{"doi":"10.6004/jnccn.2020.7680","title":"Tumor Mutational Burden and Mismatch Repair Deficiency Discordance as a Mechanism of Immunotherapy Resistance","abstract":"Lynch syndrome is a heritable cancer syndrome caused by a heterozygous germline mutation in DNA mismatch repair (MMR) genes. MMR-deficient (dMMR) tumors are particularly sensitive to immune checkpoint inhibitors, an effect attributed to the higher mutation rate in these cancers. However, approximately 15% to 30% of patients with dMMR cancers do not respond to immunotherapy. This report describes 3 patients with Lynch syndrome who each had 2 primary malignancies: 1 with dMMR and a high tumor mutational burden (TMB), and 1 with dMMR but, unexpectedly, a low TMB. Two of these patients received immunotherapy for their TMB-low tumors but experienced no response. We have found that not all Lynch-associated dMMR tumors have a high TMB and propose that tumors with dMMR and TMB discordance may be resistant to immunotherapy. The possibility of dMMR/TMB discordance should be considered, particularly in less-typical Lynch cancers, in which TMB evaluation could guide the use of immune checkpoint inhibitors.","journal":"Journal of the National Comprehensive Cancer Network","year":2021,"id":176075,"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":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9588,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":69718,"name":"Walid K. Chatila","orcid":"0000-0001-5474-218X","position":1,"is_corresponding":false},{"id":294443,"name":"Henry Walch","orcid":"0000-0003-1188-350X","position":2,"is_corresponding":false},{"id":1863,"name":"Nikolaus Schultz","orcid":"0000-0002-0131-4904","position":3,"is_corresponding":false},{"id":108796,"name":"Zsofia K. Stadler","orcid":"0000-0002-6985-2864","position":4,"is_corresponding":false},{"id":239557,"name":"Jinru Shia","orcid":"0000-0002-4351-2511","position":5,"is_corresponding":false},{"id":239546,"name":"Diane Reidy‐Lagunes","orcid":"0000-0003-2688-4556","position":6,"is_corresponding":false},{"id":90752,"name":"Rona Yaeger","orcid":"0000-0002-7233-5454","position":7,"is_corresponding":false},{"id":718024,"name":"Agata A. Bielska","orcid":"0000-0002-6502-0972","position":0,"is_corresponding":true}],"reference_count":17,"raw_metadata":null,"created_at":"2026-07-18T23:47:19.591542Z","pmid":"33545685","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":[]}