Next-generation sequencing-based clinical sequencing: toward precision medicine in solid tumors

Wakai, Toshifumi; Prasoon, Pankaj; Hirose, Yuki; Shimada, Yasuhiro; Ichikawa, Hiroshi; Nagahashi, Masayuki

doi:10.1007/s10147-018-1375-3

Cited by 44 publications

(35 citation statements)

References 55 publications

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“…3). Follow-up studies revealed a correlation between MSI status, TMB, and clinical response to treatments with ICIs in various cancers [32][33][34]. High TMB leads to the synthesis of aberrant and potentially immunogenic mutation-associated neoantigens by the cancer cells, which attract CD8?…”

Section: Clinical Importance Of Msi And/or Tmb In Gastrointestinal Mamentioning

confidence: 99%

“…CTLs and activated Th1 cells to the tumor microenvironment [32]. Furthermore, there is a significant correlation between TMB and the response to anti-PD-1/ PD-L1 therapy across various types of cancer [19,33,34]. Diaz et al reported the results of the phase 2 KEYNOTE-158 basket study, in which 77 patients with MSI-H non-CRC across 20 tumor types (52% with C 1 prior therapies) were enrolled, including endometrial (n = 17), gastric (n = 11), small intestinal (n = 10), pancreatic (n = 9), and biliary tract (n = 8) cancers [35].…”

Section: Clinical Importance Of Msi And/or Tmb In Gastrointestinal Mamentioning

confidence: 99%

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Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers

et al. 2019

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Recent innovations in the next-generation sequencing technologies have unveiled that the accumulation of genetic alterations results in the transformation of normal cells into cancer cells. Accurate and timely repair of DNA is, therefore, essential for maintaining genetic stability. Among various DNA repair pathways, the mismatch repair (MMR) pathway plays a pivotal role. MMR deficiency leads to a molecular feature of microsatellite instability (MSI) and predisposes to cancer. Recent studies revealed that MSI-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, regardless of their primary site, have a promising response to immune checkpoint inhibitors (ICIs), leading to the approval of the anti-programmed cell death protein 1 monoclonal antibody pembrolizumab for the treatment of advanced or recurrent MSI-H/dMMR solid tumors that continue to progress after conventional chemotherapies. This new indication marks a paradigm shift in the therapeutic strategy of cancers; however, when considering the optimum indication for ICIs and their safe and effective usage, it is important for clinicians to understand the genetic and immunologic features of each tumor. In this review, we describe the molecular basis of the MMR pathway, diagnostics of MSI status, and the clinical importance of MSI status and the tumor mutation burden in developing therapeutic strategies against gastrointestinal and hepatobiliary malignancies.

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Section: Clinical Importance Of Msi And/or Tmb In Gastrointestinal Mamentioning

confidence: 99%

Section: Clinical Importance Of Msi And/or Tmb In Gastrointestinal Mamentioning

confidence: 99%

Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers

et al. 2019

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“…Although tremendous efforts have been made to investigate the tumorigenesis and cancer development, the underlying mechanisms still remain elusive. Recently, technological advances such as microarrays and next-generation sequencing (NGS) have permitted for the in-depth genomic depiction of variety tumors, which increase our thoughtfulness of cancer initiation and advancement [3,4]. Numerous genetic and epigenetic variations relevant to lung development are established through these techniques.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of Thr/Tyr kinase Increases the Cancer Progression by Neurotensin and Dihydropyrimidinase-Like 3 in Lung Cancer

Tsai

Chang

et al. 2020

IJMS

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Lung cancer is one of the leading causes of cancer-related death globally, thus elucidation of its molecular pathology is highly highlighted. Aberrant alterations of the spindle assembly checkpoint (SAC) are implicated in the development of cancer due to abnormal cell division. TTK (Thr/Tyr kinase), a dual serine/threonine kinase, is considered to act as a cancer promoter by controlling SAC. However, the mechanistic details of how TTK-mediated signaling network supports cancer development is still a mystery. Here, we found that TTK was upregulated in the tumor tissue of patients with lung cancer, and enhanced tumor growth and metastasis in vitro and in vivo. Mechanistically, TTK exerted a significant enhancement in cancer growth by neurotensin (NTS) upregulation, and subsequently increased the expression of cyclin A and cdk2, which was resulting in the increase of DNA synthesis. In contrast, TTK increased cell migration and epithelial-to-mesenchymal transition (EMT) by enhancing the expression of dihydropyrimidinase-like 3 (DPYSL3) followed by the increase of snail-regulated EMT, thus reinforce metastatic potential and ultimately tumor metastasis. TTK and DPYSL3 upregulation was positively correlated with a poor clinical outcome in patients with lung cancer. Together, our findings revealed a novel mechanism underlying the oncogenic potential effect of TTK and clarified its downstream factors NTS and DPYSL3 might represent a novel, promising candidate oncogenes with potential therapeutic vulnerabilities in lung cancer.

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“…Then the guide RNA (gRNA), which contains a complemental sequence of the targeting site, was designed for the mutation. The possibility of off-target effect was checked by the GGGnome [2] software and those with higher off-targets were avoided.…”

Section: Selection Of the Target Mutations In Cancer-related Genesmentioning

confidence: 99%

“…Innovative advances in DNA sequencing technology have deepened the understanding of cancer genetic abnormalities and accumulated huge volumes of data on genetic abnormalities in various human cancers [1][2][3][4]. On the other hand, the so-called molecular targeted drugs, targeting specific cancer-related genes, have been developed based on the genetic alterations observed in human cancers [5].…”

Section: Introductionmentioning

confidence: 99%

Preparation of the standard cell lines for reference mutations in cancer gene-panels by genome editing in HEK 293 T/17 cells

et al. 2020

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Background: Next Generation Sequencer (NGS) is a powerful tool for a high-throughput sequencing of human genome. It is important to ensure reliability and sensitivity of the sequence data for a clinical use of the NGS. Various cancer-related gene panels such as Oncomine™ or NCC OncoPanel have been developed and used for clinical studies. Because these panels contain multiple genes, it is difficult to ensure the performance of mutation detection for every gene. In addition, various platforms of NGS are developed and their cross-platform validation has become necessity. In order to create mutant standards in a defined background, we have used CRISPR/Cas9 genome-editing system in HEK 293 T/17 cells. Results: Cancer-related genes that are frequently used in NGS-based cancer panels were selected as the target genes. Target mutations were selected based on their frequency reported in database, and clinical significance and on the applicability of CRISPR/Cas9 by considering distance from PAM site, and off-targets. We have successfully generated 88 hetero-and homozygous mutant cell lines at the targeted sites of 36 genes representing a total of 125 mutations. Conclusions: These knock-in HEK293T/17 cells can be used as the reference mutant standards with a steady and continuous supply for NGS-based cancer panel tests from the JCRB cell bank. In addition, these cell lines can provide a tool for the functional analysis of targeted mutations in cancer-related genes in the isogenic background.

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Next-generation sequencing-based clinical sequencing: toward precision medicine in solid tumors

Cited by 44 publications

References 55 publications

Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers

Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers

Upregulation of Thr/Tyr kinase Increases the Cancer Progression by Neurotensin and Dihydropyrimidinase-Like 3 in Lung Cancer

Preparation of the standard cell lines for reference mutations in cancer gene-panels by genome editing in HEK 293 T/17 cells

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