scholarly journals Precise Identification of Recurrent Somatic Mutations in Oral Cancer Through Whole-Exome Sequencing Using Multiple Mutation Calling Pipelines

2021 ◽  
Vol 11 ◽  
Author(s):  
Li-Han Lin ◽  
Chung-Hsien Chou ◽  
Hui-Wen Cheng ◽  
Kuo-Wei Chang ◽  
Chung-Ji Liu
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Tumor Staging ◽  
Genomic Alterations ◽  
Data Set ◽  
Tumor Mutation Burden ◽  
Coding Regions ◽  
Whole Exome ◽  
Mutation Burden ◽  
Canonical Pathways

Understanding the genomic alterations in oral carcinogenesis remains crucial for the appropriate diagnosis and treatment of oral squamous cell carcinoma (OSCC). To unveil the mutational spectrum, in this study, we conducted whole-exome sequencing (WES), using six mutation calling pipelines and multiple filtering criteria applied to 50 paired OSCC samples. The tumor mutation burden extracted from the data set of somatic variations was significantly associated with age, tumor staging, and survival. Several genes (MUC16, MUC19, KMT2D, TTN, HERC2) with a high frequency of false positive mutations were identified. Moreover, known (TP53, FAT1, EPHA2, NOTCH1, CASP8, and PIK3CA) and novel (HYDIN, ALPK3, ASXL1, USP9X, SKOR2, CPLANE1, STARD9, and NSD2) genes have been found to be significantly and frequently mutated in OSCC. Further analysis of gene alteration status with clinical parameters revealed that canonical pathways, including clathrin-mediated endocytotic signaling, NFκB signaling, PEDF signaling, and calcium signaling were associated with OSCC prognosis. Defining a catalog of targetable genomic alterations showed that 58% of the tumors carried at least one aberrant event that may potentially be targeted by approved therapeutic agents. We found molecular OSCC subgroups which were correlated with etiology and prognosis while defining the landscape of major altered events in the coding regions of OSCC genomes. These findings provide information that will be helpful in the design of clinical trials on targeted therapies and in the stratification of patients with OSCC according to therapeutic efficacy.

scholarly journals Whole-Exome Sequencing Characterized the Landscape of Somatic Mutations and Pathways in Colorectal Cancer Liver Metastasis

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Liuxing Feng ◽  
Shifu Hong ◽  
Jin Gao ◽  
Jiayi Li
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Signaling Pathways ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Acid Extraction ◽  
Tumor Mutation Burden ◽  
Colorectal Cancer Liver Metastasis ◽  
Whole Exome ◽  
Mutation Burden

Purpose. Liver metastasis remains the leading cause of cancer-related mortality in colorectal cancer. The mechanism of occurrence and development of liver metastasis from colorectal cancer is unclear. Methods. The primary tumor tissues and blood samples of 8 patients with liver metastasis of colorectal cancer were collected, followed by nucleic acid extraction and library construction. Whole-exome sequencing was performed to detect the genomic variations. Bioinformatics was used to comprehensively analyze the sequencing data of these samples, including the differences of tumor mutation burden, the characteristics of gene mutations, and signaling pathways. Results. The results showed that the top three genes with the highest mutation frequency were TP53, APC, and KRAS. Tumor mutation burden of this study, with a median of 8.34 mutations per MB, was significantly different with The Cancer Genome Atlas databases. Analysis of molecular function and signaling pathways showed that the mutated genes could be classified into five major categories and 39 signaling pathways, involving in Wnt, angiogenesis, P53, Alzheimer disease-presenilin pathway, notch, and cadherin signaling pathway. Conclusions. In conclusion, we identified the extensive landscape of altered genes and pathways in colorectal cancer liver metastasis, which will be useful to design clinical therapy for personalized medicine.

scholarly journals PATH-06. ASSESSMENT OF CIRCULATING TUMOR DNA IN CEREBROSPINAL FLUID BY WHOLE EXOME SEQUENCING TO DETECT GENOMIC ALTERATIONS OF GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii165-ii165
Author(s):  
Hao Duan ◽  
Zhenqiang He ◽  
Zhenghe Chen ◽  
Yonggao Mou
Keyword(s):  
Cerebrospinal Fluid ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Tumor Tissue ◽  
Circulating Tumor Dna ◽  
Genomic Alterations ◽  
Tissue Samples ◽  
Whole Exome ◽  
Resected Tumor ◽  
Tumor Dna

Abstract Cerebrospinal fluid (CSF) has been demonstrated as a better source of circulating tumor DNA (ctDNA) than plasma for brain tumors. However, it is unclear whether whole exome sequencing (WES) is qualified for detection of ctDNA in CSF. The aim of this study was to determine if assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma. CSFs of ten glioblastoma patients were collected pre-operatively at the Department of Neurosurgery, Sun Yat-sen University Cancer Center. ctDNA in CSF and genome DNA in the resected tumor were extracted and subjected to WES. The identified glioblastoma-associated mutations from ctDNA in CSF and genome DNA in the resected tumor were compared. Due to the ctDNA in CSF was unqualified for exome sequencing for one patient, nine patients were included into the final analysis. More glioblastoma-associated mutations tended to be detected in CSF comparing with the corresponding tumor tissue samples (3.56±0.75 vs. 2.22±0.32, P=0.097), while the statistical significance was limited by the small sample size. The average mutation frequencies were similar in CSF and tumor tissue samples (74.12% ± 6.03% vs. 73.83% ± 5.95%, P = 0.924). The R132H mutation of isocitrate dehydrogenase 1 and the G34V mutation of H3F3A which had been reported in the pathological diagnoses were also detected from ctDNA in CSF by WES. Patients who received temozolomide chemotherapy previously or those whose tumor involved subventricular zone tended to harbor more mutations in their CSF. Assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma, which may provide useful information for the decision of treatment strategy.

Novel NGS-Based Platforms For Molecular Diagnosis Of Severe Congenital Neutropenia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1034-1034
Author(s):  
Tomas Racek ◽  
Jacek Puchalka ◽  
Naschla Kohistani ◽  
Christoph Klein
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Molecular Diagnostic ◽  
Compound Heterozygous ◽  
Neutrophil Granulocytes ◽  
Diagnostic Strategy ◽  
Congenital Neutropenia ◽  
Coding Regions ◽  
Whole Exome ◽  
Custom Made

Abstract Congenital neutropenia (CN) is a heterogeneous disorder. More than 30 distinct genetic defects have been discovered in patients with genetic diseases associated with decreased numbers of peripheral neutrophil granulocytes. Currently, most molecular diagnostic laboratories use Sanger-based sequencing techniques to define disease-causing mutations in patients with CN. In approximately 50% of patients no known genetic disorder can be found. To identify novel genes that can be causative for unexplained CN cases we embarked on next-generation whole-exome sequencing using SOLiD 5500™ and Ion Proton™ sequencers. Up to date we sequenced whole exomes of 49 families, in which children were diagnosed with CN. The fragment libraries were constructed using the SureSelect™ V4+UTRs System (Agilent) allowing us to target whole coding sequence and the majority of UTRs of human genome (approx. 71 Mb). The vast majority of the families were analysed in the “Trio” approach and suitable homozygous or compound heterozygous rare variations (frequency below 1%) in protein coding regions or in splice sites were chosen for further validations. In seven cases mutations previously described as causative for neutropenia were identified including G6PC3, HAX1, and ELANE. Four other rare variants are currently being analysed for their potential to cause CN. In 35 patients, no plausible candidate could be identified so far. When we assessed variants within the genes related to CN, our data revealed unequal coverage pattern over these genes. Around 10% of the exons were insufficiently covered (coverage of less than 10) to allow for reliable variant and genotype call. These facts limit the power of whole exome sequencing as a diagnostic tool, as mutations at the non-covered positions cannot be ruled out, and demonstrate the need of an alternative comprehensive approach. We are currently assessing sensitivity and specificity of a robust, rapid, and cost-effective approach that comprehensively analyses the sequence of 34 CN-relevant genes. Our approach is based on enrichment of specific exon regions by amplification using custom made AmpliSeq™ (Life Technologies) panel. For 25 genes we are able to sequence coding region as well as both UTR sequences, for 9 genes sequencing is limited to coding regions. This approach will provide a reliable, quick, and inexpensive diagnostic strategy for CN patients which will be offered free-of-charge to patients worldwide, independent of ethnic, national, or financial considerations. Disclosures: No relevant conflicts of interest to declare.

Genomic alterations in Turcot syndrome: Insights from whole exome sequencing

2020 ◽  
Vol 417 ◽  
pp. 117056
Author(s):  
Philipp Karschnia ◽  
E. Zeynep Erson-Omay ◽  
Anita J. Huttner ◽  
Leon D. Kaulen ◽  
Daniel Duran ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genomic Alterations ◽  
Turcot Syndrome ◽  
Whole Exome

scholarly journals CopyDetective: Detection threshold–aware copy number variant calling in whole-exome sequencing data

GigaScience ◽  
2020 ◽  
Vol 9 (11) ◽  
Author(s):  
Sarah Sandmann ◽  
Marius Wöste ◽  
Aniek O de Graaf ◽  
Birgit Burkhardt ◽  
Joop H Jansen ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Copy Number ◽  
Detection Threshold ◽  
Variant Calling ◽  
Superior Performance ◽  
Quality Analysis ◽  
Data Set ◽  
Detection Thresholds ◽  
Whole Exome

Abstract Background Copy number variants (CNVs) are known to play an important role in the development and progression of several diseases. However, detection of CNVs with whole-exome sequencing (WES) experiments is challenging. Usually, additional experiments have to be performed. Findings We developed a novel algorithm for somatic CNV calling in matched WES data called “CopyDetective". Different from other approaches, CNV calling with CopyDetective consists of a 2-step procedure: first, quality analysis is performed, determining individual detection thresholds for every sample. Second, actual CNV calling on the basis of the previously determined thresholds is performed. Our algorithm evaluates the change in variant allele frequency of polymorphisms and reports the fraction of affected cells for every CNV. Analyzing 4 WES data sets (n = 100) we observed superior performance of CopyDetective compared with ExomeCNV, VarScan2, ControlFREEC, ExomeDepth, and CNV-seq. Conclusions Individual detection thresholds reveal that not every WES data set is equally apt for CNV calling. Initial quality analyses, determining individual detection thresholds—as realized by CopyDetective—can and should be performed prior to actual variant calling.

scholarly journals Genomic alterations in gastric cancers discovered via whole-exome sequencing

BMC Cancer ◽  
2018 ◽  
Vol 18 (1) ◽  
Author(s):  
Jie Zhang ◽  
Weiqing Qiu ◽  
Hua Liu ◽  
Changlin Qian ◽  
Dujuan Liu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genomic Alterations ◽  
Gastric Cancers ◽  
Whole Exome
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