腺样囊性癌（ACC）是一种MYB驱动的头颈恶性肿瘤，具有高复发率、远处转移率和不良的长期生存率。需要新的有效靶向治疗方法和临床可用的生物标志物来改善ACC患者的生存率。本研究通过综合分析ACC的拷贝数和转录组来识别新的驱动基因和预后生物标志物。共研究了598例ACC。其中366例有临床随访数据，是迄今为止最大的研究队列。1p36拷贝数缺失（70/492；14%）和肿瘤抑制基因PARK2（6q26）（85/343；25%）是预后性生物标志物；具有同时缺失的患者（n = 20）的总生存期明显较短（P < 0.0001）。1p36缺失独立预测短生存期在多元分析中（P = 0.02）。鉴定了两个促凋亡基因，TP73和KIF1B作为可能的1p36肿瘤抑制基因，其表达降低与预后差和抗凋亡能力增强相关。6q缺失的肿瘤中PARK2的表达明显降低，并且PARK2敲除增加了球状化程度并减少了凋亡，表明PARK2是ACC中的肿瘤抑制基因。此外，在30例ACC中分析全基因表达谱，发现了与短生存期、多个拷贝数变异包括1p36缺失以及TP73表达降低相关的转录组标记。综上所述，结果表明TP73和PARK2是ACC中的新的潜在肿瘤抑制基因和潜在的预后生物标志物。本研究对于深入了解ACC的发病机制具有重要意义。该结果对于临床试验中患者的生物标志物驱动分层具有重要的应用价值。© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Adenoid cystic carcinoma (ACC) is a MYB-driven head and neck malignancy with high rates of local recurrence and distant metastasis and poor long-term survival. New effective targeted therapies and clinically useful biomarkers for patient stratification are needed to improve ACC patient survival. Here, we present an integrated copy number and transcriptomic analysis of ACC to identify novel driver genes and prognostic biomarkers. A total of 598 ACCs were studied. Clinical follow-up was available from 366 patients, the largest cohort analyzed to date. Copy number losses of 1p36 (70/492; 14%) and of the tumor suppressor gene PARK2 (6q26) (85/343; 25%) were prognostic biomarkers; patients with concurrent losses (n = 20) had significantly shorter overall survival (OS) than those with one or no deletions (p < 0.0001). Deletion of 1p36 independently predicted short OS in multivariate analysis (p = 0.02). Two pro-apoptotic genes, TP73 and KIF1B, were identified as putative 1p36 tumor suppressor genes whose reduced expression was associated with poor survival and increased resistance to apoptosis. PARK2 expression was markedly reduced in tumors with 6q deletions, and PARK2 knockdown increased spherogenesis and decreased apoptosis, indicating that PARK2 is a tumor suppressor in ACC. Moreover, analysis of the global gene expression pattern in 30 ACCs revealed a transcriptomic signature associated with short OS, multiple copy number alterations including 1p36 deletions, and reduced expression of TP73. Taken together, the results indicate that TP73 and PARK2 are novel putative tumor suppressor genes and potential prognostic biomarkers in ACC. Our studies provide new important insights into the pathogenesis of ACC. The results have important implications for biomarker-driven stratification of patients in clinical trials. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.