OBJECTIVE Adrenocortical carcinoma (ACC) is a rare aggressive malignancy with heterogeneous clinical outcomes. Recent studies proposed a combination of clinical/histopathological parameters (S-GRAS score) or molecular biomarkers (BMs) to improve prognostication. We performed a comparative analysis of DNA-based BMs by evaluating their added prognostic value to the S-GRAS score. DESIGN AND METHODS A total of 194 formalin-fixed, paraffin-embedded (FFPE) ACC samples were analysed, including a retrospective training cohort (n = 107) and a prospective validation cohort (n = 87). Targeted DNA sequencing and pyrosequencing were used to detect somatic single-nucleotide variations in ACC-specific genes and methylation in the promoter region of paired box 5 (PAX5). The European Network for the Study of Adrenocortical Tumors (ENSAT) tumour stage, age, symptoms at presentation, resection status, and Ki-67 were combined to calculate S-GRAS. Endpoints were overall (OS), progression-free (PFS), and disease-free survival (DFS). Prognostic role was evaluated by multivariable survival analysis and their performance compared by Harrell's concordance index (C index). RESULTS In training cohort, an independent prognostic role was confirmed at multivariate analysis for two DNA-based BMs: alterations in Wnt/β-catenin and Rb/p53 pathways and hypermethylated PAX5 (both P< .05 for PFS and DFS, hazard ratio [HR] 1.47-2.33). These were combined to S-GRAS to obtain a combined (COMBI) score. At comparative analysis, the best discriminative prognostic model was COMBI score in both cohorts for all endpoints, followed by S-GRAS score (C index for OS 0.724 and 0.765, PFS 0.717 and 0.670, and DFS 0.699 and 0.644, respectively). CONCLUSIONS Targeted DNA-based BM evaluated on routinely available FFPE samples improves prognostication of ACC beyond routinely available clinical and histopathological parameters. This approach may help to better individualise patient's management.

中文翻译：

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用于肾上腺皮质癌分类的基于 DNA 的生物标志物的性能：一项预后研究。

目的 肾上腺皮质癌（ACC）是一种罕见的侵袭性恶性肿瘤，具有异质性的临床结果。最近的研究提出结合临床/组织病理学参数（S-GRAS 评分）或分子生物标志物（BM）来改善预后。我们通过评估基于 DNA 的 BM 对 S-GRAS 评分的附加预后价值进行了比较分析。设计和方法 总共分析了 194 个福尔马林固定石蜡包埋 (FFPE) ACC 样本，包括回顾性训练队列 (n = 107) 和前瞻性验证队列 (n = 87)。使用靶向 DNA 测序和焦磷酸测序来检测 ACC 特异性基因的体细胞单核苷酸变异以及配对框 5 (PAX5) 启动子区域的甲基化。结合欧洲肾上腺皮质肿瘤研究网络 (ENSAT) 的肿瘤分期、年龄、就诊时的症状、切除状态和 Ki-67 来计算 S-GRAS。终点为总生存期 (OS)、无进展生存期 (PFS) 和无病生存期 (DFS)。通过多变量生存分析评估预后作用，并通过 Harrell 一致性指数（C 指数）比较其表现。结果 在训练队列中，对两种基于 DNA 的 BM 的多变量分析证实了独立的预后作用：Wnt/β-连环蛋白和 Rb/p53 通路的改变以及高甲基化 PAX5（PFS 和 DFS 均 P< .05，风险比 [ HR]1.47-2.33）。将它们与 S-GRAS 合并以获得综合 (COMBI) 分数。在比较分析中，最佳判别性预后模型是两个队列中所有终点的 COMBI 评分，其次是 S-GRAS 评分（OS 的 C 指数分别为 0.724 和 0.765，PFS 0.717 和 0.670，DFS 0.699 和 0.644）。结论 对常规可用的 FFPE 样本进行基于靶向 DNA 的 BM 评估，可改善 ACC 的预后，超出常规可用的临床和组织病理学参数。这种方法可能有助于更好地实现患者的个体化管理。