scholarly journals Whole-exome sequencing of plasma cell-free DNA portrays the somatic mutation landscape of refractory metastatic colorectal cancer and enables the discovery of mutatedKDR/VEGFR2 receptors as modulators of anti-angiogenic therapies

2017 ◽  
Author(s):  
Rodrigo A. Toledo ◽  
Elena Garralda ◽  
Maria Mitsi ◽  
Tirso Pons ◽  
Jorge Monsech ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Somatic Mutation ◽  
Plasma Cell ◽  
Somatic Mutations ◽  
Free Dna ◽  
Whole Exome ◽  
Cancer Mutations

ABSTRACTThe non-invasive detection of cancer mutations is a breakthrough in oncology. Here, we applied whole-exome sequencing of matched germline and basal plasma cell-free DNA samples (WES-cfDNA) on aRAS/BRAF/PIK3CAwild-type metastatic colorectal cancer patient with primary resistance to standard treatment regimens including VEGFR inhibitors. Using WES-cfDNA, we could detect 73% (54/74) of the somatic mutations uncovered by WES-tumor including a variety of mutation types: frameshift (indels), missense, noncoding (splicing), and nonsense mutations. Additionally, WES-cfDNA discovered 14 high-confidence somatic mutations not identified by WES-tumor. Importantly, in the absence of the tumor specimen, WES-cfDNA could identify 68 of the 88 (77.3%) total mutations that could be identified by both techniques. Of tumor biology relevance, we identified the novelKDR/VEGFR2 L840F somatic mutation, which we showed was a clonal mutation event in this tumor. Comprehensivein vitroandin vivofunctional assays confirmed that L840F causes strong resistance to anti-angiogenic drugs, whereas theKDR/VEGFR2 hot-spot mutant R1032Q confers sensitivity to cabozantinib. Moreover, we found a 1-3% of recurrentKDRsomatic mutations across large and non-overlapping cancer sequencing projects, and the majority of these mutations were located in protein residues frequently mutated in other cancer-relevant kinases, such as EGFR, ABL1, and ALK, suggesting a functional role.In summary, the current study highlights the capability of exomic sequencing of cfDNA from plasma of cancer patients as a powerful platform for somatic landscape analysis and discovery of resistance-associated cancer mutations. Because of its advantage to generate results highly concordant to those of tumor sequencing without the hurdle of conventional tumor biopsies, we anticipate that WES-cfDNA will become frequently used in oncology. Moreover, our study identified for the first-timeKDR/VEGFR2 somatic mutations as potential genetic biomarkers of response to anti-angiogenic cancer therapies and will serve as reference for further studies on the topic.

scholarly journals Whole exome sequencing analysis of urine trans-renal tumour DNA in metastatic colorectal cancer patients

ESMO Open ◽  
2019 ◽  
Vol 4 (6) ◽  
pp. e000572
Author(s):  
Giovanni Crisafulli ◽  
Benedetta Mussolin ◽  
Andrea Cassingena ◽  
Monica Montone ◽  
Alice Bartolini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Weight ◽  
Metastatic Colorectal Cancer ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Information ◽  
Renal Tumour ◽  
Low Molecular Weight ◽  
Sequencing Analysis ◽  
Whole Exome

BackgroundThe analysis of circulating free tumour DNA (ctDNA) in blood, commonly referred as liquid biopsy, is being used to characterise patients with solid cancers. Tumour-specific genetic variants can also be present in DNA isolated from other body fluids, such as urine. Unlike blood, urine sampling is non-invasive, can be self-performed, and allows recurrent longitudinal monitoring. The features of tumour DNA that clears from the glomerular filtration barrier, named trans-renal tumour DNA (trtDNA), are largely unexplored.Patients and methodsSpecimens were collected from 24 patients with KRAS or BRAF mutant metastatic colorectal cancer (mCRC). Driver mutations were assessed by droplet digital PCR (ddPCR) in ctDNA from plasma and trtDNA from urine. Whole exome sequencing (WES) was performed in DNA isolated from tissue, plasma and urine.ResultsOut of the 24 CRC cases, only four had sufficient DNA to allow WES analyses in urine and plasma. We found that tumour alterations primarily reside in low molecular weight fragments (less than 112 bp). In patients whose trtDNA was more than 2.69% of the urine derived DNA, cancer-specific molecular alterations, mutational signatures and copy number profiles identified in urine DNA are comparable with those detected in plasma ctDNA.ConclusionsWith current technologies, WES analysis of trtDNA is feasible in a small fraction of mCRC patients. Tumour-related genetic information is mainly present in low molecular weight DNA fragments. Although the limited amounts of trtDNA poses analytical challenges, enrichment of low molecular weight DNAs and optimised computational tools can improve the detection of tumour-specific genetic information in urine.

Examination of Plasma Cell-Free DNA of Glioma Patients by Whole Exome Sequencing

2019 ◽  
Vol 125 ◽  
pp. e424-e428 ◽  
Author(s):  
Junlong Sun ◽  
Wenwu Zhou ◽  
Kangcheng Mao ◽  
Yunfeng He ◽  
Junzhong Yao ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Plasma Cell ◽  
Cell Free Dna ◽  
Free Dna ◽  
Whole Exome

scholarly journals Whole Exome Sequencing of Ulcerative Colitis–associated Colorectal Cancer Based on Novel Somatic Mutations Identified in Chinese Patients

2019 ◽  
Vol 25 (8) ◽  
pp. 1293-1301 ◽  
Author(s):  
Pengguang Yan ◽  
Yanan Wang ◽  
Xiangchen Meng ◽  
Hong Yang ◽  
Zhanju Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Ulcerative Colitis ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Somatic Mutations ◽  
Meta Analysis ◽  
Chinese Patients ◽  
Genomic Alteration ◽  
Whole Exome ◽  
Sporadic Crcs

AbstractBackgroundCarcinogenesis is a severe consequence of chronic ulcerative colitis. We investigated the somatic mutations and pathway alterations in ulcerative colitis–associated colorectal cancer (CRC) in Chinese patients compared with sporadic CRCs to reveal potential therapeutic targets in ulcerative colitis–associated CRC.MethodsWhole exome sequencing was performed on archival tumor tissues and paired adjacent nondysplastic mucosa from 10 ulcerative colitis–associated CRC patients at a high risk of carcinogenesis. Genomic alteration profiles from 223 primary CRCs from The Cancer Genome Atlas served as sporadic CRC controls. A meta-analysis was performed to investigate differences in major genetic mutations between ulcerative colitis–associated and Crohn’s disease–associated CRCs.ResultsWe identified 44 nonsilent recurrent somatic mutations via whole exome sequencing, including 25 deleterious mutations involved in apoptosis and the PI3K-Akt pathway (COL6A3, FN1), autophagy (ULK1), cell adhesion (PODXL, PTPRT, ZFHX4), and epigenetic regulation (ARID1A, NCOR2, KMT2D, NCOA6, MECP2, SUPT6H). In total, 11 of the 25 mutated genes significantly differed between ulcerative colitis–associated CRC and sporadic CRC (APC, APOB, MECP2, NCOR2, NTRK2, PODXL, RABGAP1, SIK3, SUPT6H, ULK1, USP48). Somatic TP53 mutations occurred in 33% of ulcerative colitis–associated CRCs. Subsequent meta-analysis revealed distinct mutation profiles for Crohn’s disease– and ulcerative colitis–associated CRCs. Mutations involving the NF-kB pathway and epigenetic regulation were more common in ulcerative colitis–associated CRCs than in sporadic CRCs.ConclusionDistinct genomic alteration profiles of deleterious somatic mutations were found in ulcerative colitis–associated and sporadic CRCs. Mutations of epigenetic regulators, such as KMT2D and NCOA6, were common, suggesting an epigenetic pathomechanism for colitis-associated carcinoma in Chinese patients.

scholarly journals DNN-Boost: Somatic mutation identification of tumor-only whole-exome sequencing data using deep neural network and XGBoost

2021 ◽  
Author(s):  
Firda Aminy Maruf ◽  
Rian Pratama ◽  
Giltae Song
Keyword(s):  
Neural Network ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Somatic Mutation ◽  
Deep Neural Network ◽  
Somatic Mutations ◽  
Sequencing Data ◽  
Exome Sequencing Data ◽  
Whole Exome ◽  
Whole Exome Sequencing Data

Detection of somatic mutation in whole-exome sequencing data can help elucidate the mechanism of tumor progression. Most computational approaches require exome sequencing for both tumor and normal samples. However, it is more common to sequence exomes for tumor samples only without the paired normal samples. To include these types of data for extensive studies on the process of tumorigenesis, it is necessary to develop an approach for identifying somatic mutations using tumor exome sequencing data only. In this study, we designed a machine learning approach using Deep Neural Network (DNN) and XGBoost to identify somatic mutations in tumor-only exome sequencing data and we integrated this into a pipeline called DNN-Boost. The XGBoost algorithm is used to extract the features from the results of variant callers and these features are then fed into the DNN model as input. The XGBoost algorithm resolves issues of missing values and overfitting. We evaluated our proposed model and compared its performance with other existing benchmark methods. We noted that the DNN-Boost classification model outperformed the benchmark method in classifying somatic mutations from paired tumor-normal exome data and tumor-only exome data.

scholarly journals Germline and somatic mutations in the pathology of pineal cyst: A whole‐exome sequencing study of 93 individuals

2021 ◽  
Author(s):  
Yuanqing Yan ◽  
Rebecca Martinez ◽  
Maria N. Rasheed ◽  
Joshua Cahal ◽  
Zhen Xu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Somatic Mutations ◽  
Pineal Cyst ◽  
Whole Exome

Whole-exome sequencing reveals potential germline and somatic mutations in 60 malignant ovarian germ cell tumors

2021 ◽  
Author(s):  
Juan Chen ◽  
Yan Li ◽  
Jianlei Wu ◽  
Yakun Liu ◽  
Shan Kang
Keyword(s):  
Germ Cell ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Peripheral Blood ◽  
Copy Number ◽  
Somatic Mutations ◽  
Germ Cell Tumors ◽  
Germline Mutations ◽  
Deletion Region ◽  
Whole Exome

Abstract Background Malignant ovarian germ cell tumors (MOGCTs) are rare and heterogeneous ovary tumors. We aimed to identify potential germline mutations and somatic mutations in MOGCTs by whole-exome sequencing. Methods The peripheral blood and tumor samples from these patients were used to identify germline mutations and somatic mutations, respectively. For those genes corresponding to copy number alterations (CNA) deletion and duplication region, functional annotation of was performed. Immunohistochemistry was performed to evaluate the expression of mutated genes corresponding to CNA deletion region. Results In peripheral blood, copy number loss and gain were mostly found in yolk sac tumors (YST). Moreover, POU5F1 was the most significant mutated gene with mutation frequency > 10% in both CNA deletion and duplication region. In addition, strong cytoplasm staining of POU5F1 (corresponding to CNA deletion region) was found in 2 YST and nuclear staining in 2 dysgerminomas (DG) tumor samples. Genes corresponding to CNA deletion region were significantly enriched in the signaling pathway of regulating pluripotency of stem cells. In addition, genes corresponding to CNA duplication region were significantly enriched in the signaling pathways of RIG-I-like receptor, Toll-like receptor, NF-kappa B and Jak–STAT. KRT4, RPL14, PCSK6, PABPC3 and SARM1 mutations were detected in both peripheral blood and tumor samples. Conclusions Identification of potential germline mutations and somatic mutations in MOGCTs may provide a new field in understanding the genetic feature of the rare biological tumor type in the ovary.

scholarly journals Whole-Exome Sequencing Identifies Somatic Mutations Associated With Mortality in Metastatic Clear Cell Kidney Carcinoma

2019 ◽  
Vol 10 ◽  
Author(s):  
Alejandro Mendoza-Alvarez ◽  
Beatriz Guillen-Guio ◽  
Adrian Baez-Ortega ◽  
Carolina Hernandez-Perez ◽  
Sita Lakhwani-Lakhwani ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Somatic Mutations ◽  
Clear Cell ◽  
Kidney Carcinoma ◽  
Whole Exome
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