Department of Oral Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai, China; National Centre for Stomatology, Shanghai, China; National Clinical Research Centre for Oral Diseases, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai, China.
Department of Oral Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai, China; National Centre for Stomatology, Shanghai, China; National Clinical Research Centre for Oral Diseases, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai, China.
Pathology. 2022 Aug;54(5):580-590. doi: 10.1016/j.pathol.2021.12.292. Epub 2022 Mar 22.
Solid-type adenoid cystic carcinomas (ACCs) are highly aggressive and heterogeneous tumours. Because of their rarity, therapeutic strategies guided by genetic profiles based on next generation sequencing (NGS) have not been published for these tumours. Forty-nine solid-type ACCs including 43 tumours with a predominantly solid pattern, and six tumours comprising a roughly equal mixture of cribriform/tubular and solid histological forms were included in our study. The solid components from the 49 solid ACCs were enriched for mutations of genes in the NOTCH pathway (NOTCH1 61%, SPEN 24%) and chromatin remodelling pathway and the absence of myoepithelial cell differentiation. Cases with NOTCH1 mutations exhibited strong NICD expression, which was associated with poor overall and distant metastasis free survival. BRCA2 mutation and BCOR/BCORL1 mutations were observed in 20% and 18.4% of solid ACCs, respectively. In six of the solid ACCs, intratumour heterogeneity was delineated between the cribriform/tubular and solid components. NOTCH1 and FGFR2 mutations as well as NOTCH2 amplification were restricted to the solid component, indicating clonal selection within the same tumour. In two recurrent/metastatic solid ACCs, the subclones evolved in progression for local relapse and distant metastasis, although they manifested close genomic resemblance to primary tumours. Guided by the genetic profiles, the preclinical efficiency of the gamma-secretase inhibitor BMS-906024 was evaluated in patient derived xenograft models (PDXs) with activating NOTCH1 mutations and demonstrated robust antitumour effects. Our report revealed intratumour heterogeneity among solid-types within an ACC as well as the inter-tumour evolution of dominant clones among two primary and recurrent/metastatic tumours. In contrast to cribriform/tubular ACCs, solid-type ACCs should be approached with a distinct therapeutic strategy, particularly targeting NOTCH1. Microdissecting the highest grade component guided by histology is a highly recommended tumour sampling strategy and facilitates the detection of key molecular targets.
实体型腺样囊性癌（ACC）是一种侵袭性强、异质性高的肿瘤。由于其罕见性，基于下一代测序（NGS）的基因谱指导的治疗策略尚未针对此类肿瘤发表。我们的研究纳入了 49 例实体型 ACC，包括 43 例以实体型为主的肿瘤和 6 例由筛状/管状和实体组织学形式大致相等混合而成的肿瘤。49 例实体型 ACC 的实体成分富集了 NOTCH 通路（NOTCH1 占 61%，SPEN 占 24%）和染色质重塑通路的基因突变，以及缺乏肌上皮细胞分化。存在 NOTCH1 突变的病例表现出强烈的 NICD 表达，与整体和远处无转移生存率差相关。在 20%和 18.4%的实体型 ACC 中分别观察到 BRCA2 突变和 BCOR/BCORL1 突变。在 6 例实体型 ACC 中，在筛状/管状和实体成分之间描绘了肿瘤内异质性。NOTCH1 和 FGFR2 突变以及 NOTCH2 扩增仅限于实体成分，表明同一肿瘤内的克隆选择。在 2 例复发性/转移性实体型 ACC 中，亚克隆在局部复发和远处转移的进展中进化，尽管它们与原发性肿瘤表现出密切的基因组相似性。根据遗传谱，在具有激活的 NOTCH1 突变的患者衍生异种移植模型（PDX）中评估了 γ-分泌酶抑制剂 BMS-906024 的临床前疗效，并显示出强大的抗肿瘤作用。我们的报告揭示了 ACC 内实体型之间的肿瘤内异质性，以及两个原发性和复发性/转移性肿瘤之间优势克隆的肿瘤间进化。与筛状/管状 ACC 不同，实体型 ACC 应采用独特的治疗策略，特别是针对 NOTCH1。通过组织学指导对高级别成分进行微解剖是一种高度推荐的肿瘤取样策略，有助于检测关键的分子靶点。
