Microsatellite Instability Is Associated with the Clinicopathologic Features of Gastric Cancer in Sporadic Gastric Cancer Patients

3123 Background: In the KEYNOTE-059 study, the anti-PD-1 checkpoint inhibitor pembrolizumab was shown to have a modest overall response of 11.6%. Common predictors of response including, high microsatellite instability (MSI-H), PD-L1 expression, tumor mutational burden (TMB) and tumor inflammation signature (TIS), were not individually sufficient for patient selection. Recent pancancer studies have highlighted a unique population of cancer patients whose tumors appear to be driven by oncogene amplifications on extrachromosomal DNA (ecDNA). These ecDNA-driven tumors are aggressive and characterized by high levels of genomic instability. We sought to understand if tumors that possess ecDNA may represent a subset of the patient group that is non-responsive to anti-PD-1 therapy. Methods: We determined the ecDNA status of gastric cancer patients (N = 108) using whole genome sequencing (WGS) from the TCGA Pan-cancer dataset These patients had been previously subtyped for EBV status, genomic stability (GS), microsatellite instability (MSI), and chromosomal instability (CIN). Patients that were ecDNA+ were re-classified into a set regardless of gastric subtype. Additionally, TMB, TIS, and PD-L1 expression levels were collected. Results: 32% of gastric cancer patients were positive for ecDNA signatures and mutually exclusive from the 23% of MSI-H patients. We found that ecDNA positive tumors had statistically significantly lower TIS than all other groups (p-value < 0.05) except CIN tumors (p-value = 0.09). The ecDNA positive tumors also had lower PD-L1 expression than all but GS tumors. Only MSI-H showed statistically significantly higher TMB scores compared to every other group (p-value < 0.001), no difference in TMB scores were observed between every other pair of groups. Conclusions: Patients whose tumors are ecDNA positive represent a unique population that display signatures for non-response to checkpoint inhibitor therapy, including MSS, low TIS, and PD-L1 expression. Thus, the determination of tumor ecDNA status may have utility as an additional patient selection strategy for checkpoint inhibitor therapy. As ecDNA are not limited to gastric cancers, this study highlights the importance of the development of a clinical diagnostic test for ecDNA status and the need for further research on ecDNA biology, its impact on immunotherapy response, and potential ecDNA-directed therapeutics

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Characteristics of Subtypes Within Microsatellite Instability-high Gastric Cancer Based on a Gene Signature Related to Immune Microenvironment Components

10.21203/rs.3.rs-31506/v1 ◽

2020 ◽

Author(s):

Xiaolong Wu ◽

Xiangyu Gao ◽

Xiaofang Xing ◽

Xianzi Wen ◽

Ziyu Li ◽

...

Keyword(s):

Gastric Cancer ◽

Microsatellite Instability ◽

Cancer Patients ◽

Immune Checkpoint ◽

Differentially Expressed Gene ◽

The Cancer Genome Atlas ◽

Immune Microenvironment ◽

Clinical Prognosis ◽

Time Signature ◽

Gastric Cancer Patients

Abstract Background: Gastric cancer patients with microsatellite instability-high (MSI-H) status have a better clinical prognosis and higher response rate to immune checkpoint inhibitors. However, recent studies have suggested that some molecular pathways in MSI-H tumors could affect tumor immune microenvironment (TIME) components, thereby leading to immunotherapy resistance. We aimed to establish subtypes based on the TIME components of MSI-H gastric cancer and analyze the characteristics of each subtype. Methods: Cohorts from the Cancer Genome Atlas, the Asian Cancer Research Group, and Peking University Cancer Hospital were used for this study. CIBERSORT software was used to analyze the TIME components. A set of genes based on the TIME component characteristics, which we named the MSI-TIME signature, was defined using k-means cluster and differentially expressed gene analysis. Results: By using the MSI-TIME signature in the aforementioned cohorts for cluster analysis, the TIME subtypes within MSI-H gastric cancer (MSI-S1, MSI-S2) were established; the differences between the subgroups were reflected in multiple aspects. The MSI-S1 subtype was characterized by a high density of CD8+ T cells, high expression levels of immune checkpoint molecules including PD-L1, PD-L2, CTLA-4, and a high T-cell inflammation level. Patients with the MSI-S1 subtype could also benefit from adjuvant chemotherapy. In contrast, the WNT/β-catenin pathway was enriched in the MSI-S2 subtype. Conclusion: We found that patients with MSI-H gastric cancer showed very different TIME characteristics and could be divided into two subtypes accordingly. These results might benefit MSI-H gastric cancer patients developing individualized treatment strategies in the future.

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Clinic-pathological Features of Epstein-barr Virus Infection, Microsatellite Instability, Tumor Mutation Burden and PD-L1 Status in 2504 Chinese Gastric Cancer Patients

10.21203/rs.3.rs-48875/v1 ◽

2020 ◽

Author(s):

Li Zhang ◽

Aiwen Wu ◽

Zhongwu Li

Keyword(s):

Gastric Cancer ◽

Next Generation Sequencing ◽

Microsatellite Instability ◽

Cancer Patients ◽

Epstein Barr Virus Infection ◽

Next Generation ◽

Barr Virus ◽

Negative Case ◽

Gastric Cancer Patients ◽

Generation Sequencing

Abstract Objectives: Gastric cancer is the 4th most common cancer worldwide. Different subtype showed unique molecular features that could potentially guide therapeutic decisions. The aim of this study was to investigate the Epstein-Barr virus infection, microsatellite instability status, PD-L1 expression and gene mutation in surgically treated gastric cancer patients. Methods: We reviewed all GC patients who underwent potentially curative gastroectomy with lymphadenectomy at Peking University Cancer Hospital between 2013 and 2018 from a prospective collected medical database. We analyzed the clinic-pathological factors associated with immunohistochemistry profiles. We also analyzed gene changes through next-generation sequencing. Results: d-MMR gastric cancer patients are more likely to expression programmed death-ligand 1 (p<0.001, programmed death-ligand 1 cut off value 1%). EBV-positive and d-MMR patients were identified in 4% and 7.5% of the 2504 gastric cancer patients, respectively. The MLH1/PMS2 negative case number was 126. The MSH2/MSH6 negative case number was 14. d-MMR status was related to diffuse/mixed group (p<0.05), but not related to tumor differentiation. In our study, the microsatellite instability results detected by next generation sequencing and d-MMR gastric cancer results detected by immunohistochemistry were in high consistency. d-MMR gastric cancer patients had more microsatellite instability core. Many pathogenic genes were detected in microsatellite instability gastric cancer patients, such as POLE, ETV6, TP53, BRCA, RNF43 and other genes. Conclusion: Through immunohistochemistry and next generation sequencing, we got MSI status, protein expression, TMB and gene changes of GC, which provided a theoretical basis for future G clinical treatment.

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Clinicopathologic Features, Survival Outcome, and Prognostic Factors in Gastric Cancer Patients 18–40 Years of Age

Journal of Adolescent and Young Adult Oncology ◽

10.1089/jayao.2019.0162 ◽

2020 ◽

Vol 9 (4) ◽

pp. 514-521

Author(s):

Bochao Zhao ◽

Di Mei ◽

Wu Lv ◽

Huiwen Lu ◽

Shiyang Bao ◽

...

Keyword(s):

Gastric Cancer ◽

Prognostic Factors ◽

Cancer Patients ◽

Survival Outcome ◽

Clinicopathologic Features ◽

Gastric Cancer Patients

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Association of activin type II receptor mutation with microsatellite instability in gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e23191 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e23191-e23191 ◽

Cited By ~ 1

Author(s):

Kizuki Yuza ◽

Masayuki Nagahashi ◽

Hiroshi Ichikawa ◽

Masato Nakajima ◽

Takaaki Hanyu ◽

...

Keyword(s):

Gastric Cancer ◽

Microsatellite Instability ◽

Cancer Patients ◽

Strong Association ◽

High Status ◽

Type Ii ◽

Wild Type ◽

Number Of Patients ◽

Significant Difference ◽

Gastric Cancer Patients

e23191 Background: Microsatellite instability-high status (MSI-H) and alterations in the DNA mismatch repair pathway associate with the efficacy of 5-FU and immune checkpoint inhibitors in patients with gastrointestinal cancers. The activin type II receptor (ACVR2) that binds to the transforming growth factor beta superfamily of ligands is frequently mutated in MSI-H colorectal cancer. However, the incidence of ACVR2 mutations in gastric cancer patients remains unclear. The aim of this study is to reveal the incidence and to examine the association between the MSI-H and ACVR2A mutations in gastric cancer patients. Methods: 124 archived FFPE gastric cancer tissues (stage I-IV), who were operated at Niigata University Medical and Dental Hospital or Niigata Cancer Center Hospital, were analyzed for ACVR2A mutation and MSI status with the NGS-based comprehensive genomic test platform. Clinicopathological characteristics of the patients were also examined. Results: All 124 gastric cancer patients were successfully analyzed. 13 out of 124 patients (10.4%) showed MSI-H status. Interestingly, 10 of 13 MSI-H patients (76.9%) showed ACVR2A mutation, where none (0%) was found among patients with microsatellite stable status (P < 0.001), indicating the strong association between ACVR2A mutation and MSI status in gastric cancer patients. In the ACVR2A mutated group, there was a female predominance (P < 0.05), and cancers of the lower part of the stomach were more common (P < 0.05), compared with the wild type group. Only one of 10 patients with ACVR2A mutation died, and the patients with ACVR2A mutation show a 5-year overall survival rate of 90%. No statistically significant difference in survival was achieved between patients with ACVR2A mutation and wild type; this is probably due to the small number of patients. Conclusions: 10 of 13 MSI-H patients showed ACVR2A mutation. Our results indicate a strong association between ACVR2A mutation and MSI-H in gastric cancer patients.

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