Clinical next-generation sequencing reveals aggressive cancer biology in adolescent and young adult patients

Abstract Brain tumors are the leading cause of death in children. Establishing an accurate diagnosis and therapy is critical for patient management. This study evaluated the clinical utility of GlioSeq, a next-generation sequencing (NGS) assay, for the diagnosis and management of pediatric and young adult patients with brain tumors. Between May 2015 and March 2017, 142 consecutive brain tumors were tested using GlioSeq v1 and subset using GlioSeq v2. Out of 142 samples, 63% were resection specimens and 37% were small stereotactic biopsies. GlioSeq sequencing was successful in 100% and 98.6% of the cases for the detection of mutations and copy number changes, and gene fusions, respectively. Average turnaround time was 8.7 days. Clinically significant genetic alterations were detected in 95%, 66.6%, and 66.1% of high-grade gliomas, medulloblastomas, and low-grade gliomas, respectively. GlioSeq enabled molecular-based stratification in 92 (65%) cases by specific molecular subtype assignment (70, 76.1%), substantiating a neuropathologic diagnosis (18, 19.6%), and diagnostic recategorization (4, 4.3%). Fifty-seven percent of the cases harbored therapeutically actionable findings. GlioSeq NGS analysis offers rapid detection of a wide range of genetic alterations across a spectrum of pediatric brain tumors using formalin-fixed, paraffin-embedded specimens and facilitates integrated molecular-morphologic classification and personalized management of pediatric brain tumors.

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EPCT-21. NEXT-GENERATION SEQUENCING OF CEREBROSPINAL FLUID FOR CLINICAL MOLECULAR DIAGNOSTICS IN ADOLESCENT AND YOUNG ADULT (AYA) BRAIN TUMOR PATIENTS

Neuro-Oncology ◽

10.1093/neuonc/noab090.207 ◽

2021 ◽

Vol 23 (Supplement_1) ◽

pp. i51-i51

Author(s):

Alexandra Miller ◽

Luca Szalontay ◽

Nancy Bouvier ◽

Hamza Ahmed ◽

Katherine Hill ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Next Generation Sequencing ◽

Young Adult ◽

Molecular Diagnostics ◽

Tumor Tissue ◽

Response To Therapy ◽

Adolescent And Young Adult ◽

Low Grade ◽

Next Generation ◽

Generation Sequencing

Abstract Purpose Pediatric central nervous system tumors remain a leading cause of cancer-related death in children and adolescents. Safe sampling of tumor tissue for diagnostic purposes may be challenging. Subclinical detection of disease prior to clinical or imaging progression may provide opportunity for earlier intervention and ultimately improve overall survival. Additionally, our understanding of molecular evolution in response to therapy remains limited, given the rarity of serial sampling of tumor tissue. Methods We report our experience with minimally invasive molecular diagnostics using a validated next generation sequencing assay for sequencing of cerebrospinal fluid (CSF) cell-free DNA (cfDNA) obtained at the time of surgery, by intraventricular catheter or lumbar puncture. All CSF samples were collected as part of clinical care, and results reported to both clinicians and patients/families. Results We analyzed 64 CSF samples from 45 pediatric and adolescent and young adult (AYA) patients (pediatric=25; AYA=20) with primary and recurrent brain tumors across 12 histopathological subtypes including high-grade glioma (n=10), medulloblastoma (n=10), pineoblastoma (n=5), low grade glioma (n=4), diffuse leptomeningeal glioneuronal tumor (DLGNT) (n=4), metastatic retinoblastoma (n=4), ependymoma (n=3), and other (n=5). Somatic alterations were detected in 28/64 samples (44.4%) and in at least one sample per unique patient in 22/45 patients (48.8%). CSF cfDNA positivity was strongly associated with the presence of disseminated disease at the time of collection (86.3%). No association was seen between CSF cfDNA positivity and the timing of CSF collection during the patient’s disease course. Conclusion We identified four general categories where CSF cfDNA testing provided additional relevant diagnostic, prognostic, and/or therapeutic information, impacting clinical assessment and decision making: 1) diagnosis; 2) identification of actionable alterations; 3) track response to therapy; and 4) monitoring tumor evolution. Our findings support broader implementation of clinical CSF cfDNA testing in this population that may improve care.

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SAT0531 NEXT GENERATION SEQUENCING AND AUTOINFLAMMATORY SYNDROMES: CLINICAL AND GENETICAL CORRELATION ON AN ADULT POPULATION FROM A REFERRAL THIRD-CARE CENTRE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5067 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1223-1223

Author(s):

J. R. Marques Soares ◽

M. Antolin Mate ◽

E. Garcia Arumi ◽

E. Tizzano Ferrari ◽

S. Bujan Rivas

Keyword(s):

Next Generation Sequencing ◽

Genetic Data ◽

Clinical Suspicion ◽

Gene Panel ◽

Adult Patients ◽

Next Generation ◽

Related Gene ◽

Unknown Significance ◽

Level Hospital ◽

Generation Sequencing

Background:Systemic autoinflammatory diseases (sAID) are a group of conditions with recurrent episodes of inflammation in absence of infection or autoimmune response. Its physiopathology mainly lies on mono/poligenic mutations involving genes related to the innate immune system response. Next Generation Sequencing (NGS) platformss have been a big step forward on sAID diagnosis, although a clinical and genetic correlation is still needed.Objectives:To review the sAID related gene panel variants identified using NGS sAID gene panel on a cohort of adult patients screened for sAID from a referral third-level hospital.To correlate genetic and clinical findings for sAID related variants identified in order to the clinical suspicion diagnosis of sAID.Methods:A retrospective review of a cohort of adult (≥ 16 yo) patients with available NGS sAID related gene panel (MiSeq Illumina sequencing platform including intron and exon variants from up to 17 sAID genes, with coverage depth > x100) among 2014 and 2019 was performed.Demographic, clinical and genetic data were collected in a database.Genetic variants were classified according to the American College of Medical Genetics/Association for Molecular Pathology classification as benign/likely benign/variable of unknown significance (VUS)/likely pathogenic/pathogenic. In case of polymorphisms or lack of genetic data, the variants were named as unclassified.A description of the cohort and an analysis of the correlation assessment between clinical data and genetic findings were performed.Results:246 out of 299 (82%) patients with NGS sAID gene panel had clinical data available. 170/246 (69%) were adult patients. The medium age was 48 yo, and the M/F ratio was 2.46. 87/170 (51%) adult patients presented 122 variants involving sAID genes (60/87 patients with a single variant). All the variants out of 7 seven were heterozygous variants.Variants were classified according to ACMG/AMP as follow: pathogenic/probably pathogenic: 22/122 (18%), unknown significance: 74/122 (60.6%), benign/probably benign: 6/122 (4.91%). 20/122 (16.4%) were unclassified variants or polymorphisms.The most frequent variants identified involved MEFV (54/122), NOD2/CARD15 (18/122) and TNFRSF1A (17/122 including 12 p.Arg121Gln variants) genes.37/122 (30%) variants correlated with the clinical picture in 33 patients, allowing to confirm the suspected diagnosis. Among the 122 variants, 7 not previously communicated variants were identified.No somatic variants were found.Conclusion:NGS sAID related gene panel is a useful tool for sAID diagnosis. In this cohort of 170 adult patients from a referral third-level hospital, genetic tests identified sAID related variants in almost half of them.20% of patients who underwent genetic NGS sAID related gene panel studies were finally diagnosed with sAID.The identification of a genetic variant (even pathogenic / likely pathogenic variant) is not diagnostic for sAID if there is not a suggestive clinical picture.Despite genetic findings, a careful evaluation of clinical – genetic correlation is needed to confirm the suspicion diagnosis, especially for low penetrance variants like TNFRSF1A p. Arg121Gln.References:Diagnostic utility of a targeted next-generation sequencing gene panel in the clinical suspicion of systemic autoinflammatory diseases: a multi-center study. Karacan I, Balamir A, Uğurlu S, et al. . Rheumatol Int. 2019 May;39(5):911-919. doi: 10.1007/s00296-019-04252-5. Epub 2019 Feb 19.Disclosure of Interests:None declared

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Assessing the Value of Next-Generation Sequencing Tests in a Dynamic Environment

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_200825 ◽

2018 ◽

pp. 139-146 ◽

Cited By ~ 3

Author(s):

Howard A. Burris ◽

Leonard B. Saltz ◽

Peter P. Yu

Keyword(s):

Next Generation Sequencing ◽

Cancer Biology ◽

Health Care Policy ◽

Clinical Care ◽

Dynamic Environment ◽

Investigational Drug ◽

Next Generation ◽

Genomic Alterations ◽

Clinical Annotation ◽

Generation Sequencing

Next-generation sequencing (NGS)–based technology has lowered the cost of cancer testing for genomic alterations and is now commercially available from a growing number of diagnostic laboratories. However, laboratories vary in the methodologies underlying their tests, the types and numbers of genomic alterations covered by the test, and the clinical annotation of the sequencing findings. Determining the value of NGS tests is dependent on whether it is used to support clinical trials or as a part of routine clinical care at a time when both the investigational drug pipeline and the list of U.S. Food and Drug Administration–approved or Compendium-listed therapeutics is in a high state of flux. Reimbursement policy for NGS testing by the Centers for Medicare & Medicaid is evolving as the value of NGS testing becomes more clearly defined for specific clinical situations. Patient care and clinical decisions-making are dependent on the oncologist’s knowledge of when NGS testing has value. Here, we review principles and practice for NGS testing in this dynamic confluence of technology, cancer biology, and health care policy.

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