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Neuroendocrine neoplasms (NENs) encompass tumors arising from neuroendocrine cells in various organs, including the gastrointestinal tract, pancreas, adrenal gland, and paraganglia. Despite advancements, accurately predicting the aggressiveness of gastroenteropancreatic (GEP) NENs based solely on pathological data remains challenging, thereby limiting optimal clinical management. Our previous research unveiled a crucial link between hypermethylation of the protocadherin PCDHGC3 gene and neuroendocrine tumors originating from the paraganglia and adrenal medulla. This epigenetic alteration was associated with increased metastatic potential and succinate dehydrogenase complex (SDH) dysfunction. Expanding upon this discovery, the current study explored PCDHGC3 gene methylation within the context of GEP‐NENs in a cohort comprising 34 cases. We uncovered promoter hypermethylation of PCDHGC3 in 29% of GEP‐NENs, with a significantly higher prevalence in gastrointestinal (GI) neuroendocrine carcinomas (NECs) compared with both pancreatic (Pan) NECs and neuroendocrine tumors (NETs) of GI and Pan origin. Importantly, these findings were validated in one of the largest multi‐center GEP‐NEN cohorts. Mechanistic analysis revealed that PCDHGC3 hypermethylation was not associated with SDH mutations or protein loss, indicating an SDH‐independent epigenetic mechanism. Clinically, PCDHGC3 hypermethylation emerged as a significant prognostic factor, correlating with reduced overall survival rates in both patient cohorts. Significantly, whereas PCDHGC3 hypermethylation exhibited a strong correlation with TP53 somatic mutations, a hallmark of NEC, its predictive value surpassed that of TP53 mutations, with an area under the curve (AUC) of 0.95 (95% CI 0.83–1.0) for discriminating GI‐NECs from GI‐NETs, highlighting its superior predictive performance. In conclusion, our findings position PCDHGC3 methylation status as a promising molecular biomarker for effectively stratifying patients with GI‐NENs. This discovery has the potential to advance patient care by enabling more precise risk assessments and tailored treatment strategies. © 2024 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]

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]

(-)-Berkelic acid is an architecturally unique secondary metabolite isolated from an extremophilic Penicillium species. In this paper, we describe a very simple protocol to construct the central core of this natural product. Using this strategy, not only (-)-berkelic acid, but also a small library of analogues has been accessed. The key point of our protocol is a remarkable silver-catalysed cascade reaction that allows the assembly of the core of the natural product in a single step and from two simple starting materials, a 4-pentynol derivative and an ortho-alkynylsalicylaldehyde. The cytotoxicity of our synthetic (-)-berkelic acid and some analogues against two cancer cell lines, OVCAR-3 and SSCC38, was evaluated. [ABSTRACT FROM AUTHOR]

Background We previously showed that activation of epidermal growth factor receptor (EGFR) induces hypoxia inducible factor-1α (HIF-1α) in head and neck squamous cell carcinoma (HNSCC) cells. In this study, we have furthered this by investigating the mechanism of HIF-1α activation by epidermal growth factor (EGF) and its association with the sensitivity to gefitinib. Methods EGFR/HIF-1α signaling was tested by immunoblot, polymerase chain reaction (PCR), cell proliferation, and apoptosis assays. Results HIF-1α accumulated in cells overexpressing EGF and phosphorylated epidermal growth factor receptor (pEGFR), phosphatidylinositol-3-kinase (pPI3K), and mitogen-activated protein kinase (pMAPK). EGF-induced expression of HIF-1α and its targets, vascular endothelial growth factor (VEGF) and BNIP3, were blocked by gefitinib and PI3K-inhibitors and MAPK-inhibitors. HIF-1α-siRNAs abrogated EGF-induced BNIP3 but not VEGF expression. Gefitinib inhibited cell proliferation and induced apoptosis more strongly in cells with constitutively active EGFR/HIF-1α signaling than in cells lacking activation of these pathways. HIF-1α-siRNA treatment reduced sensitivity to gefitinib. Conclusion The search for molecular predictors of sensitivity to gefitinib in HNSCC should be extended to the activation status of EGFR-downstream pathways, phosphorylated protein kinase B, pMAPK, and HIF-1α. © 2014 Wiley Periodicals, Inc. Head Neck 37: 1150-1162, 2015 [ABSTRACT FROM AUTHOR]