PATH-09. NEXT-GENERATION SEQUENCING OF GLIOBLASTOMA MULTIFORME ‘EXTREME RESPONDERS’

Abstract BACKGROUND Glioblastoma Multiforme (GBM) is the most common primary brain among adults. Despite steady advances in treatment, the outcome remains universally lethal. Median overall survival in a population-based study is approximately 10 to 12 months. Prognostic factors in GBM patients include age, performance score, extent of surgical resection, IDH1 mutation status and MGMT methylation status. Survival > 2 years is rare; for the purpose of this study we have defined these patients ‘extreme responders.’ This study aims to identify genomic signatures and gene alterations that may have contributed to ‘extreme response’ to standard adjuvant chemoradiotherapy. METHODS A total of 12 out of 141 primary GBM patients were identified as ‘extreme responders’ as part of a retrospective chart review between 2005 - 2016. Of the 12 suitable for NGS testing, 9 were analyzed using the Foundation One CDx® (next-generation sequencing platform) which interrogates 324 genes, microsatellite status and tumour mutational burden (TMB). Baseline demographics, clinical characteristics, and NGS results were compared. RESULTS Of the 9 patients tested, over half were female (5, 55%) and median age at diagnosis was 53 years. Gross total resection was performed at diagnosis in 3 cases. MGMT status was available for 5 patients and was methylated in 3. NGS results revealed: MSI stable in all patients, median TMB 3 muts/Mb and most common gene alterations were TP53 (5/9); ATRX (4/9); EGFR (3/9); CDKN2A/B (3/9); IDH1(3/9); PIK3R1(3/9) and PTEN (3/9). CONCLUSION Acknowledging the fact that our sample size was small and no control group was tested, our study infers a higher incidence of IDH1, TP53 and ATRX mutations which are more common in secondary glioblastomas and this may be a contributing factor towards longer survival in our cohort. We did not identify any universal molecular marker predictive of improved prognosis or exquisite sensitivity to chemoradiotherapy.

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Next-Generation Sequencing Approach to Non–Small Cell Lung Carcinoma Yields More Actionable Alterations

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2017-0046-oa ◽

2017 ◽

Vol 142 (3) ◽

pp. 353-357 ◽

Cited By ~ 12

Author(s):

Mitra Mehrad ◽

Somak Roy ◽

Humberto Trejo Bittar ◽

Sanja Dacic

Keyword(s):

Next Generation Sequencing ◽

Lung Adenocarcinoma ◽

Small Cell ◽

Gene Panel ◽

Next Generation ◽

Small Cell Lung ◽

Genomic Alterations ◽

Generation Sequencing ◽

Gene Alterations ◽

Cancer Panel

Context.— Different testing algorithms and platforms for EGFR mutations and ALK rearrangements in advanced-stage lung adenocarcinoma exist. The multistep approach with single-gene assays has been challenged by more efficient next-generation sequencing (NGS) of a large number of gene alterations. The main criticism of the NGS approach is the detection of genomic alterations of uncertain significance. Objective.— To determine the best testing algorithm for patients with lung cancer in our clinical practice. Design.— Two testing approaches for metastatic lung adenocarcinoma were offered between 2012–2015. One approach was reflex testing for an 8-gene panel composed of DNA Sanger sequencing for EGFR, KRAS, PIK3CA, and BRAF and fluorescence in situ hybridization for ALK, ROS1, MET, and RET. At the oncologist's request, a subset of tumors tested by the 8-gene panel was subjected to a 50-gene Ion AmpliSeq Cancer Panel. Results.— Of 1200 non–small cell lung carcinomas (NSCLCs), 57 including 46 adenocarcinomas and NSCLCs, not otherwise specified; 7 squamous cell carcinomas (SCCs); and 4 large cell neuroendocrine carcinomas (LCNECs) were subjected to Ion AmpliSeq Cancer Panel. Ion AmpliSeq Cancer Panel detected 9 potentially actionable variants in 29 adenocarcinomas that were wild type by the 8-gene panel testing (9 of 29, 31.0%) in the following genes: ERBB2 (3 of 29, 10.3%), STK11 (2 of 29, 6.8%), PTEN (2 of 29, 6.8%), FBXW7 (1 of 29, 3.4%), and BRAF G469A (1 of 29, 3.4%). Four SCCs and 2 LCNECs showed investigational genomic alterations. Conclusions.— The NGS approach would result in the identification of a significant number of actionable gene alterations, increasing the therapeutic options for patients with advanced NSCLCs.

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Abstract 1612: Molecular analysis of clinically actionable gene alterations in clear cell carcinoma of the ovary using next-generation sequencing and immunohistochemical CNV analysis

10.1158/1538-7445.am2018-1612 ◽

2018 ◽

Author(s):

Hiroshi Asano ◽

Yutaka Hatanaka ◽

Kanako C. Hatanaka ◽

Asami Okumura ◽

Toraji Amano ◽

...

Keyword(s):

Next Generation Sequencing ◽

Cell Carcinoma ◽

Molecular Analysis ◽

Clear Cell ◽

Clear Cell Carcinoma ◽

Next Generation ◽

Carcinoma Of The Ovary ◽

Generation Sequencing ◽

Gene Alterations

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ACTR-35. MOLECULAR MATCHMAKING: EFFICACY OF EARLY CLINICAL TRIALS GUIDED BY NEXT-GENERATION SEQUENCING IN PATIENTS WITH GLIOBLASTOMA MULTIFORME

Neuro-Oncology ◽

10.1093/neuonc/noy148.068 ◽

2018 ◽

Vol 20 (suppl_6) ◽

pp. vi19-vi19

Author(s):

Jacob Leary ◽

Michael Pearlman ◽

Gerald Falchook

Keyword(s):

Clinical Trials ◽

Next Generation Sequencing ◽

Glioblastoma Multiforme ◽

Next Generation ◽

Generation Sequencing

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Cancer related gene alterations can be detected with next-generation sequencing analysis of bile in diffusely infiltrating type cholangiocarcinoma

Experimental and Molecular Pathology ◽

10.1016/j.yexmp.2016.07.010 ◽

2016 ◽

Vol 101 (1) ◽

pp. 150-156 ◽

Cited By ~ 4

Author(s):

Chang Hun Lee ◽

Hong En Wang ◽

Seung Young Seo ◽

Seong Hun Kim ◽

In Hee Kim ◽

...

Keyword(s):

Next Generation Sequencing ◽

Sequencing Analysis ◽

Next Generation ◽

Related Gene ◽

Cancer Related Gene ◽

Next Generation Sequencing Analysis ◽

Generation Sequencing ◽

Gene Alterations

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Subacute Thyroiditis is Associated with HLA-B18:01, -DRB101 and -C*04:01—The Significance of the New Molecular Background

Journal of Clinical Medicine ◽

10.3390/jcm9020534 ◽

2020 ◽

Vol 9 (2) ◽

pp. 534

Author(s):

Magdalena Stasiak ◽

Bogusław Tymoniuk ◽

Renata Michalak ◽

Bartłomiej Stasiak ◽

Marek L. Kowalski ◽

...

Keyword(s):

Next Generation Sequencing ◽

Human Leukocyte ◽

Subacute Thyroiditis ◽

Control Group ◽

Next Generation ◽

Sequencing Method ◽

Triggering Factor ◽

Almost All ◽

Generation Sequencing ◽

Next Generation Sequencing Method

Subacute thyroiditis (SAT) is a thyroid inflammatory disease whose pathogenesis is still not completely defined. Previous viral infection is considered to be a triggering factor in genetically predisposed individuals. In about 70% of patients, susceptibility to SAT is associated with the HLA-B*35 allele. The correlation between SAT and other human leukocyte antigens (HLA) has not yet been unequivocally demonstrated and the genetic background is still unknown in about 30% of patients. The purpose of our study was to perform HLA genotyping using a next-generation sequencing method, to find out whether alleles other than HLA-B*35 are correlated with SAT morbidity. HLA-A, -B, -C, -DQB1, -DRB1 were genotyped using a next-generation sequencing method in 1083 subjects, including 60 SAT patients and 1023 healthy controls. Among 60 patients diagnosed with SAT, 81.7% of subjects were identified as having allele HLA-B*35, 23.3% had HLA-B*18:01, 28.3% had HLA-DRB1*01 and 75.5% had HLA-C*04:01. These alleles occurred in the control group at frequencies of 10.2%, 7.2%, 12.9% and 12.5%, respectively. The differences were statistically significant, with p < 0.05. In addition to its previously described relationship with HLA-B*35, genetic susceptibility to SAT was associated with the presence of HLA-B*18:01, DRB1*01 and C*04:01. The alleles HLA-B*18:01 and DRB1*01 were independent SAT risk factors. The assessment of these four alleles allows the confirmation of genetic predisposition in almost all patients with SAT.

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Next Generation Sequencing-Based Transcriptome Predicts Bevacizumab Efficacy in Combination with Temozolomide in Glioblastoma

Molecules ◽

10.3390/molecules24173046 ◽

2019 ◽

Vol 24 (17) ◽

pp. 3046 ◽

Cited By ~ 1

Author(s):

Alimu Adilijiang ◽

Masaki Hirano ◽

Yusuke Okuno ◽

Kosuke Aoki ◽

Fumiharu Ohka ◽

...

Keyword(s):

Brain Tumor ◽

Next Generation Sequencing ◽

Immune Cell ◽

Xenograft Model ◽

Idh1 Mutation ◽

World Health ◽

In Vivo Studies ◽

Next Generation ◽

U87 Cells ◽

Generation Sequencing

Glioblastoma (GBM), the most common and malignant brain tumor, is classified according to its isocitrate dehydrogenase (IDH) mutation status in the 2016 World Health Organization (WHO) brain tumor classification scheme. The standard treatment for GBM is maximal resection, radiotherapy, and Temozolomide (TMZ). Recently, Bevacizumab (Bev) has been added to basic therapy for newly diagnosed GBM, and monotherapy for recurrent GBM. However, the effect of IDH1 mutation on the combination of Bev and TMZ is unknown. In this study, we performed transcriptomic analysis by RNA sequencing with next generation sequencing (NGS), a newly developed powerful method that enables the quantification of the expression level of genome-wide genes. Extracellular matrix and immune cell migration genes were mainly upregulated whereas cell cycle genes were downregulated in IDH1-mutant U87 cells but not in IDH1-wildtype U87 cells after adding Bev to TMZ. In vitro and in vivo studies were conducted for further investigations to verify these results, and the addition of Bev to TMZ showed a significant antitumor effect only in the IDH1-mutant GBM xenograft model. Further studies of gene expression profiling in IDH1 mutation gliomas using NGS will provide more genetic information and will lead to new treatments for this refractory disease.

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MSI-WES: a simple approach for microsatellite instability testing using whole exome sequencing

Future Oncology ◽

10.2217/fon-2021-0132 ◽

2021 ◽

Author(s):

Henry O Ebili ◽

Adedeji OJ Agboola ◽

Emad Rakha

Keyword(s):

Next Generation Sequencing ◽

Microsatellite Instability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Methylation Status ◽

Molecular Targets ◽

Next Generation ◽

Variant Call ◽

Whole Exome ◽

Generation Sequencing

Aim: To demonstrate that MSI-WES is an accurate testing method for microsatellite instability (MSI). Materials & methods: Microsatellite-based indels were counted in the variant call-formatted whole exome sequencing (WES) data of 441 gastric cancer cases using Unix-based algorithms, and the counts expressed as a fraction of the genome sequenced to obtain next-generation sequencing-based MSI indices. Results: The next-generation sequencing-based MSI indices showed a near-perfect concordance with PCR-based MSI status, and moderate to good correlations with the molecular targets of MSI index, MLH1 expression and MLH1 methylation status, at a level comparable to the strengths of correlation between PCR-based MSI status and molecular targets of MSI index/ MLH1 expression and methylation. Conclusion: MSI-WES is a valid, adequate and sensitive approach for testing MSI in cancer.

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