{"doi":"10.1002/1878-0261.13698","title":"<i>ERBB2</i> mutations define a subgroup of endometrial carcinomas associated with high tumor mutational burden and the microsatellite instability‐high ( <scp>MSI</scp> ‐H) molecular subtype","abstract":"Anti-HER2 therapy is indicated for erb-b2 receptor tyrosine kinase 2 (ERBB2)-amplified/overexpressing endometrial carcinoma (EC). Mutations constitute another mode of ERBB2 activation, but only rare ERBB2-mutated ECs have been reported. We sought to characterize the clinicopathologic and genetic features of ERBB2-mutated EC. From an institutional cohort of 2638 ECs subjected to clinical tumor-normal panel sequencing, 69 (2.6%) with pathogenic ERBB2 mutation(s) were identified, of which 11 were also ERBB2-amplified. The most frequent ERBB2 hotspot mutations were V842I (38%) and R678Q (25%). ERBB2 mutations were clonal in 87% of evaluable cases. Immunohistochemistry revealed low HER2 protein expression in most ERBB2-mutated ECs (0/1+ in 66%, 2+ in 27%); all 3+ tumors (7.3%) were also ERBB2-amplified. Compared to ERBB2-wildtype ECs (with or without ERBB2 amplification), ERBB2-mutated/non-amplified ECs were enriched for the microsatellite instability-high (MSI-H) and, to a lesser extent, DNA polymerase epsilon, catalytic subunit (POLE) molecular subtypes, and associated with high tumor mutational burden and low chromosomal instability. Survival outcomes were similar between patients with ERBB2-mutated/non-amplified versus wildtype EC, whereas ERBB2 amplification was associated with worse prognosis on univariate, but not multivariate, analyses. In conclusion, ERBB2 mutation defines a rare subgroup of ECs that is pathogenically distinct from ERBB2-wildtype and ERBB2-amplified ECs.","journal":"Molecular Oncology","year":2024,"id":477180,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9633,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":242195,"name":"Pier Selenica","orcid":"0000-0003-0086-0513","position":1,"is_corresponding":false},{"id":478636,"name":"Weining Ma","orcid":"0000-0002-0166-316X","position":2,"is_corresponding":false},{"id":1050156,"name":"Sara Moufarrij","orcid":null,"position":3,"is_corresponding":false},{"id":1041688,"name":"Christian Dagher","orcid":"0000-0003-1564-8005","position":4,"is_corresponding":false},{"id":313747,"name":"Thais Basili","orcid":"0000-0003-3216-3544","position":5,"is_corresponding":false},{"id":258156,"name":"Nadeem R. Abu‐Rustum","orcid":"0000-0001-9689-1298","position":6,"is_corresponding":false},{"id":258142,"name":"Carol Aghajanian","orcid":"0000-0003-0851-3225","position":7,"is_corresponding":false},{"id":351386,"name":"Qin Zhou","orcid":"0000-0003-1225-2902","position":8,"is_corresponding":false},{"id":351395,"name":"Alexia Iasonos","orcid":"0000-0003-0471-8477","position":9,"is_corresponding":false},{"id":250491,"name":"Lora H. Ellenson","orcid":"0000-0001-9127-6982","position":10,"is_corresponding":false},{"id":244697,"name":"Britta Weigelt","orcid":"0000-0001-9927-1270","position":11,"is_corresponding":false},{"id":464294,"name":"M. Herman Chui","orcid":"0000-0002-7220-3996","position":12,"is_corresponding":false},{"id":1315000,"name":"Melica Nourmoussavi Brodeur","orcid":"0000-0002-7595-0313","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T02:06:33.741984Z","pmid":"39031567","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":[]}