{"doi":"10.1007/s00262-022-03326-x","title":"Somatic ARID1A mutation stratifies patients with gastric cancer to PD-1 blockade and adjuvant chemotherapy","abstract":"<jats:title>Abstract</jats:title><jats:sec>\n                <jats:title>Background</jats:title>\n                <jats:p>AT-rich interaction domain 1A (ARID1A) encodes a vital component of switch/sucrose non-fermentable chromatin-remodeling complex. Given its association with genomic instability, we conducted this study to determine whether <jats:italic>ARID1A</jats:italic> mutation status had an impact on therapeutic responsiveness in gastric cancer (GC), especially combinatory chemo-immunotherapy.</jats:p>\n              </jats:sec><jats:sec>\n                <jats:title>Methods</jats:title>\n                <jats:p>We retrospectively enrolled a total of 1162 patients from five independent cohorts. ZSHS Cohort and TCGA Cohort were designed to inform chemotherapeutic relevance and immunobiology of <jats:italic>ARID1A</jats:italic>-mutant GC based on tissue samples and sequencing data, respectively. MSKCC Cohort, mGC Cohort, and Melanoma Cohort were utilized to interrogate the predictive efficacy of <jats:italic>ARID1A</jats:italic> mutation to programmed cell death protein 1 (PD-1) blockade.</jats:p>\n              </jats:sec><jats:sec>\n                <jats:title>Results</jats:title>\n                <jats:p><jats:italic>ARID1A</jats:italic> mutation was enriched in EBV-positive, hypermutated-single nucleotide variant and microsatellite-unstable subtype GC, and was predictive of responsiveness to both fluorouracil-based chemotherapy and PD-1 blockade. Specifically, <jats:italic>ARID1A</jats:italic> mutation score was a highly sensitive indicator (91%) of response to pembrolizumab. Mechanistically, <jats:italic>ARID1A</jats:italic> mutation correlated with extensive DNA damage repair deficiency and immunogenic tumor microenvironment (TME) featured by elevated activated subsets of CD8<jats:sup>+</jats:sup> T cells, CD4<jats:sup>+</jats:sup> T cells, and NK cells. Type 17T helper cells were typically abundant in <jats:italic>ARID1A</jats:italic>-mutant GC and might be a precondition for chemosensitivity conferred by <jats:italic>ARID1A</jats:italic> mutation. Furthermore, <jats:italic>ARID1A</jats:italic> mutation indicated elevated expression of <jats:italic>VEGFA</jats:italic> and <jats:italic>CLDN18</jats:italic>, as well as over-representation of <jats:italic>ERBB2</jats:italic> and <jats:italic>FGFR2</jats:italic> signaling pathway.</jats:p>\n              </jats:sec><jats:sec>\n                <jats:title>Conclusions</jats:title>\n                <jats:p><jats:italic>ARID1A</jats:italic>-mutant GC displayed immunogenic TME and might be a candidate for both monotherapy and the combination of frontline chemotherapy and PD-1 blockade.</jats:p>\n              </jats:sec>","journal":"Cancer Immunology, Immunotherapy","year":2023,"id":637512,"datarank":0.5456379239589579,"base_score":3.6375861597263857,"endowment":3.6375861597263857,"self_citation_contribution":0.5456379239589579,"citation_network_contribution":0.0,"self_endowment_contribution":0.5456379239589579,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":37,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1418288,"name":"Puran Zhang","orcid":"0000-0002-8757-3535","position":1,"is_corresponding":false},{"id":1655375,"name":"Jieti Wang","orcid":null,"position":2,"is_corresponding":false},{"id":1612448,"name":"Chao Lin","orcid":null,"position":3,"is_corresponding":false},{"id":524214,"name":"Hao Liu","orcid":"0000-0001-7235-1860","position":4,"is_corresponding":false},{"id":15943,"name":"He Li","orcid":"0009-0003-9885-1865","position":5,"is_corresponding":false},{"id":1655380,"name":"Hongyong He","orcid":null,"position":6,"is_corresponding":false},{"id":1655383,"name":"Ruochen Li","orcid":null,"position":7,"is_corresponding":false},{"id":1179467,"name":"Heng Zhang","orcid":"0000-0002-3710-5573","position":8,"is_corresponding":false},{"id":1655388,"name":"Weijuan Zhang","orcid":null,"position":9,"is_corresponding":false},{"id":250586,"name":"Yun Gu","orcid":"0000-0001-6942-0749","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Somatic ARID1A mutation stratifies patients with gastric cancer to PD-1 blockade and adjuvant chemotherapy.","abstract":"<h4>Background</h4>AT-rich interaction domain 1A (ARID1A) encodes a vital component of switch/sucrose non-fermentable chromatin-remodeling complex. Given its association with genomic instability, we conducted this study to determine whether ARID1A mutation status had an impact on therapeutic responsiveness in gastric cancer (GC), especially combinatory chemo-immunotherapy.<h4>Methods</h4>We retrospectively enrolled a total of 1162 patients from five independent cohorts. ZSHS Cohort and TCGA Cohort were designed to inform chemotherapeutic relevance and immunobiology of ARID1A-mutant GC based on tissue samples and sequencing data, respectively. MSKCC Cohort, mGC Cohort, and Melanoma Cohort were utilized to interrogate the predictive efficacy of ARID1A mutation to programmed cell death protein 1 (PD-1) blockade.<h4>Results</h4>ARID1A mutation was enriched in EBV-positive, hypermutated-single nucleotide variant and microsatellite-unstable subtype GC, and was predictive of responsiveness to both fluorouracil-based chemotherapy and PD-1 blockade. Specifically, ARID1A mutation score was a highly sensitive indicator (91%) of response to pembrolizumab. Mechanistically, ARID1A mutation correlated with extensive DNA damage repair deficiency and immunogenic tumor microenvironment (TME) featured by elevated activated subsets of CD8<sup>+</sup> T cells, CD4<sup>+</sup> T cells, and NK cells. Type 17T helper cells were typically abundant in ARID1A-mutant GC and might be a precondition for chemosensitivity conferred by ARID1A mutation. Furthermore, ARID1A mutation indicated elevated expression of VEGFA and CLDN18, as well as over-representation of ERBB2 and FGFR2 signaling pathway.<h4>Conclusions</h4>ARID1A-mutant GC displayed immunogenic TME and might be a candidate for both monotherapy and the combination of frontline chemotherapy and PD-1 blockade.","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"36369379","pmcid":"PMC10110689","openalex_id":null,"authors":[],"funders":[{"funder_name":"National Natural Science Foundation of China","grant_id":"81871930","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"81902402","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"81902901","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"82003019","title":null},{"funder_name":"Shanghai Rising-Star Program","grant_id":"22QA1401700","title":null},{"funder_name":"Shanghai Sailing Program","grant_id":"21YF1407600","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"81972219","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"82203201","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"82103313","title":null},{"funder_name":"Shanghai Sailing Program","grant_id":"19YF1407500","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"81871306","title":null}],"total_grants":11,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":null,"license":null,"oa_locations":[{"url":"https://europepmc.org/articles/PMC10110689","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC10110689?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":[],"mesh_terms":["CD8-Positive T-Lymphocytes","Humans","Stomach Neoplasms","DNA-Binding Proteins","Nuclear Proteins","Transcription Factors","Chemotherapy, Adjuvant","Retrospective Studies","Mutation","Claudins","Tumor Microenvironment","Programmed Cell Death 1 Receptor"],"keywords":["Gastric cancer","Adjuvant Chemotherapy","Predictive Biomarker","Pd-1 Inhibitors","At-rich Interaction Domain 1A"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-06T19:04:34.451864Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}