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

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.

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Abstract 5528: Evaluation of tumor mutation burden as a biomarker for immune checkpoint inhibitor efficacy: A calibration study of whole exome sequencing with FoundationOne®

10.1158/1538-7445.am2018-5528 ◽

2018 ◽

Cited By ~ 5

Author(s):

Joseph D. Szustakowski ◽

George Green ◽

William J. Geese ◽

Kim Zerba ◽

Han Chang

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Tumor Mutation Burden ◽

Whole Exome ◽

Mutation Burden ◽

Calibration Study

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

Frontiers in Oncology ◽

10.3389/fonc.2021.741626 ◽

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.

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Genome variation in colorectal cancer patient with liver metastasis measured by whole-exome sequencing

Journal of Gastrointestinal Oncology ◽

10.21037/jgo-21-9 ◽

2021 ◽

Vol 12 (2) ◽

pp. 507-515

Author(s):

Hui Yi ◽

Zhi-Wei Liao ◽

Jun-Jie Chen ◽

Xin-Yu Shi ◽

Guo-Liang Chen ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastasis ◽

Cancer Patient ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Colorectal Cancer Patient ◽

Genome Variation ◽

Whole Exome

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

ESMO Open ◽

10.1136/esmoopen-2019-000572 ◽

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.

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Whole-Exome Sequencing Identifies a Somatic Cell Mutation Signature That Predicts Relapse Risk and Survival Probability in Multiple Myeloma

Blood ◽

10.1182/blood-2020-142791 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 5-5

Author(s):

Ehsan Malek ◽

E. Ricky Chan ◽

Daniel Qu ◽

Jane Reese ◽

Robert Fox ◽

...

Keyword(s):

Multiple Myeloma ◽

Signaling Pathways ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Research Funding ◽

Advisory Board ◽

High Burden ◽

Signature Genes ◽

Whole Exome ◽

Relapse Group

Introduction: Multiple myeloma (MM) is a plasma cell neoplasm associated with heterogeneous somatic alterations. Despite the development of novel anti-myeloma agents that have significantly prolonged patient survival, disease relapse remains a daunting problem. Our goal was to employ whole-exome sequencing (WES) to better describe the mutational landscape in MM beyond the tumor cell and identify genomic factors that might predict relapse. WES was performed using autograft samples obtained from MM patients that were then treated with high dose melphalan and autologous hematopoietic cell transplant (HCT). We identified a panel of genes that were most frequently mutated in all patients and then identified those genes mutated with greater frequency in patients that relapsed. A relapse burden signature was generated based upon the genes that were most frequently mutated genes in relapsed patients. Finally, the relapse burden signature was correlated with patient progression-free survival (PFS) and overall survival (OS) following autologous HCT. Methods. DNA was extracted from one ml of cryopreserved, mobilized hematopoietic cell product obtained from patients (N=93) that underwent HCT and was provided by the Case Comprehensive Cancer Center Hematopoietic Biorepository Core. Targeted sequencing was performed using the Tempus xE whole exome platform (Tempus, Chicago, IL). Variants were identified using a variant allele frequency (VAF) ≥0.1 for each sample. Variants were tabulated for each gene in each patient. Patients were grouped according to their relapse status; "No Relapse" (N=39) and "Relapse" (N=54) which corresponded to their post-HCT outcome. Relapse time was defined as time from transplant to event. Variants identified in each gene and patient group were counted and ranked. A relapse burden signature was defined and included twenty-two genes over-represented in the relapse group compared to the non-relapse group by > 10%. Genes in the relapse burden signature were subjected to gene set enrichment analysis (GSEA) and cross referenced against Gene Ontology (GO) categories. PFS and OS were defined as the time from transplant until the event of interest, with censoring at time of last follow up. Patients were regrouped according to their mutation burden in the relapse signature genes ("High burden" defined as >=six signature genes with variants) and their OS and PFS were analyzed with an R package (survival) to generate Kaplan-Meier curves and statistical significance based on a Chi-square test between low and high burden patients. Results: In total, 3,523 genes were identified as containing variants. Table 1 lists the top thirty genes that were identified and ranked based upon total number of mutations (mutational count) and most frequently mutated in relapsed and non-relapsed patients (sample count). We then identified those genes that were more frequently mutated by at least 10% in relapsed patients compared to non-relapsed patients (Fig. 1A). GSEA revealed that the relapse burden gene signature was associated with protein O-linked glycosylation, glycan processing, Golgi lumen and innate immune response activating cell surface receptor signaling pathways (Table 2). Interestingly, multiple mucin family members (Muc2, Muc3A, Muc12 and Muc19) were represented in the relapse burden signature. GO analysis indicated that the individual mucin genes were associated with the same signaling pathways that had been associated with the relapse burden signature by GSEA (Table 3). Importantly, a high relapse burden signature was correlated with a statistically significant reduction in both PFS and OS (Fig. 1B, C). Conclusion: Taken together, our results support the feasibility of WES to generate a relapse burden signature that predicts the risk of MM patients for relapse following HCT. Moreover, the mutational landscape associated with relapse, i.e. the specific genes mutated, has provided insights on the mechanisms of relapse. It is noteworthy that the relapse burden signature genes identified here were mutated at a much greater frequency than genes associated with clonal hematopoiesis of indeterminate potential (CHIP). The identification of patient subgroups at heightened risk of relapse can better guide treatment decisions. Future studies will be conducted to evaluate the effect of pathways identified here on myeloma cell survival and to validate actionable therapeutic targets. Disclosures Malek: Bluespark: Research Funding; Takeda: Other: Advisory board , Speakers Bureau; Medpacto: Research Funding; Janssen: Other: Advisory board, Speakers Bureau; Sanofi: Other: Advisory board; Clegene: Other: Advisory board , Speakers Bureau; Amgen: Honoraria; Cumberland: Research Funding. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Verastem: Other: Advisory Board; Kite pharmaceuticals: Other: Advisory Board; Celgene: Speakers Bureau; ADC therapeutics: Other: Advisory Board, Research Funding. de Lima:Celgene: Research Funding; BMS: Other: Personal Fees, advisory board; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board; Pfizer: Other: Personal fees, advisory board, Research Funding.

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Metastatic colorectal cancer and severe hypocalcemia following irinotecan administration in a patient with X-linked agammaglobulinemia: a case report

BMC Medical Genetics ◽

10.1186/s12881-019-0880-1 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 3

Author(s):

Mingming Li ◽

Wei Chen ◽

Xiaomeng Sun ◽

Zhipeng Wang ◽

Xun Zou ◽

...

Keyword(s):

Colorectal Cancer ◽

Therapeutic Drug Monitoring ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Drug Monitoring ◽

Treatment Cycle ◽

Germline Mutations ◽

Therapeutic Drug ◽

Immune Disorder ◽

Whole Exome

Abstract Background X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder caused by germline mutations in the Bruton tyrosine kinase (BTK) gene on X chromosome. These mutations disturb B-cell development, decrease immunoglobulin levels, increase susceptibility to infection or neoplasms, and increase the risk of developing colorectal cancer (CRC). For occasional cases of CRC have been reported in XLA patients, low levels of B lymphocytes and immunoglobulins induced by congenital immune disorder make them more susceptible to drug-related toxicities (DRT). Therefore, gene sequencing, therapeutic drug monitoring and any possible measurement to predict DRT should be considered before determining the course of chemotherapy for XLA patients with CRC. Case presentation In this study, we reported a 21-year-old male who developed metastatic CRC in the context of XLA. Since the whole exome sequencing and therapeutic drug monitoring did not reveal any predictive markers of DRT, we applied standard first-line chemotherapy to the patient. However, progressive disease occurred after the fifth treatment cycle. Therefore, the administration of oxaliplatin was changed to irinotecan as second-line therapy. After that, the patient firstly suffered from severe hypocalcemia and eventually died due to metastatic CRC after the eighth treatment cycle. The overall survival time was 7.5 months. Conclusions This study reported the first written record of a Chinese XLA patient with metastatic CRC and severe hypocalcemia. Whole exome sequencing and bioinformatic analysis indicated the somatic mutations in ABCA6, C6 and PAX3 genes might contribute to the early-onset and metastasis CRC. Besides, a number of germline mutations in genes related to calcium metabolism (CACNA2D4, CD36, etc.) and the administration of irinotecan were speculated to be the causes of severe hypocalcemia. We therefore suggested that in order to avoid severe DRT, clinicians should take genetic background and therapeutic drug monitoring into consideration while planning chemotherapy treatment for XLA patients with CRC.

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GENE-30. PRELIMINARY STUDY ON WHOLE-EXOME SEQUENCING TECHNOLOGY IN THE GENETIC ANALYSIS OF PEDIATRIC PATIENTS WITH GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/noz175.432 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi104-vi104

Author(s):

Mingyao Lai ◽

Juan Li ◽

Junjie Zhen ◽

jiangfen zhou ◽

Qingjun Hu ◽

...

Keyword(s):

Genetic Analysis ◽

Signaling Pathways ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Pediatric Patients ◽

Genetic Mutation ◽

Pleomorphic Xanthoastrocytoma ◽

Pathological Examination ◽

Sequencing Technology ◽

Whole Exome

Abstract OBJECTIVE To analyze the genes related to the signaling pathways in pediatric gliomas and drug-related genes with whole-exome sequencing technology. METHODS The tumor tissues and matched blood samples of 17 enrolled patients were detected with whole-exome sequencing technology. There were 3 cases of diffuse midline gliomas, 2 cases of childhood glioblastomas, 3 cases of disffuse astrocytoma, 1 case of pleomorphic xanthoastrocytoma, 1 case of ganglioglioma, 6 cases of anaplastic ependymoma and 1 case of ependymoma in this study. All the enrolled patients who were no more than 14 years old received surgery in the Department of Neurosurgery, Guangdong Sanjiu Brain Hospital. The diagnosis was confirmed by pathological examination and the sample acquisition was approved by hospital ethics committee. RESULTS With the use of whole-exome sequencing technology, a total of 31 related genetic mutations were detected in 15 cases, while no genetic mutation was detected in the other 2 cases. The genes related to the signaling pathways in pediatric gliomas included ATRX, ASL1, BCOR, EP300, FGFR1, H3F3A, IGF1R, MED12, PIK3R1, PRKDC, RB1, SETD2, SMARCA4, SOX2, TGFBR2, and the drug-related genes included AKT1, BCL2, BRAF, BRCA2, CCND1, CCND2, CDK6, EGFR, FGF3, KRAS, MET, PDGFRA, PIK3CA, PTEN, TP53, TSC1. One patient only had genes related to the signaling pathways, and 14 patients had drug-related genes. CONCLUSION Applying whole-exome sequencing technology in the genetic analysis of pediatric patients with gliomas has remarkable guiding significance for revealing the mechanism of disease, searching for therapeutic targets and adopting individualized treatment, which can bring potential benefits to pediatric patients. However, more samples and further data analysis and verification are needed in future study.

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