Clinicopathologic features of gastric cancer with synchronous and metachronous colorectal cancer in Korea: are microsatellite instability and p53 overexpression useful markers for predicting colorectal cancer in 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

Download Full-text

Association and diagnostic value of serum SPINK4 in colorectal cancer

PeerJ ◽

10.7717/peerj.6679 ◽

2019 ◽

Vol 7 ◽

pp. e6679 ◽

Cited By ~ 1

Author(s):

Mingzhi Xie ◽

Kezhi Li ◽

Jilin Li ◽

Dongcheng Lu ◽

Bangli Hu

Keyword(s):

Colorectal Cancer ◽

Gastric Cancer ◽

Cancer Patients ◽

Characteristic Curve ◽

Disease Free Survival ◽

Diagnostic Value ◽

Healthy Controls ◽

Significant Difference ◽

Peptidase Inhibitor ◽

Gastric Cancer Patients

The role of serum serine peptidase inhibitor, Kazal type 4 (SPINK4), in colorectal cancer (CRC) is largely unknown. This study aimed to explore the association and diagnostic value of serum SPINK4 in CRC. A total of 70 preoperative CRC patients, 30 postoperative CRC patients, 30 gastric cancer patients, and 30 healthy controls were enrolled. Using enzyme-linked immunosorbent assays, we found that the serum SPINK4 level was significantly increased in preoperative CRC compared with postoperative CRC patients, gastric cancer patients, and healthy controls (p < 0.05). The serum SPINK4 level was remarkably elevated in colon cancer compared with rectal cancer and was enhanced in the M1 stage compared with the M0 stage (p < 0.05). The area under the receiver operating characteristic curve of serum SPINK4 level in the diagnosis of CRC was 0.9186, with a sensitivity and specificity of 0.886 and 0.900, respectively, and a cut-off value of 2.065. There was no significant difference between high and low expression of serum SPINK4 regarding the overall survival time and disease-free survival (p > 0.05). This study demonstrated that the serum SPINK4 level increased in CRC and was associated with the location and distant metastasis of CRC. It had a high diagnostic value in CRC but was not associated with the survival of CRC patients.

Download Full-text

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.

Download Full-text

Quantitative Analysis of Methylated Adenosine Modifications Revealed Increased Levels of N6-Methyladenosine (m6A) and N6,2′-O-Dimethyladenosine (m6Am) in Serum From Colorectal Cancer and Gastric Cancer Patients

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.694673 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yiqiu Hu ◽

Zhihao Fang ◽

Jiayi Mu ◽

Yanqin Huang ◽

Shu Zheng ◽

...

Keyword(s):

Colorectal Cancer ◽

Gastric Cancer ◽

Quantitative Analysis ◽

Early Detection ◽

Human Serum ◽

Cancer Patients ◽

Healthy Controls ◽

Serum Samples ◽

Gastrointestinal Malignancies ◽

Gastric Cancer Patients

Colorectal cancer and gastric cancer are the most prevalent gastrointestinal malignancies worldwide, and early detection of these cancers is crucial to reduce their incidence and mortality. RNA methylation plays an important regulatory role in a variety of physiological activities, and it has drawn great attention in recent years. Methylated adenosine (A) modifications such as N6-methyladenosine (m6A), N1-methyladenosine (m1A), 2′-O-methyladenosine (Am), N6,2′-O-dimethyladenosine (m6Am), and N6,N6-dimethyladenosine (m62A) are typical epigenetic markers of RNA, and they are closely correlated to various diseases including cancer. Serum is a valuable source of biofluid for biomarker discovery, and determination of these adenosine modifications in human serum is desirable since they are emerging biomarkers for detection of diseases. In this work, a targeted quantitative analysis method using hydrophilic interaction liquid chromatography–tandem mass spectrometry (HILIC-MS/MS) was developed and utilized to analyze these methylated adenosine modifications in serum samples. The concentration differences between the healthy volunteers and cancer patients were evaluated by Mann–Whitney test, and receiver operator characteristic (ROC) curve analysis was performed to access the potential of these nucleosides as biomarkers. We demonstrated the presence of the m6Am in human serum for the first time, and we successfully quantified the concentrations of A, m6A, m1A, and m6Am in serum samples from 99 healthy controls, 51 colorectal cancer patients, and 27 gastric cancer patients. We found that the levels of m6A and m6Am in serum were both increased in colorectal cancer or gastric cancer patients, compared to that in healthy controls. These results indicate that m6A and m6Am in serum may act as potential biomarkers for early detection and prognosis of colorectal cancer and gastric cancer. In addition, the present work will stimulate investigations on the effects of adenosine methylation on the initiation and progression of colorectal cancer and gastric cancer.

Download Full-text

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.

Download Full-text