肾上腺皮质癌（ACC）是一种罕见的具有异质性临床结果的侵袭性恶性肿瘤。最近的研究提出了结合临床/组织病理参数（S-GRAS评分）或分子生物标志物（BMs）以改善预后的方法。我们对DNA基因标志物进行了比较分析，评估它们对S-GRAS评分的附加预后价值。分析了194个福尔马林固定、石蜡包埋（FFPE）的ACC样本，包括回顾性训练队列（n=107）和前瞻性验证队列（n=87）。采用靶向DNA测序和荧光检测法检测ACC特异基因的体细胞单核苷酸变异和PAX5启动子区域的甲基化。结合ENSAT肿瘤分期、年龄、发病症状、切除状况和Ki-67计算S-GRAS评分。终点包括总体生存期（OS）、无进展生存期（PFS）和无病复发生存期（DFS）。通过多变量生存分析评估预后作用，并通过Harrell's C指数比较它们的性能。在训练队列中，多变量分析确认了两种基于DNA的BM在预后中的独立预测作用：Wnt/β-catenin和Rb/p53通路的突变和PAX5的高甲基化（P<0.05，PFS和DFS的HR为1.47-2.33）。这些指标与S-GRAS组合得到综合评分（COMBI）。经过比较分析，无论是对于所有终点还是对于训练队列和验证队列，最好的判别性预后模型均为COMBI评分，其次是S-GRAS评分（OS的C指数分别为0.724和0.765，PFS的C指数分别为0.717和0.670，DFS的C指数分别为0.699和0.644）。在常规可用的FFPE样本上评估DNA基因标志物可以改善对ACC的预后评估，超越常规可用的临床和组织病理参数。这种方法有助于更好地个体化患者的管理。© 作者 2023。由欧洲内分泌学会代表牛津大学出版。

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.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 PAX5. 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 C index.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<0.05 for PFS and DFS, HR 1.47-2.33). These were combined to S-GRAS to obtain a combined score (COMBI). 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, DFS 0.699 and 0.644, respectively).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.© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.