Evaluating gene fusions in solid tumors – Clinical experience using an RNA based 53 gene next-generation sequencing panel

Selvam, Pavalan; Kelly, Kevin; Hesse, Andrew; Spitzer, Daniel; Reddi, Honey V.

doi:10.1016/j.cancergen.2019.03.001

Cited by 8 publications

(7 citation statements)

References 35 publications

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“…Although this specific alteration may be detected by DNA‐based sequencing assays, there are some inherent limitations related to DNA‐based, amplicon‐mediated testing, making RNA‐based testing a far superior and reliable method for detecting these alterations 13,14 . Because of the expanded use of targeted therapeutics and the need for interrogating multiple gene fusions for predictive biomarkers used as a standard of care in specific tumor types (eg, ALK , ROS1 , MET , RET , and NTRK in lung adenocarcinomas; RET and NTRK in thyroid cancer) as well as in the context of emerging biomarkers currently used in clinical trials, RNA‐based next‐generation sequencing (NGS) assays are used increasingly in conjunction with DNA‐based mutation testing for more comprehensive molecular profiling 15‐17 …”

Section: Introductionmentioning

confidence: 99%

“…13,14 Because of the expanded use of targeted therapeutics and the need for interrogating multiple gene fusions for predictive biomarkers used as a standard of care in specific tumor types (eg, ALK, ROS1, MET, RET, and NTRK in lung adenocarcinomas; RET and NTRK in thyroid cancer) as well as in the context of emerging biomarkers currently used in clinical trials, RNA-based next-generation sequencing (NGS) assays are used increasingly in conjunction with DNA-based mutation testing for more comprehensive molecular profiling. [15][16][17] In patients with advanced-stage solid-organ malignancies, minimally invasive, cost-effective, and rapid diagnostic techniques such as fine-needle aspiration (FNA) are frequently used for diagnosis as well as molecular testing. [18][19][20] Cytopathologists, confronted with molecular test requests on limited volume FNA samples, 21 have the additional responsibility to optimally triage cytologic material in an appropriate and timely manner.…”

Section: Introductionmentioning

confidence: 99%

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Utilization of cytology smears improves success rates of RNA‐based next‐generation sequencing gene fusion assays for clinically relevant predictive biomarkers

Ramani

Chen

Broaddus

et al. 2020

Cancer Cytopathology

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Background The use of RNA‐based next‐generation sequencing (NGS) assays to detect gene fusions for targeted therapy has rapidly become an essential component of comprehensive molecular profiling. For cytology specimens, the cell block (CB) is most commonly used for fusion testing; however, insufficient cellularity and/or suboptimal RNA quality are often limiting factors. In the current study, the authors evaluated the factors affecting RNA fusion testing in cytology and the added value of smears in cases with a suboptimal or inadequate CB. Methods A 12‐month retrospective review was performed to identify cytology cases that were evaluated by a targeted RNA‐based NGS assay. Samples were sequenced by targeted amplicon‐based NGS for 51 clinically relevant genes on a proprietary platform. Preanalytic factors and NGS quality parameters were correlated with the results of RNA fusion testing. Results The overall success rate of RNA fusion testing was 92%. Of the 146 cases successfully sequenced, 14% had a clinically relevant fusion detected. NGS testing success positively correlated with RNA yield (P = .03) but was independent of the tumor fraction, the tumor size, or the number of slides used for extraction. CB preparations were adequate for testing in 45% cases, but the inclusion of direct smears increased the adequacy rate to 92%. There was no significant difference in testing success rates between smears and CB preparations. Conclusions The success of RNA‐based NGS fusion testing depends on the quality and quantity of RNA extracted. The use of direct smears significantly improves the adequacy of cytologic samples for RNA fusion testing for predictive biomarkers.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Utilization of cytology smears improves success rates of RNA‐based next‐generation sequencing gene fusion assays for clinically relevant predictive biomarkers

Ramani

Chen

Broaddus

et al. 2020

Cancer Cytopathology

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“…Selvam and colleagues evaluated gene fusions in 183 solid tumor samples by means of RNA sequencing [35]. In the CRC cohort of 18 cases, they identified two novel fusion gene transcripts, SARAF (TMEM66)-NRG1 and FGFR3-SPDYE4.…”

Section: Introductionmentioning

confidence: 99%

The Landscape of Actionable Gene Fusions in Colorectal Cancer

Pagani

Randon

Guarini

et al. 2019

IJMS

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The treatment scenario of metastatic colorectal cancer (mCRC) has been rapidly enriched with new chemotherapy combinations and biological agents that lead to a remarkable improvement in patients’ outcome. Kinase gene fusions account for less than 1% of mCRC overall but are enriched in patients with high microsatellite instability, RAS/BRAF wild-type colorectal cancer. mCRC patients harboring such alterations show a poor prognosis with standard treatments that could be reversed by adopting novel therapeutic strategies. Moving forward to a positive selection of mCRC patients suitable for targeted therapy in the era of personalized medicine, actionable gene fusions, although rare, represent a peculiar opportunity to disrupt a tumor alteration to achieve therapeutic goal. Here we summarize the current knowledge on potentially actionable gene fusions in colorectal cancer available from retrospective experiences and promising preliminary results of new basket trials.

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“…Multiple groups have demonstrated the feasibility and utility of AMP-based targeted RNA sequencing panels to identify gene fusions across a breadth of hematologic, CNS, and non-CNS solid tumors in the diagnostic setting [40][41][42][43]. Panel composition across studies varied from 53 to 112 genes, with enrichment for targets in both solid tumors (n = 4 studies) and hematologic malignancies (n = 1 study).…”

Section: Discussionmentioning

confidence: 99%

Expanding the Clinical Utility of Targeted RNA Sequencing Panels beyond Gene Fusions to Complex, Intragenic Structural Rearrangements

Schieffer,

Moccia,

Bucknor

et al. 2023

Cancers

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Gene fusions are a form of structural rearrangement well established as driver events in pediatric and adult cancers. The identification of such events holds clinical significance in the refinement, prognostication, and provision of treatment in cancer. Structural rearrangements also extend beyond fusions to include intragenic rearrangements, such as internal tandem duplications (ITDs) or exon-level deletions. These intragenic events have been increasingly implicated as cancer-promoting events. However, the detection of intragenic rearrangements may be challenging to resolve bioinformatically with short-read sequencing technologies and therefore may not be routinely assessed in panel-based testing. Within an academic clinical laboratory, over three years, a total of 608 disease-involved samples (522 hematologic malignancy, 86 solid tumors) underwent clinical testing using Anchored Multiplex PCR (AMP)-based RNA sequencing. Hematologic malignancies were evaluated using a custom Pan-Heme 154 gene panel, while solid tumors were assessed using a custom Pan-Solid 115 gene panel. Gene fusions, ITDs, and intragenic deletions were assessed for diagnostic, prognostic, or therapeutic significance. When considering gene fusions alone, we report an overall diagnostic yield of 36% (37% hematologic malignancy, 41% solid tumors). When including intragenic structural rearrangements, the overall diagnostic yield increased to 48% (48% hematologic malignancy, 45% solid tumor). We demonstrate the clinical utility of reporting structural rearrangements, including gene fusions and intragenic structural rearrangements, using an AMP-based RNA sequencing panel.

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Evaluating gene fusions in solid tumors – Clinical experience using an RNA based 53 gene next-generation sequencing panel

Cited by 8 publications

References 35 publications

Utilization of cytology smears improves success rates of RNA‐based next‐generation sequencing gene fusion assays for clinically relevant predictive biomarkers

Utilization of cytology smears improves success rates of RNA‐based next‐generation sequencing gene fusion assays for clinically relevant predictive biomarkers

The Landscape of Actionable Gene Fusions in Colorectal Cancer

Expanding the Clinical Utility of Targeted RNA Sequencing Panels beyond Gene Fusions to Complex, Intragenic Structural Rearrangements

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