Pheo-Type: A Diagnostic Gene-expression Assay for the Classification of Pheochromocytoma and Paraganglioma

Flynn, Aidan; Dwight, Trisha; Harris, Jessica; Benn, Diana E.; Zhou, Li; Hogg, Annette; Catchpoole, Daniel; James, Paul; Duncan, Emma L.; Trainer, Alison H.; Gill, Anthony J.; Clifton‐Bligh, Roderick; Hicks, Rodney J.; Tothill, Richard W.

doi:10.1210/jc.2015-3889

Cited by 31 publications

(30 citation statements)

References 57 publications

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“…To our best knowledge, AMH has not been reported in these cases. In a recent study, the authors have shown that MAX -related PHEO can contain distinct morphological tumor regions with different gene-expression patterns [12] .…”

Section: Discussionmentioning

confidence: 99%

Pathological and Genetic Characterization of Bilateral Adrenomedullary Hyperplasia in a Patient with Germline MAX Mutation

et al. 2016

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Background: In recent years, familial pheochromocytoma (PHEO) with germline mutations in the MAX (MYC Associated Factor X) gene has been reported in a few cases. Here we investigated a 25 years old patient with multiple PHEOs associated with a non-sense germline MAX mutation. Preoperative 18F-FDOPA PET/CT revealed bilateral adrenal involvement with multiple tumors. In addition both adrenal glands were found to have diffuse or nodular adrenal medullary hyperplasia (AMH), a histopathological feature previously described as a precursor of MEN2 and SDHB-related PHEOs but not MAX. Materials and Methods: After bilateral adrenalectomy, different paraffin-embedded and frozen samples were analyzed for allelic imbalances of the MAX gene using allelic quantification by pyrosequencing. The expression of the protein MAX was studied by immunohistochemistry. Results: All PHEOs but also nodular AMH exhibited a loss of the normal allele. By contrast, the diffuse AMH did not show Loss-of-Heterozygosity. Nevertheless, immunohistochemistry demonstrated loss of protein MAX expression in all samples including diffuse hyperplasia, suggesting a causative role of MAX mutation for both PHEOs and AMH. Conclusion: The present case shows that both nodular and diffuse AMH belongs to the spectrum of MAX-related disease. These data support the possible continuum between nodular AMH and PHEO, expanding the qualification of micro-PHEO to nodular AMH.

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Section: Discussionmentioning

confidence: 99%

Pathological and Genetic Characterization of Bilateral Adrenomedullary Hyperplasia in a Patient with Germline MAX Mutation

et al. 2016

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“…The kinase signalling subgroup, includes characteristic mutations in REarranged during Transfection (RET) in Multiple Endocrine Neoplasia type 2 (MEN2), Neurofibromatosis type 1 (NF1), transmembrane protein 127 (TMEM127), MYC associated factor X (MAX), EGLN1 (PHD2), KIF1 and IDH1 [ 6 ]. Our group has recently described a technique for assigning tumours into these subcategories [ 7 ]. PCCs may coexist with other tumour types in MEN2A, MEN2B, VHL and NF1.…”

Section: Introductionmentioning

confidence: 99%

68Ga-DOTATATE and 18F-FDG PET/CT in Paraganglioma and Pheochromocytoma: utility, patterns and heterogeneity

et al. 2016

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BackgroundPheochromocytomas (PCC) and paragangliomas (PGL) are neuroendocrine tumours arising from pluripotent neural crest stem cells and are associated with neurons of the autonomic nervous system. PCCs/PGLs are often hereditary and multifocal, and their biologic behaviour and metabolic activity vary making imaging of these tumours challenging. The imaging gold standard has been I-123 MIBG complemented by CT or MRI. PGLs being neuroendocrine tumours express somatostatin receptors enabling imaging with Ga-68 DOTA-coupled peptides such as DOTATATE. Imaging with F-18 FDG also provides additional information regarding metabolic activity and biologic aggressiveness of these tumours, or, in some situations, reflecting metabolic reprogramming of these tumours. We report our experience using both Ga-68 DOTATATE and F-18 FDG PET/CT imaging in patients with PGLs and PCCs.MethodsThis was a retrospective review of 23 patients with proven PGL/PCC who underwent both DOTATATE and FDG PET/CT. Seven patients also had I-123 MIBG SPECT/CT and 1 patient had I-124 MIBG PET/CT. Lesional intensity and patterns of uptake were analysed.ResultsDOTATATE and FDG were positive at most sites of disease (96.2 % vs 91.4 %), although uptake intensity was significantly higher on DOTATATE with a median SUV of 21 compared to 12.5 for FDG (p < 0.001). SUVmax on F-18 FDG was significantly higher (p < 0.001) in clinically aggressive cases. I-123/I-124 MIBG detected fewer lesions (30.4 %).ConclusionOverall, Ga-68 DOTATATE PET/CT detected similar number but has significantly greater lesion-to-background contrast compared to F-18 FDG PET/CT. Combined with high specificity, patient convenience and relatively low cost, DOTATATE PET/CT should be considered the ideal first line investigation for imaging PGL/PCC. Depending on DOTATATE findings and the clinical question, FDG and MIBG remain useful and, in selected cases, may provide more accurate staging, disease characterisation and guide treatment choices.

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“…Thus, we extended our study to a more in‐depth analysis of lincRNAs in the clinically relevant molecular subtypes of PCPG. Previously, a gene expression signature was proposed as marker of PCPG subtypes . However, employing machine‐learning algorithms, we found lincRNA signature that serves as a high‐precision marker of aggressive or nonaggressive PCPG subtypes, which could be used in future diagnostic assays.…”

Section: Discussionmentioning

confidence: 95%

“…Previously, a gene expression signature was proposed as marker of PCPG subtypes. 37 However, employing machine-learning algorithms, we found lincRNA signature that serves as a high-precision marker of aggressive or nonaggressive PCPG subtypes, which could be used in future diagnostic assays. The high precision of this lincRNA signature may be attributed to the fact that lincRNA expression is more tightly regulated.…”

Section: Discussionmentioning

confidence: 95%

Long intergenic noncoding RNA profiles of pheochromocytoma and paraganglioma: A novel prognostic biomarker

Ghosal

Das

Pang

et al. 2019

Intl Journal of Cancer

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Many long intergenic noncoding RNAs (lincRNAs) serve as cancer biomarkers for diagnosis or prognostication. To understand the role of lincRNAs in the rare neuroendocrine tumors pheochromocytoma and paraganglioma (PCPG), we performed first time in‐depth characterization of lincRNA expression profiles and correlated findings to clinical outcomes of the disease. RNA‐Seq data from patients with PCPGs and 17 other tumor types from The Cancer Genome Atlas and other published sources were obtained. Differential expression analysis and a machine‐learning model were used to identify transcripts specific to PCPGs, as well as established PCPG molecular subtypes. Similarly, lincRNAs specific to aggressive PCPGs were identified, and univariate and multivariate analysis was performed for metastasis‐free survival. The results were validated in independent samples using RT‐PCR. From a pan‐cancer context, PCPGs had a specific and unique lincRNA profile. Among PCPGs, five different molecular subtypes were identified corresponding to the established molecular classification. Upregulation of 13 lincRNAs was found to be associated with aggressive/metastatic PCPGs. RT‐PCR validation confirmed the overexpression of four lincRNAs in metastatic compared to non‐metastatic PCPGs. Kaplan–Meier analysis identified five lincRNAs as prognostic markers for metastasis‐free survival of patients in three subtypes of PCPGs. Stratification of PCPG patients with a risk‐score formulated using multivariate analysis of lincRNA expression profiles, presence of key driver mutations, tumor location, and hormone secretion profiles showed significant differences in metastasis‐free survival. PCPGs thus exhibit a specific lincRNA expression profile that also corresponds to the established molecular subgroups and can be potential marker for the aggressive/metastatic PCPGs.

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Pheo-Type: A Diagnostic Gene-expression Assay for the Classification of Pheochromocytoma and Paraganglioma

Abstract: The Pheo-type gene-expression assay is a reliable method for predicting PPGL genotype using routine diagnostic tumor samples.

Cited by 31 publications

References 57 publications

Pathological and Genetic Characterization of Bilateral Adrenomedullary Hyperplasia in a Patient with Germline MAX Mutation

Pathological and Genetic Characterization of Bilateral Adrenomedullary Hyperplasia in a Patient with Germline MAX Mutation

68Ga-DOTATATE and 18F-FDG PET/CT in Paraganglioma and Pheochromocytoma: utility, patterns and heterogeneity

Long intergenic noncoding RNA profiles of pheochromocytoma and paraganglioma: A novel prognostic biomarker

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