{"doi":"10.1002/cncr.33781","title":"Reply to <i>FBXW7</i>, <i>L1CAM</i>, and <i>TGM2</i> in endometrial cancer","abstract":"There are several critical distinctions in the design of the original study by Urick et al,1 who applied proteomics to identify significantly altered protein levels (P < .05) in isogenic FBXW7 wild-type and mutated endometrial cancer (EC) cell line pairs, and the design of the study reported by Lehrer and Rheinstein, who analyzed tumor data from The Cancer Genome Atlas (TCGA). These design differences make it difficult to directly compare the findings of the 2 studies. First, Urick et al analyzed proteomic changes associated with knock-in or reversion of 3 specific FBXW7 hotspot mutations (R465C, R479Q, and R505C) in the WD repeats, which, in TCGA, represent 24.1% of FBXW7 mutations in serous ECs, 15.7% of FBXW7 mutations in endometrioid ECs, 20% of FBXW7 mutations in mixed-histology ECs, and 17.9% of FBXW7 mutations in the entire TCGA cohort of 517 endometrial tumors mutationally profiled for FBXW7.2-5 In contrast, Lehrer and Rheinstein analyzed all FBXW7 mutations in TCGA ECs. This is an important distinction because we previously showed some in vitro functional differences between WD repeat and non-WD repeat mutations.6 Second, Urick et al measured levels of L1CAM and TGM2 proteins by both proteomics and immunoblotting, whereas Lehrer and Rheinstein analyzed levels of L1CAM and TGM2 gene expression. Gene expression is not necessarily equivalent to protein expression. Third, Urick et al used multiple high-risk and grade 2 endometrioid EC cell lines to reveal that FBXW7 mutations result in altered protein levels of L1CAM and TGM2. Lehrer and Rheinstein noted that their analysis centered on 522 endometrioid ECs in the TCGA cohort. However, the TCGA cohort is composed of endometrioid, serous, and mixed-histology tumors. Additional clarification regarding the histology and grade of the 522 tumors analyzed by Lehrer and Rheinstein would be valuable. Fourth, the comparative proteomic analyses of paired isogenic FBXW7 wild-type and mutated EC cell lines by Urick et al permitted the identification of causative associations between FBXW7 mutations and altered L1CAM and TGM2 levels. In contrast, the in silico analysis of tumor data by Lehrer and Rheinstein permitted the identification of correlations between FBXW7 mutations and L1CAM and TGM2 gene expression in tumors but did not allow for conclusions regarding causation. In conclusion, the study by Lehrer and Rheinstein is an interesting and important analysis, but its design does not allow for a direct comparison with the proteomic findings of Urick et al. We agree with Lehrer and Rheinstein that additional studies of FBXW7, L1CAM, and TGM2 in ECs are warranted. This research was supported by the Intramural Research Program of the National Human Genome Research Institute of the National Institutes of Health (ZO1-HG200338 to Daphne W. Bell). Daphne W. Bell receives royalty income from US Patent No. 7,294,468 for work unrelated to the current study. The other authors made no disclosures.","journal":"Cancer","year":2021,"id":219119,"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":0.9626,"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":733658,"name":"Eun‐Jeong Yu","orcid":"0000-0002-2118-2128","position":1,"is_corresponding":false},{"id":442170,"name":"Daphne W. Bell","orcid":"0000-0001-7314-3932","position":2,"is_corresponding":false},{"id":442169,"name":"Mary Ellen Urick","orcid":"0000-0002-1032-504X","position":0,"is_corresponding":true}],"reference_count":6,"raw_metadata":null,"created_at":"2026-07-18T23:53:33.915158Z","pmid":"34324196","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":[]}