Clinically Advanced Pheochromocytomas and Paragangliomas: A Comprehensive Genomic Profiling Study

• Published in: Cancers Vol. 13; no. 13; p. 3312
• Main Authors: Bratslavsky, Gennady, Sokol, Ethan S., Daneshvar, Michael, Necchi, Andrea, Shapiro, Oleg, Jacob, Joseph, Liu, Nick, Sanford, Tom S., Pinkhasov, Ruben, Goldberg, Hanan, Killian, Jonathan K., Ramkissoon, Shakti, Severson, Eric A., Huang, Richard S. P., Danziger, Natalie, Mollapour, Mehdi, Ross, Jeffrey S., Pacak, Karel
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01-07-2021; MDPI
• Subjects: Accuracy; Cancer; Cyclin-dependent kinase 4; Fibroblast growth factor receptor 1; Genes; Genomics; Immune checkpoint inhibitors; Laboratories; Malignancy; Medical records; Metastases; Metastasis; Microsatellite instability; Mutation; Paraganglioma; Patients; PD-L1 protein; PTEN protein; Therapeutic applications
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers13133312

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.