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Gastrointestinal cancer
Effector Function Characteristics of Exhausted CD8+ T-Cell in Microsatellite Stable and Unstable Gastric Cancer
Dong-Seok Han, Yoonjin Kwak, Seungho Lee, Soo Kyung Nam, Seong-Ho Kong, Do Joong Park, Hyuk-Joon Lee, Nak-Jung Kwon, Hye Seung Lee, Han-Kwang Yang
Cancer Res Treat. 2024;56(4):1146-1163.   Published online April 12, 2024
DOI: https://doi.org/10.4143/crt.2024.317
AbstractAbstract PDFPubReaderePub
Purpose
Gastric cancer exhibits molecular heterogeneity, with the microsatellite instability–high (MSI-H) subtype drawing attention for its distinct features. Despite a higher survival rate, MSI-H gastric cancer lack significant benefits from conventional chemotherapy. The immune checkpoint inhibitors, presents a potential avenue, but a deeper understanding of the tumor immune microenvironment of MSI-H gastric cancer is essential.
Materials and Methods
We explored the molecular characteristics of CD8+ T-cell subtypes in three MSI-H and three microsatellite stable (MSS) gastric cancer samples using single-cell RNA sequencing and spatial transcriptome analysis.
Results
In MSI-H gastric cancer, significantly higher proportions of effector memory T cell (Tem), exhausted T cell (Tex), proliferative exhausted T cell (pTex), and proliferative T cell were observed, while MSS gastric cancer exhibited significantly higher proportions of mucosal-associated invariant T cell and natural killer T cell. In MSI-H gastric cancer, Tex and pTex exhibited a significant upregulation of the exhaustion marker LAG3, as well as elevated expression of effector function markers such as IFNG, GZMB, GZMH, and GZMK, compared to those in MSS gastric cancer. The interferon γ (IFN-γ) signaling pathway of Tex and pTex was retained compared to those of MSS gastric cancer. The spatial transcriptome analysis demonstrates the IFN-γ signaling pathway between neighboring Tex and malignant cell, showcasing a significantly elevated interaction in MSI-H gastric cancer.
Conclusion
Our study reveals novel finding indicating that IFN-γ signaling pathway is retained in Tex and pTex of MSI-H gastric cancer, offering a comprehensive perspective for future investigations into immunotherapy for gastric cancer.

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  • Simvastatin induces ferroptosis and activates anti-tumor immunity to sensitize anti-PD-1 immunotherapy in microsatellite stable gastric cancer
    Yumei Ning, Shilin Fang, Runan Zhang, Jun Fang, Kun Lin, Yang Ding, Haihang Nie, Jingkai Zhou, Qiu Zhao, Hengning Ke, Haizhou Wang, Fan Wang
    International Immunopharmacology.2024; 142: 113244.     CrossRef
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Identification of New Pathogenic Variants of Hereditary Diffuse Gastric Cancer
Seung-Young Oh, Giyong Jang, Jaeryuk Kim, Kyoung-Yun Jeong, Hyun Myong Kim, Yoon Jin Kwak, Seong-Ho Kong, Do Joong Park, Hyuk-Joon Lee, Sung-Yup Cho, Jong-Il Kim, Han-Kwang Yang
Cancer Res Treat. 2024;56(4):1126-1135.   Published online April 11, 2024
DOI: https://doi.org/10.4143/crt.2024.328
AbstractAbstract PDFPubReaderePub
Purpose
Hereditary diffuse gastric cancer (HDGC) presents a significant genetic predisposition, notably linked to mutations in the CDH1 and CTNNA1. However, the genetic basis for over half of HDGC cases remains unidentified. The aim of this study is to identify novel pathogenic variants in HDGC and evaluate their protein expression.
Materials and Methods
Among 20 qualifying families, two were selected based on available pedigree and DNA. Whole genome sequencing (WGS) on DNA extracted from blood and whole exome sequencing on DNA from formalin-fixed paraffin-embedded tissues were performed to find potential pathogenic variants in HDGC. After selection of a candidate variant, functional validation, and enrichment analysis were performed.
Results
As a result of WGS, three candidate germline mutations (EPHA5, MCOA2, and RHOA) were identified in one family. After literature review and in-silico analyses, the RHOA mutation (R129W) was selected as a candidate. This mutation was found in two gastric cancer patients within the family. In functional validation, it showed RhoA overexpression and a higher GTP-bound state in the RhoaR129W mutant. Decreased phosphorylation at Ser127/397 suggested altered YAP1 regulation in the Rho-ROCK pathway. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses linked RhoaR129W overexpression to changed migration/adhesion in MKN1 cell line. However, this RHOA mutation (R129W) was not found in index patients in other families.
Conclusion
The RHOA mutation (R129W) emerges as a potential causative gene for HDGC, but only in one family, indicating a need for further studies to understand its role in HDGC pathogenesis fully.

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  • Current advances and challenges in Managing Hereditary Diffuse Gastric Cancer (HDGC): a narrative review
    L. van der Sluis, J.M. van Dieren, R.S. van der Post, T.M. Bisseling
    Hereditary Cancer in Clinical Practice.2024;[Epub]     CrossRef
  • 1,377 View
  • 124 Download
  • 1 Crossref
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Gastrointestinal Cancer
Development and Validation of a Symptom-Focused Quality of Life Questionnaire (KOQUSS-40) for Gastric Cancer Patients after Gastrectomy
Bang Wool Eom, Joongyub Lee, In Seob Lee, Young-Gil Son, Keun Won Ryu, Sung Geun Kim, Hyoung-Il Kim, Young-Woo Kim, Seong-Ho Kong, Oh Kyoung Kwon, Ji-Ho Park, Ji Yeong An, Chang Hyun Kim, Byoung-Jo Suh, Hong Man Yoon, Myoung Won Son, Ji Yeon Park, Jong-Min Park, Sang-Ho Jeong, Moon-Won Yoo, Geum Jong Song, Han-Kwang Yang, Yun-Suhk Suh, Ki Bum Park, Sang-Hoon Ahn, Dong Woo Shin, Ye Seob Jee, Hye-Seong Ahn, Sol Lee, Jae Seok Min, Haejin In, Ahyoung Kim, Hoon Hur, Hyuk-Joon Lee, on behalf of KOrean QUality of life in Stomach cancer patients Study group (KOQUSS)
Cancer Res Treat. 2021;53(3):763-772.   Published online December 29, 2020
DOI: https://doi.org/10.4143/crt.2020.1270
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Patients who have undergone gastrectomy have unique symptoms that are not appropriately assessed using currently available tools. This study developed and validated a symptom-focused quality of life (QoL) questionnaire for patients who have received gastrectomy for gastric cancer. Materials and Methods Based on a literature review, patient interviews, and expert consultation by the KOrean QUality of life in Stomach cancer patients Study group (KOQUSS), the initial item pool was developed. Two large-scale developmental studies were then sequentially conducted for exploratory factor analyses for content validity and item reduction. The final item pool was validated in a separate cohort of patients and assessed for internal consistency, test-retest reliability, construct validity, and clinical validity.
Results
The initial questionnaire consisted of 46-items in 12 domains. Data from 465 patients at 11 institutions, followed by 499 patients at 13 institutions, were used to conduct item reduction and exploratory factor analyses. The final questionnaire (KOQUSS-40) comprised 40 items within 11 domains. Validation of KOQUSS-40 was conducted on 413 patients from 12 hospitals. KOQUSS-40 was found to have good model fit. The mean summary score of the KOQUSS-40 was correlated with the EORTC QLQ-C30 and STO22 (correlation coefficients, 0.821 and 0.778, respectively). The KOQUSS-40 score was also correlated with clinical factors, and had acceptable internal consistency (> 0.7). Test-retest reliability was greater than 0.8. Conclusion The KOQUSS-40 can be used to assess QoL of gastric cancer patients after gastrectomy and allows for a robust comparison of surgical techniques in clinical trials.

Citations

Citations to this article as recorded by  
  • Global status of research on gastrointestinal cancer patients’ quality of life: A bibliometric and visual analysis from 2003 to 2023
    Xiaoqin Wang, Caihua Wang, Wenjin Han, Jiaru Sun, Zhaozhao Hui, Shuangyan Lei, Huili Wu, Xiaohong Liu
    Heliyon.2024; 10(1): e23377.     CrossRef
  • Development and Feasibility Assessment of Mobile Application-Based Digital Therapeutics for Postoperative Supportive Care in Gastric Cancer Patients Following Gastrectomy
    Ji-Hyeon Park, Hyuk-Joon Lee, JeeSun Kim, Yo-Seok Cho, Sunjoo Lee, Seongmin Park, Hwinyeong Choe, Eunhwa Song, Youngran Kim, Seong-Ho Kong, Do Joong Park, Byung-Ho Nam, Han-Kwang Yang
    Journal of Gastric Cancer.2024; 24(4): 420.     CrossRef
  • Effect of Four Main Gastrectomy Procedures for Proximal Gastric Cancer on Patient Quality of Life: A Nationwide Multi-Institutional Study
    Koji Nakada, Akitoshi Kimura, Kazuhiro Yoshida, Nobue Futawatari, Kazunari Misawa, Kuniaki Aridome, Yoshiyuki Fujiwara, Kazuaki Tanabe, Hirofumi Kawakubo, Atsushi Oshio, Yasuhiro Kodera
    Journal of Gastric Cancer.2023; 23(2): 275.     CrossRef
  • Quality of life after gastric cancer surgery
    Jae Kyun Park, Hyuk-Joon Lee
    Foregut Surgery.2023; 3(2): 27.     CrossRef
  • Long-term Functional and Patient-reported Outcomes Between Intra-corporeal Delta-shaped Gastroduodenostomy and Gastrojejunostomy After Laparoscopic Distal Gastrectomy
    Sin Hye Park, Hong Man Yoon, Keun Won Ryu, Young-Woo Kim, Mira Han, Bang Wool Eom
    Journal of Gastric Cancer.2023; 23(4): 561.     CrossRef
  • Potential Applicability of Local Resection With Prophylactic Left Gastric Artery Basin Dissection for Early-Stage Gastric Cancer in the Upper Third of the Stomach
    Yoshimasa Akashi, Koichi Ogawa, Katsuji Hisakura, Tsuyoshi Enomoto, Yusuke Ohara, Yohei Owada, Shinji Hashimoto, Kazuhiro Takahashi, Osamu Shimomura, Manami Doi, Yoshihiro Miyazaki, Kinji Furuya, Shoko Moue, Tatsuya Oda
    Journal of Gastric Cancer.2022; 22(3): 184.     CrossRef
  • Systematic review of health-related quality of life (HRQoL) issues associated with gastric cancer: capturing cross-cultural differences
    Alison Rowsell, Samantha C. Sodergren, Vassilios Vassiliou, Anne-Sophie Darlington, Marianne G. Guren, Bilal Alkhaffaf, Chantelle Moorbey, Kristopher Dennis, Mitsumi Terada
    Gastric Cancer.2022; 25(4): 665.     CrossRef
  • Patient-reported gastrointestinal symptoms following surgery for gastric cancer and the relative risk factors
    Rui Xu, Qiong Gu, Shuomeng Xiao, Ping Zhao, Zhi Ding
    Frontiers in Oncology.2022;[Epub]     CrossRef
  • Prospective multicentre randomised clinical trial comparing survival rates, quality of life and nutritional status between advanced gastric cancer patients with different follow-up intensities: study protocol for the STOFOLUP trial
    Bang Wool Eom, Dong-Hoe Koo, Ji Yeong An, Han Hong Lee, Hyoung-Il Kim, Hoon Hur, Moon-Won Yoo, Min-Hee Ryu, Hyuk-Joon Lee, Su Mi Kim, Ji-Ho Park, Jae Seok Min, Kyung Won Seo, Sang-Ho Jeong, Oh Jeong, Oh Kyoung Kwon, Seung Wan Ryu, Chang Hak Yoo, Jae Moon
    BMJ Open.2021; 11(12): e056187.     CrossRef
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  • 8 Web of Science
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Gastric Carcinogenesis in the miR-222/221 Transgenic Mouse Model
Boram Choi, Jieun Yu, Tae-Su Han, Young-Kook Kim, Keun Hur, Byeong-Cheol Kang, Woo-Ho Kim, Dae-Yong Kim, Hyuk-Joon Lee, V. Narry Kim, Han-Kwang Yang
Cancer Res Treat. 2017;49(1):150-160.   Published online June 23, 2016
DOI: https://doi.org/10.4143/crt.2015.462
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
MicroRNAs (miRNAs) regulate various cellular functions, including development, cell proliferation, apoptosis, and tumorigenesis. Different signatures associated with various tissue types, diagnosis, progression, prognosis, staging, and treatment response have been identified by miRNA expression profiling of human tumors. miRNAs function as oncogenes or as tumor suppressors. The relationship between gastric cancer and miRNA garnered attention due to the high incidence of gastric cancer in Asian countries. miR-222/221 expression increases in gastric tumor tissues. The oncogenic effect of miR-222/221 was previously determined in functional studies and xenograft models. In this study, transgenic mice overexpressing miR-222/221 were generated to confirm the effect of miR-222/221 on gastric carcinogenesis. Materials and Methods At 6 weeks of age, 65 transgenic mice and 53 wild-type mice were given drinking water containing N-nitroso-N-methylurea (MNU) for 5 alternating weeks to induce gastric cancer. The mice were euthanized at 36 weeks of age and histologic analysis was performed.
Results
Hyperplasia was observed in 3.77% of the wild-type mice and in 18.46% of the transgenic mice (p=0.020). Adenoma was observed in 20.75% of the wild-type mice and 26.15% of the transgenic mice (p=0.522). Carcinoma was observed in 32.08% of the wild-type mice and 41.54% of the transgenic mice (p=0.341). The frequency of hyperplasia, adenoma, and carcinoma was higher in transgenic mice, but the difference was statistically significant only in hyperplasia. Conclusion These results suggest that hyperplasia, a gastric pre-cancerous lesion, is associated with miR-222/221 expression but miR-222/221 expression does not affect tumorigenesis itself.

Citations

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    Yi Zhang, Wei-Long Hong, Zhi-Ming Li, Qi-Yu Zhang, Kang Zeng
    Aesthetic Plastic Surgery.2021; 45(2): 749.     CrossRef
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    International Journal of Cancer.2020; 146(10): 2865.     CrossRef
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    Changde Liu, Yan Zhang, Shanghua Liang, Yuhua Ying
    Experimental and Therapeutic Medicine.2020;[Epub]     CrossRef
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    Experimental and Therapeutic Medicine.2017;[Epub]     CrossRef
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Overexpression of Plasminogen Activator Inhibitor-1 in Advanced Gastric Cancer with Aggressive Lymph Node Metastasis
Yun-Suhk Suh, Jieun Yu, Byung Chul Kim, Boram Choi, Tae-Su Han, Hye Seong Ahn, Seong-Ho Kong, Hyuk-Joon Lee, Woo Ho Kim, Han-Kwang Yang
Cancer Res Treat. 2015;47(4):718-726.   Published online February 2, 2015
DOI: https://doi.org/10.4143/crt.2014.064
AbstractAbstract PDFPubReaderePub
Purpose
The purpose of this study is to investigate differentially expressed genes using DNA microarray between advanced gastric cancer (AGC) with aggressive lymph node (LN) metastasis and that with a more advanced tumor stage but without LN metastasis.
Materials and Methods
Five sample pairs of gastric cancer tissue and normal gastric mucosa were taken from three patients with T3N3 stage (highN) and two with T4N0 stage (lowN). Data from triplicate DNA microarray experiments were analyzed, and candidate genes were identified using a volcano plot that showed ≥ 2-fold differential expression and were significant by Welch's t test (p < 0.05) between highN and lowN. Those selected genes were validated independently by reverse- transcriptase–polymerase chain reaction (RT-PCR) using five AGC patients, and tissue- microarray (TMA) comprising 47 AGC patients.
Results
CFTR, LAMC2, SERPINE2, F2R, MMP7, FN1, TIMP1, plasminogen activator inhibitor-1 (PAI- 1), ITGB8, SDS, and TMPRSS4 were commonly up-regulated over 2-fold in highN. REG3A, CD24, ITLN1, and WBP5 were commonly down-regulated over 2-fold in lowN. Among these genes, overexpression of PAI-1 was validated by RT-PCR, and TMA showed 16.7% (7/42) PAI-1 expression in T3N3, but none (0/5) in T4N0 (p=0.393).
Conclusion
DNA microarray analysis and validation by RT-PCR and TMA showed that overexpression of PAI-1 is related to aggressive LN metastasis in AGC.

Citations

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    Jimin Min, Boram Choi, Tae-Su Han, Hyuk-Joon Lee, Seong-Ho Kong, Yun-Suhk Suh, Tae-Han Kim, Hwi-Nyeong Choe, Woo Ho Kim, Keun Hur, Han-Kwang Yang
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