Gene-sequencing test detects brain tumours

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Brain tumours can be rapidly and accurately profiled with a next-generation, gene-sequencing test developed at University of Pittsburgh Medical Centre (UPMC) and the University of Pittsburgh School of Medicine.

The test, called GlioSeq™, is now being used by UPMC oncologists to help guide treatment planning of brain cancers, said senior investigator Dr Marina Nikiforova, professor of pathology, Pitt School of Medicine, and director of UPMC’s Molecular & Genomic Pathology Laboratory.

“The diagnosis of brain tumours has been based primarily on cellular features seen under the microscope,” Nikiforova said. “However, patients with tumours that look identical may experience different clinical outcomes and responses to treatment because the underlying genetic characteristics of their tumours differ. We designed this panel to quickly identify those traits from very small biopsies of the brain lesion.”

For the study, the researchers used GlioSeq™ to test 54 adult and paediatric brain tumour samples for genetic abnormalities, including point mutations, gene fusions, and small gene insertions and deletions that had already been characterised by other means. They used next-generation sequencing to simultaneously identify all previously known alterations, as well as many additional genetic markers in these tumours. This provided important information on classification of these tumours, and on possible new targets for therapy.

“This can help guide the physician and the patient in planning treatment, since the molecular information allows us to more precisely characterise tumours and more confidently predict survival and response to therapy. In addition, Glioseq™ facilitates the identification of clinical trial options with the appropriate molecular targets, as well as cases in which molecularly targeted drugs are available,” said co-investigator Dr Frank Lieberman, professor of neurology, neurosurgery and medical oncology at Pitt and director of the Adult Neuro-Oncology Programme at UPMC Cancer Centre, partner of the University of Pittsburgh Cancer Institute.

“Using GlioSeq™ helps us to understand in detail the genetic profile of brain tumors, and takes us one step closer to personalized management of our patients,” Nikiforova said. “We are also working on further improving this test to include additional, recently discovered molecular alterations.”

Background: Identification of genetic changes in CNS tumors is important for the appropriate clinical management of patients. Our objective was to develop a next-generation sequencing (NGS) assay for simultaneously detecting the various types of genetic alterations characteristic for adult and pediatric CNS tumors that can be applied to small brain biopsies.
Methods: We report an amplification-based targeted NGS assay (GlioSeq) that analyzes 30 genes for single nucleotide variants (SNVs) and indels, 24 genes for copy number variations (CNVs), and 14 types of structural alterations in BRAF, EGFR, and FGFR3 genes in a single workflow. GlioSeq performance was evaluated in 54 adult and pediatric CNS tumors, and the results were compared with fluorescence in-situ hybridization, Sanger sequencing, and reverse transcription PCR.
Results: GlioSeq correctly identified 71/71 (100%) genetic alterations known to be present by conventional techniques, including 56 SNVs/indels, 9 CNVs, 3 EGFRvIII, and 3 KIAA1549-BRAF fusions. Only 20 ng of DNA and 10 ng of RNA were required for successful sequencing of 100% frozen and 96% formalin-fixed, paraffin-embedded tissue specimens. The assay sensitivity was 3%–5% of mutant alleles for SNVs and 1%–5% for gene fusions. The most commonly detected alterations were IDH1, TP53, TERT, ATRX. CDKN2A, and PTEN in high-grade gliomas, followed by BRAF fusions in low-grade gliomas and H3F3A mutations in pediatric gliomas.
Conclusions: GlioSeq NGS assay offers accurate and sensitive detection of a wide range of genetic alterations in a single workflow. It allows rapid and cost-effective profiling of brain tumor specimens and thus provides valuable information for patient management.

University of Pittsburgh Schools of Health Sciences material
Neuro Oncology abstract

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