{"doi":"10.1136/jitc-2019-000128","title":"Complete response to anti-PD-L1 antibody in a metastatic bladder cancer associated with novel MSH4 mutation and microsatellite instability","abstract":"BACKGROUND: Microsatellite instability (MSI) occurs in 3% of urothelial carcinomas as a result of germline or somatic loss of function mutation in mismatch repair (MMR) proteins.1 Although MSH4 is a member of the DNA MMR mutS family, the association of MSH4 mutation with MSI has not been described. We report a complete responder to PD-L1 blockade who had MSH4 mutated metastatic bladder cancer with mixed histology and MSI. The genomics of urothelial, plasmacytoid and squamous histology was characterized individually through microdissection. CASE PRESENTATION: An 81-year-old man was diagnosed with metastatic urothelial carcinoma 8 months after a cystectomy for muscle invasive bladder cancer. His disease was primary refractory to first-line platinum-based chemotherapy but attained complete response to second-line atezolizumab. PCR-based assay revealed MSI high. The tumor mutational burden was elevated to 36.7 mut/Mb. However, immunohistochemistry of MLH1, MSH2, MSH6 and PMS2 was intact. Whole exome sequencing confirmed that the above mentioned four classic MMR genes were wild type but revealed a deleterious MSH4 L359I mutation with variant allele fraction of 30% and Polyphen2 score of 0.873. The association of MSH4 alterations and MSI-H was independently verified in two publicly available MSI-H colorectal cancer datasets. CONCLUSIONS: The novel MSH4 L359I mutation is associated with MSI and high mutational burden leading to remarkable response to PD-L1 blockade. More studies are warranted to establish the causality relationship between MSH4 and MSI.","journal":"Journal for ImmunoTherapy of Cancer","year":2020,"id":60739,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":60,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9484,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":320765,"name":"Rohit Jain","orcid":"0000-0002-4905-462X","position":1,"is_corresponding":false},{"id":312952,"name":"Sean T. Glenn","orcid":null,"position":2,"is_corresponding":false},{"id":294038,"name":"Bo Xu","orcid":"0000-0001-5173-2410","position":3,"is_corresponding":false},{"id":320766,"name":"Prashant K. Singh","orcid":"0000-0002-8117-4592","position":4,"is_corresponding":false},{"id":320767,"name":"Lei Wei","orcid":"0000-0002-1881-8666","position":5,"is_corresponding":false},{"id":247365,"name":"Qiang Hu","orcid":"0000-0002-4090-5539","position":6,"is_corresponding":false},{"id":247362,"name":"Mark D. Long","orcid":"0000-0003-1120-8176","position":7,"is_corresponding":false},{"id":320768,"name":"Nicholas Hutson","orcid":"0000-0001-6827-8656","position":8,"is_corresponding":false},{"id":72036,"name":"Jianming Wang","orcid":"0000-0002-9151-284X","position":9,"is_corresponding":false},{"id":320769,"name":"Sebastiano Battaglia","orcid":"0000-0002-0809-8925","position":10,"is_corresponding":false},{"id":226680,"name":"Saby George","orcid":"0000-0002-0444-5870","position":11,"is_corresponding":false},{"id":294034,"name":"Yuanquan Yang","orcid":"0000-0002-5209-9247","position":0,"is_corresponding":true}],"reference_count":25,"raw_metadata":null,"created_at":"2026-07-18T21:09:05.493770Z","pmid":"32221012","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":[]}