| Identification of New Pathogenic Variants of Hereditary Diffuse Gastric Cancer |
Seung-Young Oh1,2
, Giyong Jang3,4
, Jaeryuk Kim3,5,6, Kyoung-Yun Jeong7, Hyun Myong Kim7, Yoon Jin Kwak8, Seong-Ho Kong1,9, Do Joong Park1,9, Hyuk-Joon Lee1,9, Sung-Yup Cho5,7, Jong-Il Kim3,5,6,7, Han-Kwang Yang1,7,9
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1Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
2Department of Critical Care Medicine, Seoul National University Hospital, Seoul, Korea
3Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea
4Ewha Biomedical Research Institute, Ewha Womans University Medical Center, Seoul, Korea
5Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
6Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Korea
7Cancer Research Institute, Seoul National University, Seoul, Korea
8Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
9Department of Surgery, Seoul National University Hospital, Seoul, Korea
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| Correspondence |
Han-Kwang Yang ,Tel: 82-2-2072-3797, Fax: 82-2-3672-0047, Email: hkyang@snu.ac.kr
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Received: April 2, 2024; Accepted: April 10, 2024. Published online: April 11, 2024.
*Seung-Young Oh and Giyong Jang contributed equally to this work. |
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| ABSTRACT |
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 (WES) 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. |
| Key words:
Familial gastric cancer, Hereditary diffuse gastric cancer, Germ-Line mutation, Pathogenic variant, RHOA |
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