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Clin Cancer Res. 2019 Aug 1;25(15):4712-4722. doi: 10.1158/1078-0432.CCR-19-0225. Epub 2019 Apr 26.

High Yield of RNA Sequencing for Targetable Kinase Fusions in Lung Adenocarcinomas with No Mitogenic Driver Alteration Detected by DNA Sequencing and Low Tumor Mutation Burden.

Author information

1
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
2
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
3
Department of Pathology, Quebec Heart and Lung Institute, Quebec City, Quebec, Canada.
4
Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
5
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
6
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
7
Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
8
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. ladanyim@mskcc.org.

Abstract

PURPOSE:

Targeted next-generation sequencing of DNA has become more widely used in the management of patients with lung adenocarcinoma; however, no clear mitogenic driver alteration is found in some cases. We evaluated the incremental benefit of targeted RNA sequencing (RNAseq) in the identification of gene fusions and MET exon 14 (METex14) alterations in DNA sequencing (DNAseq) driver-negative lung cancers.

EXPERIMENTAL DESIGN:

Lung cancers driver negative by MSK-IMPACT underwent further analysis using a custom RNAseq panel (MSK-Fusion). Tumor mutation burden (TMB) was assessed as a potential prioritization criterion for targeted RNAseq.

RESULTS:

As part of prospective clinical genomic testing, we profiled 2,522 lung adenocarcinomas using MSK-IMPACT, which identified 195 (7.7%) fusions and 119 (4.7%) METex14 alterations. Among 275 driver-negative cases with available tissue, 254 (92%) had sufficient material for RNAseq. A previously undetected alteration was identified in 14% (36/254) of cases, 33 of which were actionable (27 in-frame fusions, 6 METex14). Of these 33 patients, 10 then received matched targeted therapy, which achieved clinical benefit in 8 (80%). In the 32% (81/254) of DNAseq driver-negative cases with low TMB [0-5 mutations/Megabase (mut/Mb)], 25 (31%) were positive for previously undetected gene fusions on RNAseq, whereas, in 151 cases with TMB >5 mut/Mb, only 7% were positive for fusions (P < 0.0001).

CONCLUSIONS:

Targeted RNAseq assays should be used in all cases that appear driver negative by DNAseq assays to ensure comprehensive detection of actionable gene rearrangements. Furthermore, we observed a significant enrichment for fusions in DNAseq driver-negative samples with low TMB, supporting the prioritization of such cases for additional RNAseq.See related commentary by Davies and Aisner, p. 4586.

PMID:
31028088
PMCID:
PMC6679790
[Available on 2020-08-01]
DOI:
10.1158/1078-0432.CCR-19-0225
[Indexed for MEDLINE]

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