Clinical targeted exome-based sequencing in combination with genome-wide copy number profiling: precision medicine analysis of 203 pediatric brain tumors

Ramkissoon, Shakti; Bandopadhayay, Pratiti; Hwang, Jaeho; Ramkissoon, Lori; Greenwald, Noah F.; Schumacher, Steven E.; O’Rourke, Ryan; Pinches, Nathan; Ho, Patricia; Malkin, Hayley; Sinai, Claire; Filbin, Mariella G.; Plant, Ashley; Bi, Wenya Linda; Chang, Michael S.; Yang, Edward; Wright, Karen; Manley, Peter; Ducar, Matthew D.; Alexandrescu, Sanda; Lidov, Hart G.W.; Delalle, Ivana; Goumnerova, Liliana; Church, Alanna J.; Janeway, Katherine A.; Harris, Marian H.; MacConaill, Laura E.; Folkerth, Rebecca D.; Lindeman, Neal I.; Stiles, Charles D.; Kieran, Mark W.; Ligon, Azra H.; Santagata, Sandro; Dubuc, Adrian M.; Susan, N.; Beroukhim, Rameen; Ligon, Keith L.

doi:10.1093/neuonc/now294

Cited by 67 publications

(70 citation statements)

References 42 publications

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“…13). Similar efforts on childhood cancers such as pediatric glioma and neuroblastoma were also reported (14,15). These studies laid the foundation for the approval of clinical use of highthroughput sequencing-based gene panels such as the Foundation Medicine panel and Memorial Sloan Kettering IMPACT panel by the FDA.…”

Section: Introductionmentioning

confidence: 72%

Prospective Clinical Sequencing of Adult Glioma

Zheng

Alfaro-Munoz

Wei

et al. 2019

Molecular Cancer Therapeutics

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Malignant gliomas are a group of intracranial cancers associated with disproportionately high mortality and morbidity. Here, we report ultradeep targeted sequencing of a prospective cohort of 237 tumors from 234 patients consisting of both glioblastoma (GBM) and lower-grade glioma (LGG) using our customized gene panels. We identified 2,485 somatic mutations, including single-nucleotide substitutions and small indels, using a validated in-house protocol. Sixty-one percent of the mutations were contributed by 12 hypermutators. The hypermutators were enriched for recurrent tumors and had comparable outcome, and most were associated with temozolomide exposure. TP53 was the most frequently mutated gene in our cohort, followed by IDH1 and EGFR. We detected at least one EGFR mutation in 23% of LGGs, which was significantly higher than 6% seen in The Cancer Genome Atlas, a pattern that can be partially explained by the different patient composition and sequencing depth. IDH hotspot mutations were found with higher frequencies in LGG (83%) and secondary GBM (77%) than primary GBM (9%). Multivariate analyses controlling for age, histology, and tumor grade confirm the prognostic value of IDH mutation. We predicted 1p/19q status using the panel sequencing data and received only modest performance by benchmarking the prediction to FISH results of 50 tumors. Targeted therapy based on the sequencing data resulted in three responders out of 14 participants. In conclusion, our study suggests ultradeep targeted sequencing can recapitulate previous findings and can be a useful approach in the clinical setting.

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Section: Introductionmentioning

confidence: 72%

Prospective Clinical Sequencing of Adult Glioma

Zheng

Alfaro-Munoz

Wei

et al. 2019

Molecular Cancer Therapeutics

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“…Several recent publications have defined the utility of broad genomic screening in pediatric CNS tumors, including the following: (a) University of California San Francisco, using targeted sequencing of 510 genes; (b) Dana‐Farber Cancer Institute, using the OncoPanel of 309 genes, OncoCopy, and array comparative genomic hybridization; (c) University of Washington, utilizing the OncoPlex platform evaluating 262 cancer‐related genes; (d) University of Michigan, utilizing transcriptome sequencing augmented by either whole exome sequencing or targeted sequencing of 1706 genes; and (e) a study conducted at Foundation Medicine, Inc. reporting the analysis of 315 cancer‐related genes in 282 pediatric LGGs and HGGs . We report the utility of fusion analysis of pediatric CNS tumors using a smaller RNA‐based panel consisting of 53 genes.…”

Section: Discussionmentioning

confidence: 99%

“…Many tertiary care centers currently utilize a broad, panel‐based approach for assessment of potentially actionable genetic alterations in CNS tumors. Recently, a handful of studies demonstrated the feasibility and utility of incorporating molecular diagnosis into the care of children with CNS tumors . These reports detail the use of large 300‐500‐gene panels focused on mutations common in human cancers but not specific to pediatric tumors.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a handful of studies demonstrated the feasibility and utility of incorporating molecular diagnosis into the care of children with CNS tumors. [4][5][6][7][8] These reports detail the use of large 300-500-gene panels focused on mutations common in human cancers but not specific to pediatric tumors. They are also costly and often have limited reimbursement from insurance companies.…”

Section: Introductionmentioning

confidence: 99%

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Targeted fusion analysis can aid in the classification and treatment of pediatric glioma, ependymoma, and glioneuronal tumors

Lake

Donson

Prince

et al. 2019

Pediatric Blood & Cancer

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Background The use of next‐generation sequencing for fusion identification is being increasingly applied and aids our understanding of tumor biology. Some fusions are responsive to approved targeted agents, while others have future potential for therapeutic targeting. Although some pediatric central nervous system tumors may be cured with surgery alone, many require adjuvant therapy associated with acute and long‐term toxicities. Identification of targetable fusions can shift the treatment paradigm toward earlier integration of molecularly targeted agents. Methods Patients diagnosed with glial, glioneuronal, and ependymal tumors between 2002 and 2019 were retrospectively reviewed for fusion testing. Testing was done primarily using the ArcherDx FusionPlex Solid Tumor panel, which assesses fusions in 53 genes. In contrast to many previously published series chronicling fusions in pediatric patients, we compared histological features and the tumor classification subtype with the specific fusion identified. Results We report 24 cases of glial, glioneuronal, or ependymal tumors from pediatric patients with identified fusions. With the exception of BRAF:KIAA1549 and pilocytic/pilomyxoid astrocytoma morphology, and possibly QKI‐MYB and angiocentric glioma, there was not a strong correlation between histological features/tumor subtype and the specific fusion. We report the unusual fusions of PPP1CB‐ALK, CIC‐LEUTX, FGFR2‐KIAA159, and MN1‐CXXC5 and detail their morphological features. Conclusions Fusion testing proved to be informative in a high percentage of cases. A large majority of fusion events in pediatric glial, glioneuronal, and ependymal tumors can be identified by relatively small gene panels.

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“…Recently, altered QKI expression was implicated in various human cancers, including colorectal cancer, 33 paediatric brain tumours, 34 glioma, 35 renal clear cell carcinoma, 9 lung cancer 17 and prostate cancer. 18 In this study, we measured QKI-6 expression and determined its role in regulating bladder cancer in vitro and in vivo, and we also investigated the molecular mechanism underlying QKI-6's effect in bladder cancer cells.…”

Section: Discussionmentioning

confidence: 99%

QKI‐6 inhibits bladder cancer malignant behaviours through down‐regulating E2F3 and NF‐κB signalling

Shi

Deng

Zhou

et al. 2019

J Cellular Molecular Medi

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Quaking homolog (QKI) is a member of the RNA‐binding signal transduction and activator of proteins family. Previous studies showed that QKI possesses the tumour suppressor activity in human cancers by interacting with the 3'‐untraslated region (3'‐UTR) of various gene transcripts via the STAR domain. This study first assessed the association of QKI‐6 expression with clinicopathological and survival data from bladder cancer patients and then investigated the underlying molecular mechanisms. Bladder cancer tissues (n = 223) were subjected to immunohistochemistry, and tumour cell lines and nude mice were used for different in vitro and in vivo assays following QKI‐6 overexpression or knockdown. QKI‐6 down‐regulation was associated with advanced tumour TNM stages and poor patient overall survival. QKI‐6 overexpression inhibited bladder cancer cell growth and invasion capacity, but induced tumour cell apoptosis and cell cycle arrest. Furthermore, ectopic expression of QKI‐6 reduced tumour xenograft growth and expression of proliferation markers, Ki67 and PCNA. However, knockdown of QKI‐6 expression had opposite effects in vitro and in vivo. QKI‐6 inhibited expression of E2 transcription factor 3 (E2F3) by directly binding to the E2F3 3'‐UTR, whereas E2F3 induced QKI‐6 transcription by binding to the QKI‐6 promoter in negative feedback mechanism. QKI‐6 expression also suppressed activity and expression of nuclear factor‐κB (NF‐κB) signalling proteins in vitro, implying a novel multilevel regulatory network downstream of QKI‐6. In conclusion, QKI‐6 down‐regulation contributes to bladder cancer development and progression.

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Clinical targeted exome-based sequencing in combination with genome-wide copy number profiling: precision medicine analysis of 203 pediatric brain tumors

Abstract: The combination of OncoPanel and OncoCopy multiplex genomic assays can identify critical diagnostic, prognostic, and treatment-relevant alterations and represents an effective precision medicine approach for clinical evaluation of pediatric brain tumors.

Cited by 67 publications

References 42 publications

Prospective Clinical Sequencing of Adult Glioma

Prospective Clinical Sequencing of Adult Glioma

Targeted fusion analysis can aid in the classification and treatment of pediatric glioma, ependymoma, and glioneuronal tumors

QKI‐6 inhibits bladder cancer malignant behaviours through down‐regulating E2F3 and NF‐κB signalling

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