Identification of early genetic changes in well-differentiated intramucosal gastric carcinoma by target deep sequencing

Yoshida, Takashi; Yamaguchi, Tatsuya; Maekawa, Shinya; Takano, Shinichi; Kuno, Toru; Tanaka, Keisuke; Iwamoto, Fumihiko; Tsukui, Yuya; Kobayashi, Shōji; Asakawa, Yukiko; Shindo, Hiroko; Fukasawa, Mitsuharu; Nakayama, Yasuhiro; Inoue, Taisuke; Uetake, Tomoyoshi; Ohtaka, Masahiko; Satô, Tadashi; Mochizuki, Kazuki; Enomoto, Nobuyuki

doi:10.1007/s10120-019-00926-y

Cited by 23 publications

(13 citation statements)

References 20 publications

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“…Moreover, Yoshida et al performed target sequencing on 50 genes for 31 non-invasive GCs. They reported that mutation in TP53 and Wnt-signaling pathway genes (APC and CTNNB1) were frequently found and were mutually exclusive [32]. This result is almost the same in our data, that is, 10 out of 12 cases with TP53 mutation had no mutation in APC and CTNNB1.…”

Section: Discussionsupporting

confidence: 88%

“…This result is almost the same in our data, that is, 10 out of 12 cases with TP53 mutation had no mutation in APC and CTNNB1. Furthermore, the frequency of the following gene mutations did not differ significantly between our data and their data (ARID1A, ARID2, APC, SMAD4, PIK3CA, RHOA, KRAS, MUC6, and APC: Fisher's exact test, data not shown) [14,32]. However, LRP1, which was detected as a significant gene mutation following TP53 in our study was not included in their target-sequencing panel.…”

Section: Discussioncontrasting

confidence: 59%

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Genomic Characterization of Non-Invasive Differentiated-Type Gastric Cancer in the Japanese Population

Nakamura

Urabe

Kagemoto

et al. 2020

Cancers

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Background and aims: Recent genomic characterization of gastric cancer (GC) by sequencing has revealed a large number of cancer-related genes. Research to characterize the genomic landscape of cancer has focused on established invasive cancer to develop biomarkers for therapeutic or diagnostic targets, and nearly all GC reports have been about advanced GC. The aim of this study is to identify recurrently mutated genes in non-invasive GC and, in particular, the driver mutations that are associated with the development of GC. Methods and results: We performed whole-exome sequencing of 19 fresh frozen specimens of differentiated-type non-invasive GC and targeted sequencing for 168 genes of 30 formalin-fixed paraffin-embedded archival specimens of differentiated-type non-invasive GC. We found that TP53 and LRP1 are significantly associated with non-invasive GC. It has been reported that LPR1 is associated with CagA autophagy in gastric mucosa. Therefore, we downloaded RNA sequence data for gastric cancer from the The Cancer Genome Atlas (TCGA) Genomic Data Commons Data Portal and examined the differences in LRP1 gene expression levels. The expression level was significantly lower in cases without LRP1 mutation than in cases with LRP1 mutation. Based on these results, fluorescent immunostaining for CagA was performed for 49 of the above samples to evaluate CagA accumulation within the cancerous tissue. Accumulation of CagA was significantly greater when an LRP1 mutation was present than without a mutation. Conclusion: These data suggest that LRP1 mutation is an important change promoting the transformation of gastric mucosa to GC early in the carcinogenesis of cancer.

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Section: Discussionsupporting

confidence: 88%

Section: Discussioncontrasting

confidence: 59%

Genomic Characterization of Non-Invasive Differentiated-Type Gastric Cancer in the Japanese Population

Nakamura

Urabe

Kagemoto

et al. 2020

Cancers

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“…Clinically relevant biomarkers are genetic, epigenetic, proteinic, or cellular alterations that are intrinsic to cancer cells. These biomarkers can be used to predict patients' responses to Huang et al [50] , 2017 Pasternack et al [112] , 2018 Kakiuchi et al [42] , 2014 Yoshida et al [113] , 2019 Nagahashi et al [39] , 2016…”

Section: Biomarkers For Gi Cancermentioning

confidence: 99%

Precision medicine for gastrointestinal cancer: Recent progress and future perspective

Matsuoka

Yashiro

2019

WJGO

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Gastrointestinal (GI) cancer has a high tumor incidence and mortality rate worldwide. Despite significant improvements in radiotherapy, chemotherapy, and targeted therapy for GI cancer over the last decade, GI cancer is characterized by high recurrence rates and a dismal prognosis. There is an urgent need for new diagnostic and therapeutic approaches. Recent technological advances and the accumulation of clinical data are moving toward the use of precision medicine in GI cancer. Here we review the application and status of precision medicine in GI cancer. Analyses of liquid biopsy specimens provide comprehensive real-time data of the tumor-associated changes in an individual GI cancer patient with malignancy. With the introduction of gene panels including next-generation sequencing, it has become possible to identify a variety of mutations and genetic biomarkers in GI cancer. Although the genomic aberration of GI cancer is apparently less actionable compared to other solid tumors, novel informative analyses derived from comprehensive gene profiling may lead to the discovery of precise molecular targeted drugs. These progressions will make it feasible to incorporate clinical, genome-based, and phenotype-based diagnostic and therapeutic approaches and apply them to individual GI cancer patients for precision medicine.

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“…These different subtypes exhibit unique molecular features that could potentially be used to guide therapeutic decisions, and have been shown to have prognostic signi cance; for example, Epstein-Barr virus (EBV) infection has been associated with improved prognosis. Since the molecular classi cation of GC has potential prognostic and therapeutic implications, it may be used identify biomarkers and therapeutic targets for each subtype, particularly through strati cation according to EBV infection and microsatellite instability (MSI) [4][5][6][7][8]. Currently, the expression of programmed death-ligand 1 (PD-L1) in tumor cells is a validated predictive marker for the tumor response to anti programmed cell death-1 protein (anti-PD-1) or PD-L1 immunotherapy in different malignancies, including GC [9].…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological features of Epstein-Barr virus infection, microsatellite instability, tumor mutation burden and PD-L1 status in Chinese patients with gastric cancer

Zhang

Li³

2020

Preprint

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Objectives: Gastric cancer (GC) is the 4th most common type of cancer worldwide. Different GC subtypes exhibit unique molecular features that may potentially guide therapeutic decisions. The aim of the present study was to investigate Epstein-Barr virus (EBV) infection, microsatellite instability (MSI) status, the expression of programmed death-ligand 1 (PD-L1) and gene mutations in patients with surgically-treated GC. Methods: The data of 2,504 GC patients, who underwent potentially curative gastrectomy with lymphadenectomy at Peking University Cancer Hospital between 2013 and 2018, were reviewed from a prospectively collected medical database. We also analyzed the clinicopathological factors associated with the immunohistochemistry (IHC) profiles of these patients, and genetic alterations were analyzed using next generation sequencing (NGS). Results: Mismatch repair-deficient (d-MMR) GC patients were found to have a higher probability of expressing PD-L1 (p<0.001, PD-L1 cutoff value = 1%). In addition, 4 and 6.9% of the 2,504 gastric cancer patients were EBV-positive and d-MMR, respectively. The number of MLH1/PMS2-negative cases was 126 (6%), and the number of MSH2/MSH6-negative cases was 14 (0.9%). d-MMR status was associated with a diffuse/mixed group (p<0.05), but not with tumor differentiation. Furthermore, MSI and d-MMR GC status (detected by NGS and IHC, respectively) were consistently high, and the rate of MSI was higher in patients with d-MMR GC. A number of genes associated with DNA damage repair were detected in GC patients with MSI, including POLE, ETV6, BRCA and RNF43. In patients with a high tumor mutation burden, the most significantly mutated genes were LRP1B (79.07%), ARID1A (74.42%), RNF43 (69.77%), ZFHX3 (65.12%), TP53 (58.14%), GANS (51.16%), BRCA2 (51.16%), PIK3CA (51.16%), NOTCH1 (51.16%), SMARCA4 (48.84%), ATR (46.51%), POLE (41.86%) and ATM (39.53%). Conclusions: Using IHC and NGS, MSI status, protein expression, TMB and genetic alterations were identified in patients with GC, which provides a theoretical basis for the future clinical treatment of GC.

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Identification of early genetic changes in well-differentiated intramucosal gastric carcinoma by target deep sequencing

Cited by 23 publications

References 20 publications

Genomic Characterization of Non-Invasive Differentiated-Type Gastric Cancer in the Japanese Population

Genomic Characterization of Non-Invasive Differentiated-Type Gastric Cancer in the Japanese Population

Precision medicine for gastrointestinal cancer: Recent progress and future perspective

Clinicopathological features of Epstein-Barr virus infection, microsatellite instability, tumor mutation burden and PD-L1 status in Chinese patients with gastric cancer

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