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Comprehensive Genomic Profiling of Adult Renal Sarcomas Provides Insight into Disease Biology and Opportunities for
Evgeny Yakirevich1, Russell Madison2, Eduard Fridman3
1Department of Pathology, Rhode Island Hospital, Providence, RI, USA; Alpert Medical School at Brown University, Providence, RI, USA.
Background:
Primary adult renal sarcomas (RSs) are rare aggressive neoplasms. Clinical outcomes are extremely poor, and optimal treatment remains challenging.
Objective:
To identify genomic alterations (GAs) in patients with RSs.
Design, Setting, And Participants:
Comprehensive genomic profiling (CGP) was conducted on DNA/RNA extracted from formalin-fixed paraffin-embedded tissue using the FoundationOne Heme/Sarcoma assay in 13 adult, locally advanced or metastatic RSs of various histologic types.
Outcome Measurements And Statistical Analysis:
All classes of GAs, including base substitutions, small indels, rearrangements, copy number alterations, tumor mutational burden (TMB), and microsatellite instability (MSI), were analyzed.
Results And Limitations:
CGP revealed 55 GAs (4.2 per tumor), 29 of which were clinically relevant genomic alterations (CRGAs; 2.2 per tumor). At least one CRGA was detected in nine (69%) cases. High-level amplifications (more than six copies) involving 4q12 amplicon of the KIT and PDGFRA genes were identified in four (31%) cases (two undifferentiated pleomorphic sarcomas [UPSs], one sarcomatoid renal cell carcinoma, and one myxofibrosarcoma). Both UPSs also had KDR gene amplification in addition to KIT and PDGFRA. Additional CRGAs were found in CDKN2A/B (23%), NF1 (23%), and MET (8%). All RSs were MSI stable, the mean TMB was 3.5 mutations/megabase (Mb), and none (0%) featured TMB >10 mutations/Mb. Limitations include the small sample size.
Conclusions:
RSs are characterized by diverse histology and genomic profiles including 31% of cases with 4q12 amplification harboring the KIT/PDGFRA/KDR genes. Of the tumors, 69% carry CRGAs, which could lead to potential benefit from targeted therapies; however, a low TMB also suggests that these cases are unlikely to respond to checkpoint inhibitors.
Patient Summary:
This study provides insights into molecular biology of renal sarcoma, a rare aggressive subtype of kidney tumors. We demonstrated that renal sarcomas harbor unique, recurrent, clinically relevant molecular abnormalities that provide new opportunities for targeted therapies.
Insights
Primary adult renal sarcomas (RSs) are rare, aggressive kidney tumors. Comprehensive genomic profiling revealed that 69% of RSs harbor clinically relevant genomic alterations (CRGAs), offering potential targets for therapy.
Area of Science:
- Oncology
- Genomics
- Nephrology
Background:
- Primary adult renal sarcomas (RSs) are rare and aggressive neoplasms.
- Clinical outcomes for RSs are poor, and treatment remains challenging.
Purpose of the Study:
- To identify genomic alterations (GAs) in adult patients with renal sarcomas.
- To explore potential targeted therapy opportunities based on identified GAs.
Main Methods:
- Comprehensive genomic profiling (CGP) using the FoundationOne Heme/Sarcoma assay on DNA/RNA from 13 adult RS tissue samples.
- Analysis of various GAs including base substitutions, indels, rearrangements, copy number alterations, tumor mutational burden (TMB), and microsatellite instability (MSI).
Main Results:
- CGP identified 55 GAs (4.2 per tumor), with 29 clinically relevant genomic alterations (CRGAs; 2.2 per tumor).
- CRGAs were present in 69% of cases. Notably, 31% of RSs exhibited 4q12 amplicon (KIT, PDGFRA, KDR genes).
- Additional CRGAs included CDKN2A/B (23%), NF1 (23%), and MET (8%). All RSs were MSI stable with a mean TMB of 3.5 mutations/Mb.
Conclusions:
- Renal sarcomas display diverse genomic profiles with recurrent abnormalities, including 4q12 amplifications.
- The presence of CRGAs in most RSs suggests potential benefit from targeted therapies.
- Low TMB indicates limited efficacy of checkpoint inhibitors for these tumors.
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