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.
Clinically advanced pheochromocytomas and paragangliomas: A comprehensive genomic profiling study / Bratslavsky, G.; Sokol, E. S.; Daneshvar, M.; Necchi, A.; Shapiro, O.; Jacob, J.; Liu, N.; Sanford, T. S.; Pinkhasov, R.; Goldberg, H.; Killian, J. K.; Ramkissoon, S.; Severson, E. A.; Huang, R. S. P.; Danziger, N.; Mollapour, M.; Ross, J. S.; Pacak, K.. - In: CANCERS. - ISSN 2072-6694. - 13:13(2021), p. 3312. [10.3390/cancers13133312]
Clinically advanced pheochromocytomas and paragangliomas: A comprehensive genomic profiling study
Necchi A.;
2021-01-01
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
