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Clinically Advanced Pheochromocytomas and Paragangliomas: A Comprehensive Genomic Profiling Study.

ABSTRACT: Patients with clinically advanced paragangliomas (CA-Para) and pheochromocytomas (CA-Pheo) have limited surgical or systemic treatments. We used comprehensive genomic profiling (CGP) to compare genomic alterations (GA) in CA-Para and CA-Pheo to identify potential therapeutic targets. Eighty-three CA-Para and 45 CA-Pheo underwent hybrid-capture-based CGP using a targeted panel of 324 genes. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined. The GA/tumor frequencies were low for both tumor types (1.9 GA/tumor for CA-Para, 2.3 GA/tumor for CA-Pheo). The most frequent potentially targetable GA in CA-Para were in FGFR1 (7%, primarily amplifications), NF1, PTEN, NF2, and CDK4 (all 2%) and for CA-Pheo in RET (9%, primarily fusions), NF1 (11%) and FGFR1 (7%). Germline mutations in known cancer predisposition genes were predicted in 13 (30%) of CA-Pheo and 38 (45%) of CA-Para cases, predominantly involving SDHA/B genes. Both CA-Para and CA-Para had low median TMB, low PD-L1 expression levels and none had MSI high status. While similar GA frequency is seen in both CA-Para and CA-Para, germline GA were seen more frequently in CA-Para. Low PD-L1 expression levels and no MSI high status argue against strong potential for novel immune checkpoint inhibitors. However, several important potential therapeutic targets in both CA-Para and CA-Para are identified using CGP.

SUBMITTER: Bratslavsky G

PROVIDER: S-EPMC8268679 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Clinically Advanced Pheochromocytomas and Paragangliomas: A Comprehensive Genomic Profiling Study.

Bratslavsky Gennady G Sokol Ethan S ES Daneshvar Michael M Necchi Andrea A Shapiro Oleg O Jacob Joseph J Liu Nick N Sanford Tom S TS Pinkhasov Ruben R Goldberg Hanan H Killian Jonathan K JK Ramkissoon Shakti S Severson Eric A EA Huang Richard S P RSP Danziger Natalie N Mollapour Mehdi M Ross Jeffrey S JS Pacak Karel K

Cancers 20210701 13

Patients with clinically advanced paragangliomas (CA-Para) and pheochromocytomas (CA-Pheo) have limited surgical or systemic treatments. We used comprehensive genomic profiling (CGP) to compare genomic alterations (GA) in CA-Para and CA-Pheo to identify potential therapeutic targets. Eighty-three CA-Para and 45 CA-Pheo underwent hybrid-capture-based CGP using a targeted panel of 324 genes. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined. The GA/tumor frequencie ...[more]

PMID: 34282751

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Project description:ContextNo effective methods for separating primary pheochromocytomas and paragangliomas with metastatic potential are currently available. The identification of specific asparagine-linked glycan (N-glycan) structures, which are associated with metastasized pheochromocytomas and paragangliomas, may serve as a diagnostic tool.ObjectiveTo identify differences in N-glycomic profiles of primary metastasized and nonmetastasized pheochromocytomas and paragangliomas.SettingThis study was conducted at Helsinki University Hospital, University of Helsinki, and Glykos Finland Ltd. and included 16 pheochromocytomas and paragangliomas: 8 primary metastasized pheochromocytomas or paragangliomas and 8 nonmetastasized tumors.MethodsN-glycan structures were analyzed with matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) profiling of formalin-fixed, paraffin-embedded tissue samples.Main outcome measureN-glycan profile of tumor tissue.ResultsFour groups of neutral N-glycan signals were more abundant in metastasized tumors than in nonmetastasized tumors: complex-type N-glycan signals of cancer-associated terminal N-acetylglucosamine, multifucosylated glycans (complex fucosylation), hybrid-type N-glycans, and fucosylated pauci-mannose-type N-glycans. Three groups of acidic N-glycans were more abundant in metastasized tumors: multifucosylated glycans, acid ester-modified (sulfated or phosphorylated) glycans, and hybrid-type/monoantennary N-glycans. Fucosylation and complex fucosylation were significantly more abundant in metastasized paragangliomas and pheochromocytomas than in nonmetastasized tumors for individual tests but were over the false positivity critical rate, when adjusted for multiplicity testing.ConclusionsMALDI-TOF MS profiling of primary pheochromocytomas and paragangliomas can identify diseases with metastatic potential based on their different N-glycan profiles. Thus, malignancy-linked N-glycan structures may serve as potential diagnostic tools for pheochromocytomas and paragangliomas.

Dataset Information

Clinically Advanced Pheochromocytomas and Paragangliomas: A Comprehensive Genomic Profiling Study.

Publications

Clinically Advanced Pheochromocytomas and Paragangliomas: A Comprehensive Genomic Profiling Study.

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