Comprehensive Genomic Profiling of Adult Renal Sarcomas Provides Insight into Disease Biology and Opportunities for Targeted Therapies.
4q12 Amplicon
Comprehensive genomic profiling
Renal sarcoma
Journal
European urology oncology
ISSN: 2588-9311
Titre abrégé: Eur Urol Oncol
Pays: Netherlands
ID NLM: 101724904
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
01
02
2019
revised:
12
03
2019
accepted:
01
04
2019
pubmed:
15
8
2019
medline:
23
11
2021
entrez:
15
8
2019
Statut:
ppublish
Résumé
Primary adult renal sarcomas (RSs) are rare aggressive neoplasms. Clinical outcomes are extremely poor, and optimal treatment remains challenging. To identify genomic alterations (GAs) in patients with RSs. 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. All classes of GAs, including base substitutions, small indels, rearrangements, copy number alterations, tumor mutational burden (TMB), and microsatellite instability (MSI), were analyzed. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 31412008
pii: S2588-9311(19)30044-6
doi: 10.1016/j.euo.2019.04.002
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
282-288Informations de copyright
Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.