TP53和PI-3激酶/AKT通路的致癌突变是晚期甲状腺癌生存的独立预测因子：来自分子筛查与治疗（MoST）项目的分析

Oncogenic mutations in the TP53 and PI-3 kinase/AKT pathway are independent predictors of survival for advanced thyroid cancer: Analysis from the Molecular Screening and Therapeutics (MoST) program

SURGERY

影响因子:2.7

分区:医学2区 / 外科2区

发表日期:2025 Jan

作者: Elan Novis, Anthony Glover, John P Grady, Audrey Silvestri, Subotheni Thavaneswaran, Frank Lin, Mandy L Ballinger, David M Thomas

DOI: 10.1016/j.surg.2024.05.058

摘要

带有磷脂酰肌醇-3激酶/AKT通路突变的甲状腺癌预后较差。然而，关于组织学类型、突变谱与预后关系的认识仍在发展中。本研究评估了在传统治疗中出现进展的晚期甲状腺癌患者的基因组谱的预后价值。研究对象为招募到国家临床肿瘤学项目中的治疗难治性局部晚期、复发或转移性癌症患者。患者的存档肿瘤样本进行了全面基因组分析，并将特定的致癌突变及相关癌症通路与总生存期相关联。2018年至2021年间，共招募4955名患者，44例（0.9%）被诊断为甲状腺癌，其中4例为髓样甲状腺癌，其余为滤泡型：17例分化型、13例未分化型和10例未分化型甲状腺癌。在40个滤泡型甲状腺癌样本中，17例（42.5%）携带TP53突变，其次为11例BRAF V600E突变（27.5%）、9例NRAS突变（22.5%）、9例在磷脂酰肌醇-3激酶/AKT通路的突变（22.5%），以及7例TERT启动子突变（17.5%）。TP53和磷脂酰肌醇-3激酶/AKT通路的突变均与总生存期下降相关（风险比HR：5.19；95%置信区间：1.59-16.70，P=0.02；和风险比10.12；95%置信区间：1.61-63.76，P=0.01）。Cox回归分析显示，未分化甲状腺癌（风险比12.93，P=0.004）、未分化型甲状腺癌（风险比5.19，P=0.039）以及TP53和/或磷脂酰肌醇-3激酶/AKT通路突变（风险比4.73，P=0.017）与总生存期独立相关。TP53和/或磷脂酰肌醇-3激酶/AKT通路突变与患者的总生存期无关组织类型。全面的基因组分析具有潜力用于预后评估，并可帮助识别晚期甲状腺癌患者的治疗靶点。

Abstract

Thyroid cancers with mutations in the phosphatidylinositol-3 kinase/AKT pathway have a poorer prognosis. However, knowledge about the relationship between histology, mutation profile, and outcomes is still developing. This study assessed the prognostic value of genomic profiles for patients with advanced thyroid cancer who experienced progression on conventional treatment.Patients recruited to a national clinical oncology program for treatment-refractory locally advanced, recurrent or metastatic cancers were analyzed. Patients' archival tumor samples underwent comprehensive genomic profiling. Specific oncogenic mutations and the presence of cancer related pathways were correlated with overall survival.From 2018 to 2021, 4,955 patients were recruited, with 44 (0.9%) having a diagnosis of thyroid cancer with 4 medullary and the remaining follicular derived: 17 differentiated, 13 poorly differentiated, and 10 anaplastic thyroid cancers. Of the 40 follicular-derived thyroid cancer samples, 17 (42.5%) carried TP53 mutations, followed by 11 with BRAF V600E (27.5%), 9 with NRAS (22.5%), 9 with mutations in the phosphatidylinositol-3 kinase/AKT pathway (22.5%), and 7 with TERT promoter mutations (17.5%). Both TP53 and phosphatidylinositol-3 kinase/AKT pathway alterations were associated with reduced overall survival (hazard ratio, 5.19; 95% confidence interval, 1.59-16.70, P = .02 and hazard ratio, 10.12; 95% confidence interval, 1.61-63.76, P = .01). Cox regression showed histologic type anaplastic thyroid cancer (hazard ratio, 12.93, P = .004), poorly differentiated thyroid cancer (hazard ratio, 5.19, P = .039), and TP53 and/or phosphatidylinositol-3 kinase/AKT pathway mutations (hazard ratio, 4.73, P = .017) were independently associated with overall survival.TP53 and/or phosphatidylinositol-3 kinase/AKT pathway mutations correlated with overall survival independently of histotype in patients with advanced thyroid cancer. Comprehensive genomic profiling has potential to inform prognosis, as well as identifying treatment targets for patients with advanced thyroid cancer.