Potent therapeutic strategy in gastric cancer with microsatellite instability-high and/or deficient mismatch repair

Sep 21, 2026

Upload by Asher

Gastric cancer (GC) is a prevalent malignancy whose mismatch repair (MMR) biology shapes distinct clinical and molecular behaviors. Deficient MMR (dMMR) causes microsatellite instability-high (MSI-H), driven often by MLH1 epigenetic silencing, producing genomic instability and high somatic mutational burden. MSI-H/dMMR tumors show strong immunogenicity, tumor-infiltrating lymphocytes, and PD-L1 overexpression, making dMMR/MSI-H a predictive biomarker for immune checkpoint inhibitors (ICIs). A subset resists immunotherapy, so the review outlines mechanisms, biomarkers, resistance, and the role of ICIs including neoadjuvant potential, to guide future precision strategies.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages25

Reading Time1 h 3 min

AccessFree to download

Introduction

Clinicopathological and molecular features of MSI-H/dMMR gastric cancer

Clinicopathological features of MSI-H/dMMR gastric cancer

Gastric Cancer (2024) 27:907–931 [https://doi.org/10.1007/s10120-024-01523-4](https://doi.org/10.1007/s10120-024-01523-4) Potent therapeutic strategy in gastric cancer with microsatellite instability‑high and/or deficient mismatch repair Akira Ooki1 · Hiroki Osumi1 · Koichiro Yoshino1 · Kensei Yamaguchi1 Received: 17 April 2024 / Accepted: 12 June 2024 / Published online: 26 June 2024 © The Author(s) 2024 Abstract Gastric cancer (GC) is a common malignancy that presents challenges in patient care worldwide. The mismatch repair (MMR) system is a highly conserved DNA repair mechanism that protects genome integrity during replication. Deficient MMR (dMMR) results in an increased accumulation of genetic errors in microsatellite sequences, leading to the development of a microsatellite instability-high (MSI-H) phenotype. Most MSI-H/dMMR GCs arise sporadically, mainly due to MutL homolog 1 (MLH1) epigenetic silencing. Unlike microsatellite-stable (MSS)/proficient MMR (pMMR) GCs, MSI-H/dMMR GCs are relatively rare and represent a distinct subtype with genomic instability, a high somatic mutational burden, favorable immunogenicity, different responses to treatment, and prognosis. dMMR/MSI-H status is a robust predictive biomarker for treatment with immune checkpoint inhibitors (ICIs) due to high neoantigen load, prominent tumor-infiltrating lymphocytes, and programmed cell death ligand 1 (PD-L1) overexpression. However, a subset of MSI-H/dMMR GC patients does not benefit from immunotherapy, highlighting the need for further research into predictive biomarkers and resistance mechanisms. This review provides a comprehensive overview of the clinical, molecular, immunogenic, and therapeutic aspects of MSI-H/dMMR GC, with a focus on the impact of ICIs in immunotherapy and their potential as neoadjuvant therapies. Understanding the complexity and diversity of the molecular and immunological profiles of MSI-H/dMMR GC will drive the development of more effective therapeutic strategies and molecular targets for future precision medicine. Keywords Gastric cancer · Microsatellite instability-high · Deficient mismatch repair · Immunotherapy · Chemotherapy Introduction Gastric cancer (GC) is the fifth most common cancer and the fourth leading cause of cancer-related deaths worldwide [1] . Based on comprehensive genomic analyses, GC has been demonstrated to be a heterogeneous disease composed of different subtypes, each with peculiar molecular aspects and specific clinical behavior. GC can be categorized into four subtypes according to The Cancer Genome Atlas (TCGA) molecular classification: microsatellite instability (MSI), chromosomal instability (CIN), Epstein–Barr virus (EBV) -positive, and genomically stable (GS) tumors [2] . Similarly, the Asian Cancer Research Group (ACRG) proposed the MSI subtype as one of four molecular subtypes with distinct * Akira Ooki[sp9y9tq9@piano.ocn.ne.jp](sp9y9tq9@piano.ocn.ne.jp) 1 Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo 135-8550, Japan molecular profiles and clinical outcomes [3] . The molecular classification of GC has paved the way for personalized therapies, among which the MSI subtype has gained significant attention. Microsatellites (MSs) are widespread, short, and repetitive DNA sequences throughout the human genome that are prone to DNA replication errors [4] . Asthe DNA mismatch repair (MMR) system plays a key role in recognizing and correcting these errors, the genetic and epigenetic inactivation of MMR genes leads to a deficient MMR (dMMR) system, resulting in a MSI-high (MSI-H) phenotype with genomic instability and a high tumor mutation burden (TMB) [5, 6] . Thus, considerable research effort has been invested in characterizing the genomic landscape of MSI-H/dMMR GC and identifying potential therapeutic targets for precision medicine. The discovery of immune checkp

FAQs

What does dMMR lead to in gastric cancer and why does it matter?

Deficient MMR (dMMR) leads to a microsatellite instability-high (MSI-H) phenotype, characterized by increased replication errors in microsatellite sequences. This produces genomic instability and a high tumor mutational burden, which influences treatment responses.

Why are MSI-H/dMMR gastric cancers predicted to respond to immune checkpoint inhibitors?

MSI-H/dMMR status correlates with immunotherapy efficacy because it is associated with high neoantigen load, prominent tumor-infiltrating lymphocytes, and PD-L1 overexpression. These factors support stronger antitumor immune activity under ICIs.

Do all MSI-H/dMMR gastric cancer patients benefit from immunotherapy?

No. The review notes that a subset of MSI-H/dMMR patients does not benefit from immunotherapy, indicating intrinsic resistance. This drives the need to identify resistance mechanisms and additional predictive biomarkers.

Sep 21, 2026

Upload by Asher