Journal Article

Clinical outcome and molecular landscape of patients with ARID1A‐loss gastric cancer

Liu, Hao, Li, He, Fang, Hanji, Li, Ruochen, Lin, Chao, Wang, Jieti, Sun, Mengyao, Gu, Yun, Zhang, Heng, Shao, Fei, He, Hongyong, Xu, Jiejie

2024

Overview

Chromatin remodelers are commonly altered in human cancer. The mutation of AT‐rich interactive domain 1A (ARID1A) in gastric cancer (GC), a component of the SWI/SNF chromatin remodeling complex, was proven associated with treatment response in our previous study. However, ARID1A loss of function was caused not only by mutations but also copy number deletions. The clinicopathologic, genomic, and immunophenotypic correlates of ARID1A loss is largely uncharacterized in GC. Here, 819 patients with clinicopathological information and sequencing data or formalin‐fixed paraffin‐embedded tissues from four cohorts, Zhongshan Hospital (ZSHS) cohort (n = 375), The Cancer Genome Atlas (TCGA) cohort (n = 371), Samsung Medical Center (SMC) cohort (n = 53), and ZSHS immunotherapy cohort (n = 20), were enrolled. ARID1A loss was defined by genome sequencing or deficient ARID1A expression by immunohistochemistry. We found that ARID1A mutation and copy number deletion were enriched in GC with microsatellite instability (MSI) and chromosomal‐instability (CIN), respectively. In the TCGA and ZSHS cohorts, only CIN GC with ARID1A loss could benefit from fluorouracil‐based adjuvant chemotherapy. In the SMC and ZSHS immunotherapy cohorts, ARID1A loss exhibited a tendency of superior responsiveness and indicated favorable overall survival after anti‐PD‐1 immunotherapy. ARID1A‐loss tumors demonstrated elevated mutation burden, neoantigen load, and interferon gamma pathway activation. Moreover, in CIN GC, ARID1A loss was correlated with higher homologous recombination deficiency. ARID1A loss defines a distinct subtype of GC characterized by high levels of genome instability, neoantigen formation, and immune activation. These tumors show sensitivity to both chemotherapy and anti‐PD‐1 immunotherapy. This study provides valuable insights for precision treatment strategies in GC. Our data indicate that ARID1A loss predicted superior benefit from adjuvant chemotherapy (ACT) and anti‐PD‐1 immunotherapy in gastric cancer (GC), especially in chromosomal instability (CIN) subtype, while in non‐CIN subtype, we did not observe any survival benefit from ACT regardless of ARID1A status. ARID1A‐loss GC is associated with elevated mutation burden, neoantigen load, homologous recombination deficiency, and interferon gamma pathway activation. This study may help clinicians stratify patients according to ARID1A status and develop personalized treatment for each molecular subtype in future.

• Publisher: John Wiley & Sons, Inc
• Subject: 5-Fluorouracil / adjuvant chemotherapy / anti‐PD‐1 immunotherapy / ARID1A loss / Cell cycle / Chemotherapy / Chromatin remodeling / Chromosome deletion / Copy number / DNA-Binding Proteins - genetics / Epstein-Barr virus / Fibroblasts / Gastric cancer / Gene deletion / Gene expression / Genomes / Genomic instability / Homologous recombination / Humans / Immune response / Immunohistochemistry / Immunotherapy / Medical prognosis / Metastasis / Microsatellite instability / molecular subtype / Mutation / Neoantigens / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Patients / PD-1 protein / Statistical analysis / Stomach Neoplasms - drug therapy / Stomach Neoplasms - genetics / Survival analysis / Transcription Factors - genetics / Transcription Factors - metabolism / Tumors / Whole genome sequencing