{"doi":"10.1093/jnci/djad265","title":"Genetic trio of <i>BRAF</i> and <i>TERT</i> alterations and rs2853669TT in papillary thyroid cancer aggressiveness","abstract":"BACKGROUND: BRAF V600E and TERT promoter alterations are core components in current genetics-based risk assessment for precision management of papillary thyroid cancer. It remains unknown whether this approach could achieve even better precision through a widely recognized prognostic single-nucleotide variation (SNV, formerly SNP), rs2853669T>C, in the TERT promoter. METHODS: The genetic status of alterations and SNV were examined by sequencing genomic DNA from papillary thyroid cancer in 608 patients (427 women and 181 men) aged 47 years (interquartile range = 37-57), with a median follow-up time of 75 months (interquartile range = 36-123), and their relationship with clinical outcomes was analyzed. A luciferase reporter assay was performed to examine TERT promoter activities. RESULTS: TERT promoter alterations showed a strong association with papillary thyroid cancer recurrence in the presence of genotype TT of rs2853669 (adjusted hazard ratio [HR] = 2.12, 95% confidence interval [CI] = 1.10 to 4.12) but not TC/CC (adjusted HR = 1.17, 95% CI = 0.56 to 2.41). TERT and BRAF alterations commonly coexisted and synergistically promoted papillary thyroid cancer recurrence. With this genetic duet, TT of rs2853669 showed a robustly higher disease recurrence than TC/CC (adjusted HR = 14.26, 95% CI = 2.86 to 71.25). Patients with the genetic trio of BRAF V600E, TERT alteration, and TT of rs2853669 had a recurrence of 76.5% vs recurrence of 8.4% with neither variation and with TC/CC (HR = 13.48, 95% CI = 6.44 to 28.21). T allele of rs2853669 strongly increased TERT promoter activities, particularly the variant promoters. CONCLUSIONS: The SNV rs2853669T>C dramatically refines the prognostic power of BRAF V600E and TERT promoter alterations to a higher precision, suggesting the need for including this SNV in the current genetics-based risk prognostication of papillary thyroid cancer.","journal":"JNCI Journal of the National Cancer Institute","year":2023,"id":345452,"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":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9661,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":457706,"name":"Guangwu Zhu","orcid":"0000-0003-2533-7171","position":1,"is_corresponding":false},{"id":457704,"name":"Jie Tan","orcid":"0000-0003-0958-7840","position":2,"is_corresponding":false},{"id":651374,"name":"Xiaopei Shen","orcid":"0000-0002-0004-4228","position":3,"is_corresponding":false},{"id":457707,"name":"Mingzhao Xing","orcid":"0000-0003-4797-610X","position":4,"is_corresponding":false},{"id":457705,"name":"Rengyun Liu","orcid":"0000-0002-1408-2372","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-19T01:11:39.484741Z","pmid":"38113409","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":[]}