Clinical genomic sequencing of pediatric and adult osteosarcoma reveals distinct molecular subsets with potentially targetable alterations Journal Article
| Authors: | Suehara, Y.; Alex, D.; Bowman, A.; Middha, S.; Zehir, A.; Chakravarty, D.; Wang, L.; Jour, G.; Nafa, K.; Hayashi, T.; Jungbluth, A. A.; Frosina, D.; Slotkin, E.; Shukla, N.; Meyers, P.; Healey, J. H.; Hameed, M.; Ladanyi, M. |
| Article Title: | Clinical genomic sequencing of pediatric and adult osteosarcoma reveals distinct molecular subsets with potentially targetable alterations |
| Abstract: | Purpose: Although multimodal chemotherapy has improved outcomes for patients with osteosarcoma, the prognosis for patients who present with metastatic and/or recurrent disease remains poor. In this study, we sought to define how often clinical genomic sequencing of osteosarcoma samples could identify potentially actionable alterations. Experimental Design: We analyzed genomic data from 71 osteosarcoma samples from 66 pediatric and adult patients sequenced using MSK-IMPACT, a hybridization capture-based large panel next-generation sequencing assay. Potentially actionable genetic events were categorized according to the OncoKB precision oncology knowledge base, of which levels 1 to 3 were considered clinically actionable. Results: We found at least one potentially actionable alteration in 14 of 66 patients (21%), including amplification of CDK4 (n 1⁄4 9, 14%: level 2B) and/or MDM2 (n 1⁄4 9, 14%: level 3B), and somatic truncating mutations/deletions in BRCA2 (n 1⁄4 3, 5%: level 2B) and PTCH1 (n 1⁄4 1, level 3B). In addition, we observed mutually exclusive patterns of alterations suggesting distinct biological subsets defined by gains at 4q12 and 6p12-21. Specifically, potentially targetable gene amplifications at 4q12 involving KIT, KDR, and PDGFRA were identified in 13 of 66 patients (20%), which showed strong PDGFRA expression by IHC. In another largely nonoverlap-ping subset of 14 patients (24%) with gains at 6p12-21, VEGFA amplification was identified. Conclusions: We found potentially clinically actionable alterations in approximately 21% of patients with osteosarcoma. In addition, at least 40% of patients have tumors harboring PDGFRA or VEGFA amplification, representing candidate subsets for clinical evaluation of additional therapeutic options. We propose a new genomically based algorithm for directing patients with osteosarcoma to clinical trial options. 2019 American Association for Cancer Research. |
| Keywords: | osteosarcoma; vasculotropin; child; controlled study; human tissue; aged; gene sequence; major clinical study; somatic mutation; gene deletion; cancer grading; prospective study; platelet derived growth factor alpha receptor; gene amplification; gene expression; chromosome 9p; vasculotropin receptor 2; retrospective study; protein p53; carcinogenesis; tumor suppressor gene; dna; gene rearrangement; gene identification; dna sequence; chromosome loss; protein patched 1; chromosome 12q; cyclin dependent kinase 4; chromosome 4q; protein mdm2; kit gene; copy number variation; pdgfra gene; chromosome 6p; tp53 gene; rb1 gene; next generation sequencing; vegf gene; cdk4 gene; mdm2 gene; human; male; female; priority journal; article; ptch1 gene; kdr gene; chromosome 12q14; chromosome 4q12; chromosome 6p12; chromosome 9p21 |
| Journal Title: | Clinical Cancer Research |
| Volume: | 25 |
| Issue: | 21 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2019-11-01 |
| Start Page: | 6346 |
| End Page: | 6356 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-18-4032 |
| PUBMED: | 31175097 |
| PROVIDER: | scopus |
| PMCID: | PMC6825534 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 December 2019 -- Source: Scopus |
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