Cancer Research and Treatment

Original Articles

Gastrointestinal cancer

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

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 Rhoa^R129W 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 Rhoa^R129W 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.

Citations

Citations to this article as recorded by

Association of C5AR1 polymorphisms with increased gastric cancer risk: mechanistic insights and therapeutic implications targeting JAK/STAT pathway
Zhongqi Wang, Ying Jian, Xiaomei Jiang, Hongmei Zhang, Zhi Zhang, Xuemei Zhang
Gene.2026; 991: 150086. CrossRef
Hereditary diffuse gastric cancer: the evolution of a cancer syndrome
Lyvianne Decourtye‐Espiard, Tanis Godwin, Parry Guilford
Journal of the Royal Society of New Zealand.2025; 55(6): 2636. CrossRef
A Comprehensive Review of Genetic Mutations Occurring in the Development and Progression of Gastric Cancer
Yalan Li, Qianqian Xu, Zhuo Chen, Mengting Chen, Kunyu Han, Zhuqing Zhang, Aling Shen, Xiaoyan Fu
Digestive Diseases.2025; 43(6): 630. CrossRef
Helicobacter pylori infection status and evolution of gastric cancer
Wenlin Zhang, Yuxin Zhang, Jing Ning, Weiwei Fu, Shigang Ding
Chinese Medical Journal.2025; 138(23): 3083. CrossRef
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

4,514 View
181 Download
3 Web of Science
5 Crossref

Adjuvant Chemotherapy in Microsatellite Instability–High Gastric Cancer: Jin Won Kim, Sung-Yup Cho, Jeesoo Chae, Ji-Won Kim, Tae-Yong Kim, Keun-Wook Lee, Do-Youn Oh, Yung-Jue Bang, Seock-Ah Im; Cancer Res Treat. 2020;52(4):1178-1187. Published online June 11, 2020; DOI: https://doi.org/10.4143/crt.2020.313

Abstract PDF Supplementary Material PubReader ePub

Purpose
Microsatellite instability (MSI) status may affect the efficacy of adjuvant chemotherapy in gastric cancer. In this study, the clinical characteristics of MSI-high (MSI-H) gastric cancer and the predictive value of MSI-H for adjuvant chemotherapy in large cohorts of gastric cancer patients were evaluated. Material and Methods This study consisted of two cohorts. Cohort 1 included gastric cancer patients who received curative resection with pathologic stage IB-IIIC. Cohort 2 included patients with MSI-H gastric cancer who received curative resection with pathologic stage II/III. MSI was examined using two mononucleotide markers and three dinucleotide markers.
Results
Of 359 patients (cohort 1), 41 patients (11.4%) had MSI-H. MSI-H tumors were more frequently identified in older patients (p < 0.001), other histology than poorly cohesive, signet ring cell type (p=0.005), intestinal type (p=0.028), lower third tumor location (p=0.005), and absent perineural invasion (p=0.027). MSI-H status has a tendency of better disease-free survival (DFS) and overall survival (OS) in multivariable analyses (hazard ratio [HR], 0.4; p=0.059 and HR, 0.4; p=0.063, respectively). In the analysis of 162 MSI-H patients (cohort 2), adjuvant chemotherapy showed a significant benefit with respect to longer DFS and OS (p=0.047 and p=0.043, respectively). In multivariable analysis, adjuvant chemotherapy improved DFS (HR, 0.4; p=0.040).
Conclusion
MSI-H gastric cancer had distinct clinicopathologic findings. Even in MSI-H gastric cancer of retrospective cohort, adjuvant chemotherapy could show a survival benefit, which was in contrast to previous prospective studies and should be investigated in a further prospective trial.

Citations

Citations to this article as recorded by

Diagnostic Challenges and Clinical Implications of Microsatellite Instability/Mismatch Repair Deficiency in Solid Tumors
Yoonjin Kwak, Jeong Mo Bae, Hye Seung Lee
Cancer Research and Treatment.2026; 58(1): 1. CrossRef
Gastric Cancer
Anuj Kishor Patel, Nilay S. Sethi, Haeseong Park
JAMA.2026; 335(5): 439. CrossRef
Perioperative chemotherapy for gastric cancer patients with microsatellite instability or deficient mismatch repair: A systematic review and meta‐analysis
Baike Liu, Chaoyong Shen, Xiaonan Yin, Tianxiang Jiang, Yihui Han, Ruiwan Yuan, Yuan Yin, Zhaolun Cai, Bo Zhang
Cancer.2025;[Epub] CrossRef
Management of Microsatellite Instability High (MSI-H) Gastroesophageal Adenocarcinoma
Katherine I. Zhou, Brent A. Hanks, John H. Strickler
Journal of Gastrointestinal Cancer.2024; 55(2): 483. CrossRef
The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023
Feng‐Hua Wang, Xiao‐Tian Zhang, Lei Tang, Qi Wu, Mu‐Yan Cai, Yuan‐Fang Li, Xiu‐Juan Qu, Hong Qiu, Yu‐Jing Zhang, Jie‐Er Ying, Jun Zhang, Ling‐Yu Sun, Rong‐Bo Lin, Chang Wang, Hao Liu, Miao‐Zhen Qiu, Wen‐Long Guan, Sheng‐Xiang Rao, Jia‐Fu Ji, Yan Xin, Wei‐
Cancer Communications.2024; 44(1): 127. CrossRef
Clinical Significance of Fibrinogen and Platelet to Pre-Albumin Ratio in Predicting the Prognosis of Advanced Gastric Cancer
Huakai Tian, Zitao Liu, Zuo Zhang, Lipeng Zhang, Zhen Zong, Jiang Liu, Houqun Ying, Hui Li
Journal of Inflammation Research.2023; Volume 16: 4373. CrossRef
Fatty acid metabolism is related to the immune microenvironment changes of gastric cancer and RGS2 is a new tumor biomarker
Shifeng Yang, Boshi Sun, Wenjing Li, Hao Yang, Nana Li, Xinyu Zhang
Frontiers in Immunology.2022;[Epub] CrossRef
Chemotherapy in Neuroendocrine Tumors
Satya Das, Taymeyah Al-Toubah, Jonathan Strosberg
Cancers.2021; 13(19): 4872. CrossRef

13,376 View
271 Download
27 Web of Science
8 Crossref

First
Prev
Page of 1
Next
Last

Search