Abstract：
OBJECTIVE: Adrenal cortical carcinoma (ACC) is a rare malignancy with a generally poor but heterogeneous prognosis, especially depending on the tumour stage at diagnosis. Identification of somatic gene alterations combined with clinical/histopathological evaluation of the tumour can help improve prognostication. We applied a simplified targeted-Next-Generation Sequencing (NGS) panel to characterise the mutational profiles of ACCs, providing potentially relevant information for better patient management.
METHODS: Thirty frozen tumour specimens from a local ACC series were retrospectively analysed by a custom-NGS panel (CDKN2A, CTNNB1, DAXX, MED12, NF1, PRKAR1A, RB1, TERT, TP53, ZNRF3) to detect somatic prioritised single-nucleotide variants. This cohort was integrated with 86 patients from the ACC-TCGA series bearing point-mutations in the same genes and their combinations identified by our panel. Primary endpoints of the analysis on the total cohort (113 patients) were overall survival (OS) and progression-free survival (PFS), and hazard ratio (HR) for the different alterations grouped by the signalling pathways/combinations affected.
RESULTS: Different PFS, OS, and HR were associated to the different pathways/combinations, being NF1 + TP53 and Wnt/β-catenin + Rb/p53 combined mutations the most deleterious, with a statistical significance for progression HR which is retained only in low-(I/II) stages-NF1 + TP53 combination: HR = 2.96[1.01-8.69] and HR = 13.23[3.15-55.61], all and low stages, respectively; Wnt/β-catenin + Rb/p53 combined pathways: HR = 6.47[2.54-16.49] and HR = 16.24[3.87-68.00], all and low-stages, respectively.
CONCLUSIONS: A simplified targeted-NGS approach seems the best routinely applicable first step towards somatic genetic characterisation of ACC for prognostic assessment. This approach proved to be particularly promising in low-stage cases, suggesting the need for more stringent surveillance and personalised treatment.
METHODS: Thirty frozen tumour specimens from a local ACC series were retrospectively analysed by a custom-NGS panel (CDKN2A, CTNNB1, DAXX, MED12, NF1, PRKAR1A, RB1, TERT, TP53, ZNRF3) to detect somatic prioritised single-nucleotide variants. This cohort was integrated with 86 patients from the ACC-TCGA series bearing point-mutations in the same genes and their combinations identified by our panel. Primary endpoints of the analysis on the total cohort (113 patients) were overall survival (OS) and progression-free survival (PFS), and hazard ratio (HR) for the different alterations grouped by the signalling pathways/combinations affected.
RESULTS: Different PFS, OS, and HR were associated to the different pathways/combinations, being NF1 + TP53 and Wnt/β-catenin + Rb/p53 combined mutations the most deleterious, with a statistical significance for progression HR which is retained only in low-(I/II) stages-NF1 + TP53 combination: HR = 2.96[1.01-8.69] and HR = 13.23[3.15-55.61], all and low stages, respectively; Wnt/β-catenin + Rb/p53 combined pathways: HR = 6.47[2.54-16.49] and HR = 16.24[3.87-68.00], all and low-stages, respectively.
CONCLUSIONS: A simplified targeted-NGS approach seems the best routinely applicable first step towards somatic genetic characterisation of ACC for prognostic assessment. This approach proved to be particularly promising in low-stage cases, suggesting the need for more stringent surveillance and personalised treatment.
摘要：
目的：肾上腺皮质癌（ACC）是一种罕见的恶性肿瘤，通常预后较差，但预后不均匀，特别是取决于诊断时的肿瘤分期。体细胞基因改变的鉴定与肿瘤的临床/组织病理学评估相结合可以帮助改善预后。我们应用了一个简化的靶向NGS面板来表征ACCs的突变谱，为更好的患者管理提供潜在的相关信息。
方法：通过自定义NGS面板对来自局部ACC系列的30个冷冻肿瘤标本进行了回顾性分析（CDKN2A，CTNNB1,DAXX,MED12,NF1,PRKAR1A,RB1,TERT,TP53，ZNRF3）以检测体细胞优先的单核苷酸变体。该队列与来自ACC-TCGA系列的86名患者整合，这些患者在相同的基因中携带点突变，并由我们的小组鉴定。总队列（113例）分析的主要终点是总体（OS）和无进展（PFS）生存期，和由受影响的信号通路/组合分组的不同改变的风险比(HR)。
结果：不同的PFS，OS和HR与不同的途径/组合相关，NF1+TP53和Wnt/β-catenin+Rb/p53联合突变最有害，仅在低（I/II）阶段保留的进展HR具有统计学意义-NF1+TP53组合：HR=2.96[1.01-8.69]和HR=13.23[3.15-55.61]，所有和低阶段，分别;Wnt/β-catenin+Rb/p53联合通路:HR=6.47[2.54-16.49]和HR=16.24[3.87-68.00],所有和低阶段，分别。
结论：简化的靶向NGS方法似乎是对ACC进行体细胞遗传学表征以进行预后评估的最佳常规应用的第一步。事实证明，这种方法在低级案件中特别有希望，建议需要更严格的监测和个性化治疗。
方法：通过自定义NGS面板对来自局部ACC系列的30个冷冻肿瘤标本进行了回顾性分析（CDKN2A，CTNNB1,DAXX,MED12,NF1,PRKAR1A,RB1,TERT,TP53，ZNRF3）以检测体细胞优先的单核苷酸变体。该队列与来自ACC-TCGA系列的86名患者整合，这些患者在相同的基因中携带点突变，并由我们的小组鉴定。总队列（113例）分析的主要终点是总体（OS）和无进展（PFS）生存期，和由受影响的信号通路/组合分组的不同改变的风险比(HR)。
结果：不同的PFS，OS和HR与不同的途径/组合相关，NF1+TP53和Wnt/β-catenin+Rb/p53联合突变最有害，仅在低（I/II）阶段保留的进展HR具有统计学意义-NF1+TP53组合：HR=2.96[1.01-8.69]和HR=13.23[3.15-55.61]，所有和低阶段，分别;Wnt/β-catenin+Rb/p53联合通路:HR=6.47[2.54-16.49]和HR=16.24[3.87-68.00],所有和低阶段，分别。
结论：简化的靶向NGS方法似乎是对ACC进行体细胞遗传学表征以进行预后评估的最佳常规应用的第一步。事实证明，这种方法在低级案件中特别有希望，建议需要更严格的监测和个性化治疗。
