited HNSCC-cell invasion but did not significantly alter cell proliferation. Importantly, amplification and concomitant overexpression of TRPC6 was also found in HNSCC tumour samples. Conclusions: Altogether, these data show that TRPC6 is likely to be a target for 11q21-22.2 amplification that confers enhanced invasive behavior to HNSCC cells. Therefore, TRPC6 may be a promising therapeutic target in the treatment of HNSCC. [ABSTRACT FROM AUTHOR]

Ten-eleven translocation (TET) enzymes are frequently deregulated in cancer, but the underlying molecular mechanisms are still poorly understood. Here we report that TET2 shows frequent epigenetic alterations in human glioblastoma including DNA hypermethylation and hypo-hydroxymethylation, as well as loss of histone acetylation. Ectopic overexpression of TET2 regulated neural differentiation in glioblastoma cell lines and impaired tumor growth. Our results suggest that epigenetic dysregulation of TET2 plays a role in human glioblastoma., Competing Interests: CONFLICTS OF INTEREST The authors declare no potential conflicts of interest

The hypoxia-inducible factor 1α (HIF-1α) and its microRNA target, miR-210, are candidate tumor-drivers of metabolic reprogramming in cancer. Neuroendocrine neoplasms such as paragangliomas (PGLs) are particularly appealing for understanding the cancer metabolic adjustments because of their associations with deregulations of metabolic enzymes, such as succinate dehydrogenase (SDH), and the von Hippel Lindau (VHL) gene involved in HIF-1α stabilization. However, the role of miR-210 in the pathogenesis of SDH-related tumors remains an unmet challenge. Herein is described an in vivo genetic analysis of the role of VHL, HIF1A and SDH on miR-210 by using knockout murine models, siRNA gene silencing, and analyses of human tumors. HIF-1α knockout abolished hypoxia-induced miR-210 expression in vivo but did not alter its constitutive expression in paraganglia. Normoxic miR-210 levels substantially increased by complete, but not partial, VHL silencing in paraganglia of knockout VHL-mice and by over-expression of p76del-mutated pVHL. Similarly, VHL-mutated PGLs, not those with decreased VHL-gene/mRNA dosage, over-expressed miR-210 and accumulate HIF-1α in most tumor cells. Ablation of SDH activity in SDHD-null cell lines or reduction of the SDHD or SDHB protein levels elicited by siRNA-induced gene silencing did not induce miR-210 whereas the presence of SDH mutations in PGLs and tumor-derived cell lines was associated with mild increase of miR-210 and the presence of a heterogeneous, HIF-1α-positive and HIF-1α-negative, tumor cell population. Thus, activation of HIF-1α is likely an early event in VHL-defective PGLs directly linked to VHL mutations, but it is a late event favored but not directly triggered by SDHx mutations. This combined analysis provides insights into the mechanisms of HIF-1α/miR-210 regulation in normal and tumor tissues potentially useful for understanding the pathogenesis of cancer and other diseases sharing similar underpinnings.

Introduction and Objectives: It is now generally accepted that angiogenesis is crucial in tumour growth. However, controversy still exists regarding the prognostic significance of angiogenesis in head and neck carcinomas. The aim of this paper is to determine the prognostic significance of angiogenesis in a homogeneously treated group of supraglottic squamous cell carcinomas., Material and Methods: 108 patients surgically treated for squamous cell carcinoma of the supraglottic larynx were studied. Angiogenesis was estimated in the primary tumour and in the nodal metastases by determining microvessel density using the "hot spot" method. Anti-CD34 antibody was used to stain blood vessels., Results: The mean microvessel density in primary tumours was 72+/-34 vessels/mm(2) and 58.5+/-31.5 vessels/mm(2) in nodal metastases. No correlation was found between microvessel density in the primary tumours and the corresponding nodal metastasis (P=0.195). No significant differences in microvessel density were observed in relation to clinico-pathological parameters or survival (P=0.19)., Conclusions: Our results suggest that microvessel density is not a useful prognostic marker in surgically treated supraglottic squamous cell carcinomas.