Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy

Cassie Kline(University of California, San Francisco), Nancy M. Joseph(University of California, San Francisco), James P. Grenert(University of California, San Francisco), Jessica Van Ziffle(University of California, San Francisco), Eric Talevich(Cancer Genomics Centre), Courtney Onodera(Cancer Genomics Centre), Mariam Aboian(University of California, San Francisco), Soonmee Cha(University of California, San Francisco), David R. Raleigh(University of California, San Francisco), Steve Braunstein(University of California, San Francisco), Joseph C. Torkildson(UCSF Benioff Children's Hospital), David Samuel(Children's Hospital Central California), Michelle Bloomer(University of California, San Francisco), Alejandra G. de Alba Campomanes(University of California, San Francisco), Anuradha Banerjee(University of California, San Francisco), Nicholas Butowski(Neurological Surgery), Corey Raffel(Neurological Surgery), Tarık Tihan(University of California, San Francisco), Andrew W. Bollen(University of California, San Francisco), Joanna J. Phillips(University of California, San Francisco), W. Michael Korn(University of California San Francisco Medical Center), Iwei Yeh(University of California, San Francisco), Boris C. Bastian(University of California, San Francisco), Nalin Gupta(Neurological Surgery), Sabine Mueller(University of California, San Francisco), Arie Perry(University of California, San Francisco), Theodore Nicolaides(University of California, San Francisco), David A. Solomon(University of California, San Francisco)
Neuro-Oncology
October 4, 2016
10.1093/neuonc/now254
Cited by 233Open Access
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Abstract

Background: Molecular profiling is revolutionizing cancer diagnostics and leading to personalized therapeutic approaches. Herein we describe our clinical experience performing targeted sequencing for 31 pediatric neuro-oncology patients. Methods: We sequenced 510 cancer-associated genes from tumor and peripheral blood to identify germline and somatic mutations, structural variants, and copy number changes. Results: Genomic profiling was performed on 31 patients with tumors including 11 high-grade gliomas, 8 medulloblastomas, 6 low-grade gliomas, 1 embryonal tumor with multilayered rosettes, 1 pineoblastoma, 1 uveal ganglioneuroma, 1 choroid plexus carcinoma, 1 chordoma, and 1 high-grade neuroepithelial tumor. In 25 cases (81%), results impacted patient management by: (i) clarifying diagnosis, (ii) identifying pathogenic germline mutations, or (iii) detecting potentially targetable alterations. The pathologic diagnosis was amended after genomic profiling for 6 patients (19%), including a high-grade glioma to pilocytic astrocytoma, medulloblastoma to pineoblastoma, ependymoma to high-grade glioma, and medulloblastoma to CNS high-grade neuroepithelial tumor with BCOR alteration. Multiple patients had pathogenic germline mutations, many of which were previously unsuspected. Potentially targetable alterations were identified in 19 patients (61%). Additionally, novel likely pathogenic alterations were identified in 3 cases: an in-frame RAF1 fusion in a BRAF wild-type pleomorphic xanthoastrocytoma, an inactivating ASXL1 mutation in a histone H3 wild-type diffuse pontine glioma, and an in-frame deletion within exon 2 of MAP2K1 in a low-grade astrocytic neoplasm. Conclusions: Our experience demonstrates the significant impact of molecular profiling on diagnosis and treatment of pediatric brain tumors and confirms its feasibility for use at the time of diagnosis or recurrence.

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