scholarly journals PATH-03. CLINICAL UTILITY OF NEXT GENERATION SEQUENCING IN IDH-WILDTYPE GLIOBLASTOMA: THE DANA-FARBER CANCER INSTITUTE EXPERIENCE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii164-ii164
Author(s):  
Mary Jane Lim-Fat ◽  
Gilbert Youssef ◽  
Mehdi Touat ◽  
Bryan Iorgulescu ◽  
Eleanor Woodward ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Next Generation Sequencing ◽  
Immune Checkpoint Blockade ◽  
Next Generation ◽  
Single Nucleotide Variants ◽  
Dana Farber Cancer Institute ◽  
Clinical Records ◽  
Ngs Data ◽  
Generation Sequencing

Abstract BACKGROUND Comprehensive next generation sequencing (NGS) is available through many academic institutions and commercial entities, and is incorporated in practice guidelines for glioblastoma (GBM). We retrospective evaluated the practice patterns and utility of incorporating NGS data into routine care of GBM patients at a clinical trials-focused academic center. METHODS We identified 1,011 consecutive adult patients with histologically confirmed GBM with OncoPanel testing, a targeted exome NGS platform of 447 cancer-associated genes at Dana Farber Cancer Institute (DFCI), from 2013-2019. We selected and retrospectively reviewed clinical records of all IDH-wildtype GBM patients treated at DFCI. RESULTS We identified 557 GBM IDH-wildtype patients, of which 227 were male (40.7%). OncoPanel testing revealed 833 single nucleotide variants and indels in 44 therapeutically relevant genes (Tier 1 or 2 mutations) including PIK3CA (n=51), BRAF (n=9), FGFR1 (n=8), MSH2 (n=4), MSH6 (n=2) and MLH1 (n=1). Copy number analysis revealed 509 alterations in 18 therapeutically relevant genes including EGFR amplification (n= 186), PDGFRA amplification (N=39) and CDKN2A/2B homozygous loss (N=223). Median overall survival was 17.5 months for the whole cohort. Seventy-four therapeutic clinical trials accrued 144 patients in the upfront setting (25.9%) and 203 patients (36.4%) at recurrence. Altogether, NGS data for 107 patients (19.2%) were utilized for clinical trial enrollment or targeted therapy indications. High mutational burden (>17mutations/Mb) was identified in 11/464 samples (2.4%); of whom 3/11 received immune checkpoint blockade. Four patients received compassionate use therapy targeting EGFRvIII (rindopepimut, n=2), CKD4/6 (abemaciclib, n=1) and BRAFV600E (dabrafenib/trametinib, n=1). CONCLUSION While NGS has greatly improved diagnosis and molecular classification, we highlight that NGS remains underutilized in selecting therapy in GBM, even in a setting where clinical trials and off-label therapies are relatively accessible. Continued efforts to develop better targeted therapies and efficient clinical trial design are required to maximize the potential benefits of genomically-stratified data.

scholarly journals Clinical Trial Accrual Targeting Genomic Alterations After Next-Generation Sequencing at a Non-National Cancer Institute–Designated Cancer Program

2016 ◽  
Vol 12 (4) ◽  
pp. e396-e404 ◽  
Author(s):  
Kalyan C. Mantripragada ◽  
Adam J. Olszewski ◽  
Andrew Schumacher ◽  
Kimberly Perez ◽  
Ariel Birnbaum ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Next Generation Sequencing ◽  
National Cancer Institute ◽  
Next Generation ◽  
Genomic Alterations ◽  
Cancer Centers ◽  
Cancer Program ◽  
Clinical Trial Accrual ◽  
Generation Sequencing

Purpose: Successful clinical trial accrual targeting uncommon genomic alterations will require broad national participation from both National Cancer Institute (NCI)–designated comprehensive cancer centers and community cancer programs. This report describes the initial experience with clinical trial accrual after next-generation sequencing (NGS) from three affiliated non–NCI-designated cancer programs. Materials and Methods: Clinical trial participation was reviewed after enrollment of the first 200 patients undergoing comprehensive genomic profiling by NGS as part of an institutional intuitional review board–approved protocol at three affiliated hospitals in Rhode Island and was compared with published experience from NCI-designated cancer centers. Results: Patient characteristics included a median age of 64 years, a median of two lines of prior therapy, and a predominance of GI carcinomas (58%). One hundred sixty-four of 200 patients (82%) had adequate tumor for NGS, 95% had genomic alterations identified, and 100% had variants of unknown significance. Fifteen of 164 patients (9.2%) enrolled in genotype-directed clinical trials, and three patients (1.8%) received commercially available targeted agents off clinical trials. The reasons for nonreceipt of NGS-directed therapy were no locally available matching trial (48.6%), ineligibility (33.6%) because of comorbidities or interim clinical deterioration, physician's choice of a different therapy (6.8%), or stable disease (11%). Conclusion: This experience demonstrates that a program enrolling patients in specific targeted agent clinical trials after NGS can be implemented successfully outside of the NCI-designated cancer program network, with comparable accrual rates. This is important because targetable genes have rare mutation rates and clinical trial accrual after NGS is low.

No-cost next generation sequencing of advanced cancer patients within the Strata Precision Oncology Network supports clinical trial enrollment.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3073-3073
Author(s):  
Marc Ryan Matrana ◽  
Scott A. Tomlins ◽  
Kat Kwiatkowski ◽  
Khalis Mitchell ◽  
Jennifer Marie Suga ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Next Generation Sequencing ◽  
Clinical Samples ◽  
Precision Oncology ◽  
Cancer Type ◽  
Next Generation ◽  
Match Trial ◽  
The Impact ◽  
Generation Sequencing

3073 Background: Widespread integration of systematized next generation sequencing (NGS)-based precision oncology is hindered by numerous barriers. Hence, we developed the Strata trial (NCT03061305), a screening protocol to determine the impact of scaled precision oncology. Methods: We implemented no-cost NGS on formalin fixed paraffin embedded (FFPE) clinical samples for all patients with advanced tumors, a common portfolio of partnered therapeutic clinical trials, and robust infrastructure development across the Strata Precision Oncology Network. Results: Across the network of 17 centers, specimens from 8673/9222 (94%) patients were successfully tested in the Strata CLIA/CAP/NCI-MATCH accredited laboratory using comprehensive amplicon-based DNA and RNA NGS. Patients were tested with one of three StrataNGS test versions; the most recent panel assesses all classes of actionable alterations (mutations, copy number alterations, gene fusions, microsatellite instability, tumor mutation burden and PD-L1 expression). Median surface area of received FFPE tumor samples was 25mm2 (interquartile range 9-95mm2), and the median turnaround time from sample receipt to report was 6 business days. 2577 (27.9%) patients had highly actionable alterations, defined as alterations associated with within-cancer type FDA approved or NCCN guideline recommended therapies (1072 patients), NCI-MATCH trial arms (1467 patients), Strata-partnered therapeutic trials (327 patients), or specific alteration-matched FDA approved therapies in patients with cancers of unknown primary (71 patients). Of the 1467 patients matched to an NCI-MATCH trial arm, 15 enrolled. Of the 327 patients matched to one of nine Strata-partnered clinical trials, 77 (24%) were screen failures, while 250 (76%) have either enrolled or are being actively followed for enrollment upon progression. Conclusions: Through streamlined consent methods, electronic medical record queries, and high throughput laboratory testing at no cost to patients, we demonstrate that scaled precision oncology is feasible across a diverse network of healthcare systems when paired with access to relevant clinical trials. Clinical trial information: NCT03061305.

Clinical application of comprehensive next generation sequencing in the management of metastatic cancer in adults.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 101-101 ◽  
Author(s):  
Erin Frances Cobain ◽  
Dan R. Robinson ◽  
Yi-Mi Wu ◽  
Jessica Everett ◽  
Erica Rabban ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Next Generation Sequencing ◽  
Metastatic Cancer ◽  
Tumor Board ◽  
Next Generation ◽  
Genomic Alterations ◽  
Targeted Ngs ◽  
Generation Sequencing ◽  
Over Time

101 Background: Next generation sequencing (NGS) platforms are frequently utilized in the care of patients (pts) with metastatic cancer to identify tumor genomic alterations that may serve as therapeutic targets. Biomarker driven clinical trials, such as NCI-Molecular Analysis for Therapy Choice (MATCH) and Targeted Agent and Profiling Utilization Registry (TAPUR) have augmented clinicians’ ability use this strategy in clinical practice. Methods: From 2011-2015 over 500 adult pts with metastatic solid tumors of diverse lineage underwent biopsy for whole exome and transcriptome sequencing of tumor and matched normal sample through the Michigan Oncology Sequencing Center (Mi-Oncoseq). Genomic alterations identified were reviewed at Precision Medicine Tumor Board and tiered according to their clinical relevance. Alterations were also classified as being identifiable or not identifiable by a commercially available NGS assay such as Oncomine Focus or FoundationOne. Results: Genomic alterations identified by Mi-Oncoseq provided rationale for enrollment in a clinical trial in 72% (n = 360) of cases. The percentage of pts who did receive therapy informed by NGS results increased over time (5% in 2012 versus 11% in 2015). 11% of pts (n = 55) had a pathogenic germline variant (PGV) conferring increased cancer risk identified, none of which were known prior to study entry. Numerous pts had clinically relevant molecular alterations identified by Mi-Oncoseq that would not have been identifiable utilizing targeted NGS assays, including PGVs and activating/deleterious gene fusions. Conclusions: Comprehensive NGS, including DNA and RNA sequencing, readily identifies potentially actionable alterations in the vast majority of pts beyond what is observed with use of targeted NGS platforms. Observed modest increase in utilization of NGS results to direct subsequent therapy over time is due to clinician employment of this strategy earlier in the therapeutic algorithm, increased availability of biomarker driven clinical trials and changes in physician referral patterns. Comprehensive NGS identified many unanticipated PGVs of clinical importance for pts and their families. Clinical trial information: HUM00067928.

An observational study profiling biospecimens from 10,000 metastatic prostate cancer (mPCa) patients to screen for molecular alterations.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS402-TPS402
Author(s):  
Won Kim ◽  
Kat Kwiatkowski ◽  
Justin Brown ◽  
Dan R Rhodes ◽  
Scott A Tomlins ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Next Generation Sequencing ◽  
Observational Study ◽  
Large Scale ◽  
Screening Program ◽  
Next Generation ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

TPS402 Background: Despite recent success in development and use of targeted agents in patients with solid tumors, there is a paucity of such therapies approved for use in prostate cancer. This observational study provides next-generation sequencing (NGS) to men with mPCa to evaluate the proportion of patients available for targeted therapy clinical trials in mPCa and to assess the feasibility of using a large-scale NGS screening program to match patients for eligibility criteria in clinical trials. Methods: Using a virtual clinical trial model to maximize patient access and enrollment, this study is providing next-generation sequencing (NGS) to 10,000 men with mPCa. Patients with histologically-documented mPCa and surplus formalin-fixed paraffin-embedded tumor tissue are eligible for enrollment. Leftover archival tissue is submitted for NGS to Strata Oncology, a clinical laboratory improvement amendments (CLIA)-certified lab. The StrataNGS assay sequences DNA and RNA, and simultaneously detects a range of actionable genomic alterations including gene mutations, small insertions and deletions, copy number changes, and gene fusions in 87 cancer-related genes. Microsatellite instability status is determined via the number of length variant alleles observed in NGS sequencing data at several microsatellite loci. Test reports presented to the clinician include all positive and negative variants detected, and information about potential matching therapeutic protocols. Clinical trial information: NCT03061305.

Influence of Next-Generation Sequencing on Advancements in the Diagnosis of Major Psychiatric Diseases - A Review

2020 ◽  
Author(s):  
Maheen Nisar
Keyword(s):  
Next Generation Sequencing ◽  
Mental Disorders ◽  
Attention Deficit Disorder ◽  
Autism Spectrum ◽  
Next Generation ◽  
Single Nucleotide Variants ◽  
New Genes ◽  
Depth Analysis ◽  
Pubmed Search ◽  
Generation Sequencing

Rapid progress is being made in the development of next-generation sequencing (NGS) technologies, allowing repeated findings of new genes and a more in-depth analysis of genetic polymorphisms behind the pathogenesis of a disease. In a field such as psychiatry, characteristic of vague and highly variable somatic manifestations, these technologies have brought great advances towards diagnosing various psychiatric and mental disorders, identifying high-risk individuals and towards more effective corresponding treatment. Psychiatry has the difficult task of diagnosing and treating mental disorders without being able to invariably and definitively establish the properties of its illness. This calls for diagnostic technologies that go beyond the traditional ways of gene manipulation to more advanced methods mainly focusing on new gene polymorphism discoveries, one of them being NGS. This enables the identification of hundreds of common and rare genetic variations contributing to behavioral and psychological conditions. Clinical NGS has been useful to detect copy number and single nucleotide variants and to identify structural rearrangements that have been challenging for standard bioinformatics algorithms. The main objective of this article is to review the recent applications of NGS in the diagnosis of major psychiatric disorders, and hence gauge the extent of its impact in the field. A comprehensive PubMed search was conducted and papers published from 2013-2018 were included, using the keywords, “schizophrenia” or “bipolar disorder” or “depressive disorder” or “attention deficit disorder” or “autism spectrum disorder” and “next-generation sequencing”

scholarly journals NGSremix: A software tool for estimating pairwise relatedness between admixed individuals from next-generation sequencing data

2021 ◽  
Author(s):  
Anne Krogh Nøhr ◽  
Kristian Hanghøj ◽  
Genis Garcia Erill ◽  
Zilong Li ◽  
Ida Moltke ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Genetic Research ◽  
Likelihood Estimation ◽  
Software Tool ◽  
Estimation Methods ◽  
Next Generation Sequencing Data ◽  
Next Generation ◽  
Sequencing Data ◽  
Ngs Data ◽  
Generation Sequencing

Abstract Estimation of relatedness between pairs of individuals is important in many genetic research areas. When estimating relatedness, it is important to account for admixture if this is present. However, the methods that can account for admixture are all based on genotype data as input, which is a problem for low-depth next-generation sequencing (NGS) data from which genotypes are called with high uncertainty. Here we present a software tool, NGSremix, for maximum likelihood estimation of relatedness between pairs of admixed individuals from low-depth NGS data, which takes the uncertainty of the genotypes into account via genotype likelihoods. Using both simulated and real NGS data for admixed individuals with an average depth of 4x or below we show that our method works well and clearly outperforms all the commonly used state-of-the-art relatedness estimation methods PLINK, KING, relateAdmix, and ngsRelate that all perform quite poorly. Hence, NGSremix is a useful new tool for estimating relatedness in admixed populations from low-depth NGS data. NGSremix is implemented in C/C ++ in a multi-threaded software and is freely available on Github https://github.com/KHanghoj/NGSremix.

scholarly journals Mining and Development of Novel SSR Markers Using Next Generation Sequencing (NGS) Data in Plants

Molecules ◽  
2018 ◽  
Vol 23 (2) ◽  
pp. 399 ◽  
Author(s):  
Sima Taheri ◽  
Thohirah Lee Abdullah ◽  
Mohd Yusop ◽  
Mohamed Hanafi ◽  
Mahbod Sahebi ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Ssr Markers ◽  
Next Generation ◽  
Next Generation Sequencing Ngs ◽  
Ngs Data ◽  
Generation Sequencing

scholarly journals Design and validation of a next generation sequencing assay for hereditaryBRCA1andBRCA2mutation testing

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2162 ◽  
Author(s):  
Hyunseok P. Kang ◽  
Jared R. Maguire ◽  
Clement S. Chu ◽  
Imran S. Haque ◽  
Henry Lai ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Copy Number Variants ◽  
Next Generation ◽  
Single Nucleotide Variants ◽  
Cancer Syndrome ◽  
Cancer Screen ◽  
Inherited Cancer ◽  
Increased Risk ◽  
Large Rearrangements ◽  
Generation Sequencing

Hereditary breast and ovarian cancer syndrome, caused by a germline pathogenic variant in theBRCA1orBRCA2(BRCA1/2) genes, is characterized by an increased risk for breast, ovarian, pancreatic and other cancers. Identification of those who have aBRCA1/2mutation is important so that they can take advantage of genetic counseling, screening, and potentially life-saving prevention strategies. We describe the design and analytic validation of the Counsyl Inherited Cancer Screen, a next-generation-sequencing-based test to detect pathogenic variation in theBRCA1andBRCA2genes. We demonstrate that the test is capable of detecting single-nucleotide variants (SNVs), short insertions and deletions (indels), and copy-number variants (CNVs, also known as large rearrangements) with zero errors over a 114-sample validation set consisting of samples from cell lines and deidentified patient samples, including 36 samples withBRCA1/2pathogenic germline mutations.

scholarly journals Next generation sequencing of RB1gene for the molecular diagnosis of ethnic minority with retinoblastoma in Yunnan

2020 ◽  
Author(s):  
Huaiyu Gu ◽  
Zhen Zhang ◽  
Yi-shuang Xiao ◽  
Ru Shen ◽  
Hong-chao Jiang ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Next Generation Sequencing ◽  
Low Income ◽  
Eastern China ◽  
Low Income Countries ◽  
Next Generation ◽  
Single Nucleotide Variants ◽  
Bioinformatics Pipeline ◽  
Generation Sequencing

Abstract Background: Retinoblastoma is a rare intraocular malignancy and typically initiated by inactivating biallelic mutations of RB1 gene. Each year, ~8,000 children worldwide are diagnosed for retinoblastoma. In high-income countries, patient survival is over 95% while low-income countries is ~30%.If disease is diagnosed early and treated in centers specializing in retinoblastoma, the survival might exceed 95% and many eyes could be safely treated and support a lifetime of good vision. In China, approximate 1,100 newly diagnosed cases are expected annually and 28 hospitals covering 25 provinces established centers classified by expertise and resources for better treatment options and follow-up. Comparing with other province of eastern China, Yunnan province is remote geographically. This might result that healthcare staff have low awareness of the role of genetic testing in management and screening in families.Methods: The patients with retinoblastoma were selected in Yunnan. DNA from blood was used for targeted gene sequencing. Then, an in-house bioinformatics pipeline was done to detect both single nucleotide variants and small insertions/deletions. The pathogenic mutations were identified and further confirmed by conventional methods and cosegregation in families.Results: Using our approach, targeted next generation sequencing was used to detect the mutation of these 12 probands. Bioinformatic predictions showed that nine mutations were found in our study and four were novel pathogenic variants in these nine mutations.Conclusions: It’s the first report to describe RB1 mutations in Yunnan children with retinoblastoma. This study would improve role of genetic testing for management and family screening.

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