Molecular variations in uterine carcinosarcomas identify therapeutic opportunities

2020 ◽  
Vol 30 (4) ◽  
pp. 480-484
Author(s):  
Erin Crane ◽  
Wendel Naumann ◽  
David Tait ◽  
Robert Higgins ◽  
Thomas Herzog ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Protein Expression ◽  
Copy Number ◽  
Treatment Options ◽  
Therapeutic Targets ◽  
Mutational Load ◽  
Next Generation ◽  
Comprehensive Genomic Profiling ◽  
Poor Outcomes ◽  
Generation Sequencing

ObjectiveTo perform comprehensive genomic profiling on a large cohort of patients with uterine carcinosarcomas to identify potential therapeutic targets.MethodsMolecular profiling was conducted on 168 retrospectively de-identified patients with uterine carcinosarcomas using the Caris Life Sciences platform. Specimens were evaluated for aberrations in protein expression by immunohistochemistry, DNA sequence mutation using a 592-gene next generation sequencing panel, copy number amplification using next generation sequencing or in situ hybridization, and fusion events using NextGen RNA sequencing. Tumor mutational load and microsatellite instability were also evaluated.ResultsWe identified 168 patients with uterine carcinosarcoma; median age of the cohort was 67 years. The most common mutations were observed in the following genes: TP53 (86%), PIK3CA (34%), FBXW7 (23%), PTEN (18%), KRAS (16%), PPP2R1A (10%). Tumor mutational load was low to moderate in most cases (50% and 45%, respectively). HER2/neu (ERBB2) was amplified in 9% of tumors. Immunohistochemistry protein expression was elevated in TOP2A (95%), TS (80%), PTEN (76%), and TUBB3 (66%). Mismatch repair deficiency was rare (4%).ConclusionsMultiple somatic mutations and copy number alterations in genes that are therapeutic targets were identified in half of cases. Uterine carcinosarcomas represent an aggressive histology with limited treatment options and poor outcomes, and clinical trials are needed to validate new therapeutic targets.

Novel Next-Generation Sequencing and Networks-Based Therapeutic Targets: Realistic and More Effective Drug Design and Discovery

2014 ◽  
Vol 20 (1) ◽  
pp. 11-22 ◽  
Author(s):  
Dimitrios Roukos ◽  
Giannis Baltogiannis ◽  
Christos Katsouras ◽  
Aris Bechlioulis ◽  
Katerina Naka ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Drug Design ◽  
Therapeutic Targets ◽  
Effective Drug ◽  
Next Generation ◽  
Generation Sequencing

scholarly journals Next-generation sequencing of adrenocortical carcinoma reveals new routes to targeted therapies

2014 ◽  
Vol 67 (11) ◽  
pp. 968-973 ◽  
Author(s):  
J S Ross ◽  
K Wang ◽  
J V Rand ◽  
L Gay ◽  
M J Presta ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Adrenocortical Carcinoma ◽  
Single Case ◽  
Next Generation ◽  
Illumina Hiseq ◽  
Modest Improvement ◽  
Aggressive Form ◽  
Comprehensive Genomic Profiling ◽  
Cytotoxic Therapies ◽  
Generation Sequencing

AimsAdrenocortical carcinoma (ACC) carries a poor prognosis and current systemic cytotoxic therapies result in only modest improvement in overall survival. In this retrospective study, we performed a comprehensive genomic profiling of 29 consecutive ACC samples to identify potential targets of therapy not currently searched for in routine clinical practice.MethodsDNA from 29 ACC was sequenced to high, uniform coverage (Illumina HiSeq) and analysed for genomic alterations (GAs).ResultsAt least one GA was found in 22 (76%) ACC (mean 2.6 alterations per ACC). The most frequent GAs were in TP53 (34%), NF1 (14%), CDKN2A (14%), MEN1 (14%), CTNNB1 (10%) and ATM (10%). APC, CCND2, CDK4, DAXX, DNMT3A, KDM5C, LRP1B, MSH2 and RB1 were each altered in two cases (7%) and EGFR, ERBB4, KRAS, MDM2, NRAS, PDGFRB, PIK3CA, PTEN and PTCH1 were each altered in a single case (3%). In 17 (59%) of ACC, at least one GA was associated with an available therapeutic or a mechanism-based clinical trial.ConclusionsNext-generation sequencing can discover targets of therapy for relapsed and metastatic ACC and shows promise to improve outcomes for this aggressive form of cancer.

scholarly journals Next-Generation Sequencing–Based Assessment of JAK2, PD-L1, and PD-L2 Copy Number Alterations at 9p24.1 in Breast Cancer

2019 ◽  
Vol 21 (2) ◽  
pp. 307-317 ◽  
Author(s):  
Sounak Gupta ◽  
Chad M. Vanderbilt ◽  
Paolo Cotzia ◽  
Javier A. Arias-Stella ◽  
Jason C. Chang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Next Generation Sequencing ◽  
Copy Number ◽  
Copy Number Alterations ◽  
Next Generation ◽  
Generation Sequencing

scholarly journals Use of next-generation sequencing to detectLDLRgene copy number variation in familial hypercholesterolemia

2017 ◽  
Vol 58 (11) ◽  
pp. 2202-2209 ◽  
Author(s):  
Michael A. Iacocca ◽  
Jian Wang ◽  
Jacqueline S. Dron ◽  
John F. Robinson ◽  
Adam D. McIntyre ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Copy Number Variation ◽  
Familial Hypercholesterolemia ◽  
Copy Number ◽  
Next Generation ◽  
Number Variation ◽  
Generation Sequencing

scholarly journals Genome-wide characterization of copy number variations in the host genome in genetic resistance to Marek's disease using next generation sequencing

2020 ◽  
Author(s):  
Hao Bai ◽  
Yanghua He ◽  
Yi Ding ◽  
Huanmin Zhang ◽  
Jilan Chen ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Copy Number ◽  
Marek's Disease ◽  
Neoplastic Disease ◽  
Marek’S Disease ◽  
Next Generation ◽  
Qrt Pcr ◽  
Genome Wide ◽  
A Genome ◽  
Generation Sequencing

Abstract Background: Marek’s disease (MD) is a highly neoplastic disease primarily affecting chickens, and remains as a chronic infectious disease that threatens the poultry industry. Copy number variation (CNV) has been examined in many species and is recognized as a major source of genetic variation that directly contributes to phenotypic variation such as resistance to infectious diseases. Two highly inbred chicken lines 63 (MD-resistant) and 72 (MD-susceptible), as well as their F1 generation and six recombinant congenic strains (RCSs) with varied susceptibility to MD, are considered as ideal models to identify the complex mechanisms of genetic and molecular resistance to MD.Results: In the present study, to unravel the potential genetic mechanisms underlying resistance to MD, we performed a genome-wide CNV detection using next generation sequencing on the inbred chicken lines with the assistance of CNVnator. As a result, a total of 1,649 CNV regions (CNVRs) were successfully identified after merging all the nine datasets, of which 90 CNVRs were overlapped across all the chicken lines. Within these shared regions, 1,360 harbored genes were identified. In addition, 55 and 44 CNVRs with 62 and 57 harbored genes were specifically identified in line 63 and 72, respectively. Bioinformatics analysis showed that the nearby genes were significantly enriched in 36 GO terms and 6 KEGG pathways including JAK/STAT signaling pathway. Ten CNVRs (nine deletions and one duplication) involved in 10 disease-related genes were selected for validation by using qRT-PCR, all of which were successfully confirmed. Finally, qRT-PCR was also used to validate two deletion events in line 72 that were definitely normal in line 63. One high-confidence gene, IRF2 was identified as the most promising candidate gene underlying resistance and susceptibility to MD in view of its function and overlaps with data from previous study.Conclusions: Our findings provide valuable insights for understanding the genetic mechanism of resistance to MD and the identified gene and pathway could be considered as the subject of further functional characterization.

scholarly journals Comprehensive Assessment of Somatic Copy Number Variation Calling Using Next-Generation Sequencing Data

2021 ◽  
Author(s):  
Yun-Ching Chen ◽  
Fayaz Seifuddin ◽  
Cu Nguyen ◽  
Zhaowei Yang ◽  
Wanqiu Chen ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Copy Number Variation ◽  
Cancer Progression ◽  
Copy Number ◽  
Tissue Sample ◽  
Next Generation Sequencing Data ◽  
Next Generation ◽  
Dna Amount ◽  
Number Variation ◽  
Generation Sequencing

AbstractCopy number variation (CNV) is a common type of mutation that often drives cancer progression. With advances in next-generation sequencing (NGS), CNVs can be detected in a detailed manner via newly developed computational tools but quality of such CNV calls has not been carefully evaluated. We analyzed CNV calls reported by 6 cutting-edge callers for 91 samples which were derived from the same cancer cell line, prepared and sequenced by varying the following factors: type of tissue sample (Fresh vs. Formalin Fixed Paraffin Embedded (FFPE)), library DNA amount, tumor purity, sequencing platform (Whole-Genome Sequencing (WGS) versus Whole-Exome Sequencing (WES)), and sequencing coverage. We found that callers greatly determined the pattern of CNV calls. Calling quality was drastically impaired by low purity (<50%) and became variable when WES, FFPE, and medium purity (50%-75%) were applied. Effects of low DNA amount and low coverage were relatively minor. Our analysis demonstrates the limitation of benchmarking somatic CNV callers when the real ground truth is not available. Our comprehensive analysis has further characterized each caller with respect to confounding factors and examined the consistency of CNV calls, thereby providing guidelines for conducting somatic CNV analysis.

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