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

IF 6 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gastric Cancer Pub Date : 2024-09-01 Epub Date: 2024-06-26 DOI:10.1007/s10120-024-01523-4
Akira Ooki, Hiroki Osumi, Koichiro Yoshino, Kensei Yamaguchi
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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.

Abstract Image

微卫星不稳定性高和/或错配修复缺陷胃癌的有效治疗策略。
胃癌(GC)是一种常见的恶性肿瘤,给全球患者的治疗带来了挑战。错配修复(MMR)系统是一种高度保守的 DNA 修复机制,可在复制过程中保护基因组的完整性。缺乏 MMR(dMMR)会导致微卫星序列中遗传错误的积累增加,从而形成微卫星不稳定性高(MSI-H)表型。大多数 MSI-H/dMMR GC 都是偶发性的,主要是由于 MutL 同源物 1(MLH1)的表观遗传沉默造成的。与微卫星稳定型(MSS)/功能良好型MMR(pMMR)GCs不同,MSI-H/dMMR GCs相对罕见,是一个独特的亚型,具有基因组不稳定性、高体细胞突变负荷、良好的免疫原性、不同的治疗反应和预后。dMMR/MSI-H状态是使用免疫检查点抑制剂(ICIs)治疗的一个强有力的预测性生物标志物,因为它具有高新抗原负荷、突出的肿瘤浸润淋巴细胞和程序性细胞死亡配体1(PD-L1)过表达。然而,一部分 MSI-H/dMMR GC 患者并不能从免疫疗法中获益,这凸显了进一步研究预测性生物标志物和耐药机制的必要性。本综述全面概述了MSI-H/dMMR GC的临床、分子、免疫原性和治疗方面,重点关注ICIs在免疫疗法中的影响及其作为新辅助疗法的潜力。了解 MSI-H/dMMR GC 分子和免疫学特征的复杂性和多样性将推动开发更有效的治疗策略和未来精准医疗的分子靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Gastric Cancer
Gastric Cancer 医学-胃肠肝病学
CiteScore
14.70
自引率
2.70%
发文量
80
审稿时长
6-12 weeks
期刊介绍: Gastric Cancer is an esteemed global forum that focuses on various aspects of gastric cancer research, treatment, and biology worldwide. The journal promotes a diverse range of content, including original articles, case reports, short communications, and technical notes. It also welcomes Letters to the Editor discussing published articles or sharing viewpoints on gastric cancer topics. Review articles are predominantly sought after by the Editor, ensuring comprehensive coverage of the field. With a dedicated and knowledgeable editorial team, the journal is committed to providing exceptional support and ensuring high levels of author satisfaction. In fact, over 90% of published authors have expressed their intent to publish again in our esteemed journal.
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