Validation of OncoPanel: A Targeted Next-Generation Sequencing Assay for the Detection of Somatic Variants in Cancer

Garcia, Elizabeth; Minkovsky, Alissa; Jia, Yonghui; Ducar, Matthew D.; Shivdasani, Priyanka; Gong, Xin; Ligon, Azra H.; Sholl, Lynette M.; Kuo, Frank C.; MacConaill, Laura E.; Lindeman, Neal I.; Dong, Fei

doi:10.5858/arpa.2016-0527-oa

Cited by 370 publications

(293 citation statements)

References 18 publications

(23 reference statements)

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“…For biopsies where whole exome sequencing failed, somatic mutation calls, copy number alterations, and ETS fusion status were taken from OncoPanel, a clinical panel sequencing test available at DFCI 65 .…”

Section: Methodsmentioning

confidence: 99%

Transcriptional mediators of treatment resistance in lethal prostate cancer

Cuoco

Crowdis

et al. 2020

Preprint

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Metastatic castration resistant prostate cancer (mCRPC) is primarily treated with therapies that prevent transcriptional activity of the androgen receptor (AR), cause DNA damage, or prevent cell division. Clinical resistance to these therapies, including second-generation androgen-targeting compounds such as enzalutamide and abiraterone, is nearly universal. Other treatment modalities, including immune checkpoint inhibitors, have provided minimal benefit except in rare subsets of patients1,2. Both tumour intrinsic and extrinsic cellular programs contributing to therapeutic resistance remain areas of active investigation. Here we use full-length single-cell RNA-sequencing (scRNA-seq) to identify the transcriptional states of cancer and immune cells in the mCRPC microenvironment. Within cancer cells, we identified transcriptional patterns that mediate a significant proportion of inherited risk for prostate cancer, extensive heterogeneity in AR splicing within and between tumours, and vastly divergent regulatory programs between adenocarcinoma and small cell carcinoma. Moreover, upregulation of TGF-β signalling and epithelial-mesenchymal transition (EMT) were both associated with resistance to enzalutamide. We found that some lymph node metastases, but no bone metastases, were heavily infiltrated by dysfunctional CD8+ T cells, including cells undergoing dramatic clonal expansion during enzalutamide treatment. Our findings suggest avenues for rational therapeutic approaches targeting both tumour-intrinsic and immunological pathways to combat resistance to current treatment options.

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Section: Methodsmentioning

confidence: 99%

Transcriptional mediators of treatment resistance in lethal prostate cancer

Cuoco

Crowdis

et al. 2020

Preprint

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“…Libraries were pooled in equal volume and sequenced on an Illumina MiSeq Nano flow cell to estimate concentration based on the number of index reads per sample (all samples yielded ≥250 ng DNA to pursue hybrid capture). Library hybridization used a custom biotinylated RNA bait set (Agilent SureSelect) targeting the full coding regions of 447 genes and 60 intronic regions (OncoPanel version 3; Garcia et al, ; Sholl et al, ; Appendix ). Hybrid‐capture libraries were then sequenced on an Illumina HiSeq 3,000.…”

Section: Methodsmentioning

confidence: 99%

Oral keratosis of unknown significance shares genomic overlap with oral dysplasia

et al. 2019

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Objectives To identify molecular characteristics of keratosis of unknown significance and to nominate pathways of molecular progression to oral cancer. Our work could provide a rationale for monitoring and treating these lesions definitively. Methods Patients with oral leukoplakia were eligible for our prospective observational study. We correlated alterations in cancer‐associated genes with clinical and histopathologic variables (keratosis of unknown significance vs. moderate‐to‐severe dysplasia) and compared these alterations to a previously molecularly characterized oral cancer population. Results Of 20 enrolled patients, 13 (65%) had evidence of keratosis of unknown significance, while seven (35%) had dysplasia. Nine patients (45%) developed oral cancer (4/13 with keratosis of unknown significance, 5/7 with dysplasia). At a median follow‐up of 67 (range 22–144) months, median overall survival was significantly shorter for patients with dysplasia (hazard ratio 0.11, p = .02). KMT2C and TP53 alterations were most frequent (75% and 35%, respectively). There were molecular similarities between keratosis of unknown significance and dysplasia patients, with no significant differences in mutational frequency among genes with ≥15% rate of alteration. Conclusions Among patients with leukoplakia, both patients with keratosis of unknown significance and patients with dysplasia developed oral cancer. Molecular alterations between these two groups were similar at this sample size.

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“…Oncopanel is a next generation hybrid capture sequencing assay that interrogates the exons of 447 genes and 191 intronic regions across 60 genes for structural rearrangements. Structural rearrangements are evaluated with BreaKmer analysis, as previously described . The assay was performed on DNA isolated from FFPE tissue.…”

Section: Methodsmentioning

confidence: 99%

“…Structural rearrangements are evaluated with BreaKmer analysis, as previously described. 12 The assay was performed on DNA isolated from FFPE tissue.…”

Section: Targeted Exome Sequencing (Oncopanel)mentioning

confidence: 99%

Expanding the spectrum of pediatric NTRK‐rearranged fibroblastic tumors to the central nervous system: A case report with RBPMS‐NTRK3 fusion

et al. 2018

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We report a case of a 20-month-old male presenting with seizures who was found to have a hyperintense lesion on T2-weighted images of magnetic resonance imaging in the left medial temporal lobe that was initially clinically and radiologically thought to be either low-grade glioma or focal cortical dysplasia. Histologic, immunohistochemical and molecular evaluation (array comparative genomic hybridization, Archer fusion panel) of the resection specimen demonstrated a highly infiltrative fibroblastic spindle cell neoplasm with mild nuclear atypia and an RBPMS-NTRK3 fusion. NTRK-fused mesenchymal tumors are known to involve extracranial sites but, to our knowledge, have not been described within the central nervous system. Accurate and timely diagnosis of this entity has important prognostic and therapeutic implications, as NTRK-fused tumors may recur locally and may respond to selective kinase inhibitor therapies.

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Validation of OncoPanel: A Targeted Next-Generation Sequencing Assay for the Detection of Somatic Variants in Cancer

Abstract: - The analytical validation of OncoPanel demonstrates the ability of targeted next-generation sequencing to detect multiple types of genetic alterations across a panel of genes implicated in cancer biology.

Cited by 370 publications

References 18 publications

Transcriptional mediators of treatment resistance in lethal prostate cancer

Transcriptional mediators of treatment resistance in lethal prostate cancer

Oral keratosis of unknown significance shares genomic overlap with oral dysplasia

Expanding the spectrum of pediatric NTRK‐rearranged fibroblastic tumors to the central nervous system: A case report with RBPMS‐NTRK3 fusion

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