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PubMed2025

The genetic changes in 11p15.5-related pheochromocytomas and paragangliomas.

Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors. The development of these tumors is associated with more than 20 genes. The aforementioned genes are subdivided into three clusters. The pseudohypoxic, kinase-signaling and Wnt clusters. The pseudohypoxic cluster is the only one that has been demonstrated to be associated with DNA methylation changes, including alterations in the 11p15.5 region. The objective of this study was to identify alterations in the 11p15.5 region, ascertain their prevalence in PPGLs, and subsequently compare them with the genomic and somatic mutations that cluster PPGLs. One hundred and fifty tumor samples were subjected to analysis. A total of 90 cases (60%) exhibited no alterations in the 11p15.5 region. The most prevalent alterations were maternal allele loss, observed in 45 cases (30%), pUPD (paternal uniparental disomy) in five cases (3.33%), and paternal allele gain in four cases (2.67%). The data presented here suggest that two mechanisms may be involved in the formation of PPGLs. These are reduced expression of CDKN1C (maternal allele deletion) and overexpression of IGF2 (pUPD, paternal allele gain). A statistically significant difference was observed in the frequency of alterations in the 11p15.5 region when comparing cluster 1 and cluster 2 (P-value <0.0001). This study is the first to describe pUPD and paternal allele gain as somatic alterations in PPGLs. In addition, our findings indicate that alterations in the 11p15.5 region are not exclusive to cluster 1. Consequently, the alterations in the 11p15.5 region cannot be regarded as a marker for cluster 1.

Humans↗
PubMed2026

Clinical relevance of HRD score in pheochromocytomas and paragangliomas: molecular cluster distribution and prognostic implications.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with variable metastatic potential across molecular clusters. While the homologous recombination deficiency (HRD) score has been established as a surrogate for HRD-related genomic instability to guide prognostic evaluation and therapeutic options in multiple solid tumors, its relevance in PPGLs remains unexplored. Here, data from 133 PPGL patients in the TCGA database were extracted to assess relationships between the HRD score and molecular clusters, metastasis, metastasis-free survival (MFS), and other clinical characteristics. Subsequently, a real-world cohort of 54 matched blood-tumor pairs was subjected to whole-exome sequencing, with HRD scores calculated to confirm the prior observations. The median HRD score was 7.0 and 9.0 in the TCGA-PPGL dataset and the clinical cohort, respectively. In the TCGA dataset, an elevated HRD score significantly correlated with metanephrine secretion, C2 cluster, and metastasis. Multivariate analysis identified a higher HRD score as an independent risk factor for shorter MFS (HR = 1.33, P = 0.008). Patients with HRD scores &#x2265; 7 exhibited significantly shorter MFS (P = 0.037), which was observed exclusively within the C1A cluster (P = 0.007). Analyses of our clinical validation cohort corroborated this cluster-specific distribution and further revealed higher HRD scores in three temozolomide-treated PPGLs compared with those treatment-naive C1A tumors (P = 0.043). In conclusion, despite exhibiting lower levels in C1A clusters, an elevated HRD score emerges as a promising indicator for refined metastatic risk stratification in PPGLs. Futhermore, the substantial increase in HRD score following temozolomide treatment provides a rationale for PARP inhibitor sequential or combination therapy in metastatic PPGLs.

Humans↗
PubMed2026

Molecular clusters and precision medicine in pheochromocytomas and paragangliomas.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from chromaffin cells of the adrenal medulla and extra-adrenal paraganglia. Over the past two decades, the genomic characterization of PPGLs has profoundly transformed their diagnosis, classification, risk stratification, and therapeutic management. Up to 40% of PPGLs harbor germline pathogenic variants, the highest proportion among human neoplasms, and somatic driver events are identified in a substantial fraction of the remaining cases. Integrative multi-omic studies have established three main molecular clusters: a pseudohypoxic cluster driven by Krebs-cycle alterations (SDHx, FH, MDH2, DLST) and HIF-2&#x3b1; pathway alterations (VHL, EPAS1, EGLN1/2); a kinase-signaling cluster driven by activation of RAS/MAPK and PI3K/AKT pathways (RET, NF1, HRAS, TMEM127, MAX); and a Wnt-signaling cluster characterized primarily by MAML3 fusions. This review summarizes progress in PPGL genomics, highlighting geographic and sex-related particularities. Using EPAS1/HIF-2&#x3b1; and RET as paradigmatic examples, we illustrate how diverse germline, somatic, mosaic, and fusion events converge on common core signaling hubs that can be therapeutically exploited with FDA-approved selective inhibitors for relevant targets (e.g. belzutifan for HIF-2&#x3b1;; selpercatinib and pralsetinib for RET). We further review the genomic determinants of metastatic risk (SDHB, ATRX, TERT, and MAML3 fusions), the immune microenvironment of metastatic disease, and emerging radionuclide theranostics, liquid biopsy biomarkers, and integrative multi-omic approaches that are reshaping precision medicine for PPGLs.

Humans↗
PubMed2026

Biomarkers of metastatic disease in pheochromocytoma and paraganglioma.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with variable metastatic potential. While metastatic disease occurs in approximately 10-20% of cases, its prediction remains a major clinical challenge, as no histological system has been universally validated to reliably identify aggressive tumors at diagnosis. This review aims to provide a comprehensive and updated overview of current and emerging biomarkers of metastatic risk in PPGL, encompassing histopathological scoring systems, genetic and molecular markers, biochemical phenotyping, liquid biopsy approaches, and imaging-based biomarkers. Among established markers, germline SDHB mutation status, loss of SDHB expression by immunohistochemistry, elevated plasma 3-methoxytyramine, and histopathological scoring systems, such as GAPP and COPPS, represent the most clinically validated tools for risk stratification. Emerging biomarkers - including somatic alterations in ATRX and TERT, genomic instability indices, tumor immune microenvironment characterization, circulating tumor DNA, and oncometabolite quantification - show promise in refining prognostic assessment but require prospective validation before routine clinical implementation. Accurate risk stratification in PPGL demands a multiparametric and dynamic approach, integrating clinical, genetic, biochemical, and molecular parameters. Future progress will depend on large prospective international cohorts, standardized biomarker platforms, and biomarker-driven clinical trial designs to translate emerging molecular knowledge into improved patient outcomes.

SDHB↗
PubMed2026

Immunological Features of Neuroendocrine Neoplasms and Adrenal Tumors.

Neuroendocrine neoplasms, which occur throughout the human body, as well as adrenocortical carcinoma and pheochromocytoma, which originate in the adrenal gland, are primarily classified as rare malignancies. Immunotherapy, including immune checkpoint inhibitors (ICIs), is generally not incorporated into the standard care protocols for these tumors. The clinical efficacy of ICIs in these tumors has been modest. This may be due to the biological heterogeneity of these tumors. The tumor immune microenvironment profiles are heterogeneous among the molecular subtypes of pheochromocytoma/paraganglioma, suggesting a potential benefit observed in selected subgroups. Poorly differentiated neuroendocrine carcinoma (NEC) exhibits spontaneous activation of adaptive immunity, unlike well-differentiated neuroendocrine tumors. A delta-like ligand 3-directed T-cell-engaging bispecific antibody, tarlatamab, has recently demonstrated prolonged survival in small cell lung cancer, and investigations into its use in extrapulmonary NEC are underway. This review examines the immunological features of representative neuroendocrine and adrenal tumors (neuroendocrine tumor, neuroendocrine carcinoma, adrenocortical carcinoma, and pheochromocytoma/paraganglioma). In the future, elucidating the relationship between specific molecular subtypes and immunophenotypes may facilitate the development of personalized therapies and guide clinical investigations in promising patient subpopulations.

Humans↗
PubMed2025

Role of GDH and PARP inhibitors as novel treatments for SDHB-deficient PPGLs.

SDHB, one of the four genes encoding the subunits of the Krebs cycle enzyme succinate dehydrogenase (SDH), acts as a tumor suppressor in several human cancers, including pheochromocytomas/paragangliomas. Mutations in SDHB lead to a reduction or complete loss of enzymatic activity, linking SDHB to paraganglioma malignancy. Given the difficulty in curing metastatic paragangliomas and the limited value of surgery, new treatments are needed. Glutamine dehydrogenase 1 (GDH1), a key regulator of glutathione metabolism, and poly (ADP-ribose) polymerase (PARP), essential for repairing single- or double-stranded DNA breaks, are crucial in cancer initiation and progression. We treated the human pheochromocytoma cell line (hPheo1) with knocked-down SDHB using radiation, the GDH inhibitor 'R162', and the PARP inhibitor 'olaparib'. Combining R162 with radiation enhances anticancer effectiveness, reduces cell proliferation, and causes G2/M phase arrest in the wild-type and KD-SDHB hPheo1 cell line. KD-SDHB hPheo1 cells treated with olaparib alone were more resistant than wild-type cells but were more sensitive in combination with radiation, activated repair mechanisms, and halted cell cycle progression at the G2/M phase. These results suggest that enhancing radiation-induced DNA damage could be a potential treatment strategy for metastatic pheochromocytomas/paragangliomas. Inhibiting GDH1 and PARP activities, with radiation, may represent promising strategies for the treatment of SDHB-deficient pheochromocytoma/paraganglioma; however, their effects do not appear to be specific to SDHB-deficient cells and require further validation.

Humans↗
PubMed2025

Mechanisms of resistance to RET-directed therapies.

The association between RET and multiple endocrine neoplasia type 2 was established in 1993 and remains one of the very few oncogenes for which distinct phenotypes (medullary thyroid cancer or pheochromocytoma) are associated with the same hot-spot variants occurring in either germline or somatic DNA. Somatic RET fusion events have also been described in several cancers, including papillary thyroid cancer, non-small-cell lung cancer, breast cancer, salivary gland cancer and pancreatic cancer. Highly selective RET inhibitors have improved outcomes in RET-altered cancers and have been well-tolerated. Nevertheless, primary and acquired drug resistance has been observed, arising from distinct genomic alterations either in RET (on-target resistance) or via alternate oncogenic pathways (bypass resistance). The same mechanisms of resistance have been observed across multiple cancer types, which implies RET-altered cancers evolve away from RET addiction via stochastic subclonal events. Understanding these mechanisms is crucial for identifying therapeutic opportunities to overcome resistance. Successful treatment targeting bypass oncogenes has been reported in several instances, at least for short-term outcomes; in contrast, although several compounds have been reported to overcome on-target RET alterations, none have yet been translated into routine clinical practice and this remains an area of urgent clinical need.

Animals↗
PubMed2026

Convergent IGF2 overexpression in pheochromocytoma/paraganglioma: insights from Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by overgrowth and tumor predisposition, caused by dysregulated expression of genes on chromosome 11p15.5. An association between BWS and pheochromocytoma/paraganglioma (PPGL) has been suggested in isolated case reports over the past fifty years, but the molecular basis for this link remains unclear. We identified four patients with BWS who developed metastatic PPGL and investigated IGF2 pathway activation in these tumors and in PPGL across various genotypes. Pan-cancer transcriptomic analysis of The Cancer Genome Atlas (TCGA) demonstrated that PPGL overexpresses IGF2, with pseudohypoxic tumors exhibiting higher expression compared to other molecular clusters. Loss of heterozygosity and loss of imprinting at 11p15.5 partially explain this overexpression, with PPGL additionally demonstrating globally elevated expression of imprinted genes compared to most other tumor types, suggesting a broader relaxation of genomic imprinting. Cognate receptor profiling revealed that PPGLs are equipped to respond to IGF2 signaling, with high expression of IGF1R and insulin receptor isoform A (IR-A). Immunohistochemistry confirmed IGF2 protein overexpression in both BWS-associated and genotypically diverse sporadic PPGLs. Our results indicate that IGF2 overexpression is a convergent molecular feature of PPGL across genotypes and suggest the IGF2 pathway as a potential diagnostic and therapeutic target.

Humans↗