Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2021 Feb 1;27(3):852-864. doi: 10.1158/1078-0432.CCR-20-1192. Epub 2020 Nov 10.
Salivary gland adenoid cystic carcinoma (ACC) has heterogeneous clinical behavior. Currently, all patients are treated uniformly, and no standard-of-care systemic therapy exists for metastatic ACC. We conducted an integrated proteogenomic analyses of ACC tumors to identify dysregulated pathways and propose a classification with therapeutic implications.
RNA/DNA sequencing of 54 flash-frozen salivary ACCs and reverse phase protein array (RPPA) in 38 specimens were performed, with validation by Western blotting and/or IHC. Three independent ACC cohorts were used for validation.
Both unbiased RNA sequencing (RNA-seq) and RPPA analysis revealed two molecular subtypes: ACC-I (37%) and ACC-II (63%). ACC-I had strong upregulation of , MYC target genes, and mRNA splicing, enrichment of -activating mutations, and dramatically worse prognosis. ACC-II exhibited upregulation of and receptor tyrosine kinases (AXL, MET, and EGFR) and less aggressive clinical course. TP63 and MYC were sufficient to assign tumors to ACC subtypes, which was validated in one independent cohort by IHC and two additional independent cohorts by RNA-seq. Furthermore, IHC staining for MYC and P63 protein levels can be used to identify ACC subtypes, enabling rapid clinical deployment to guide therapeutic decisions. Our data suggest a model in which ACC-I is driven by MYC signaling through either NOTCH mutations or direct amplification, which in turn suppress P63 signaling observed in ACC-II, producing unique therapeutic vulnerabilities for each subtype.
Cooccurrence of multiple actionable protein/pathways alterations in each subtype indicates unique therapeutic vulnerabilities and opportunities for optimal combination therapy for this understudied and heterogeneous disease.
唾液腺腺样囊性癌（ACC）具有异质性的临床行为。目前，所有患者均接受统一治疗，转移性 ACC 也没有标准的系统治疗方法。我们对 ACC 肿瘤进行了综合蛋白质基因组分析，以确定失调的途径，并提出具有治疗意义的分类。
对 54 例冷冻唾液腺 ACC 进行了 RNA/DNA 测序和 38 例标本的反向蛋白阵列（RPPA）分析，并通过 Western blot 和/或 IHC 进行了验证。使用三个独立的 ACC 队列进行验证。
无偏 RNA 测序（RNA-seq）和 RPPA 分析均显示出两种分子亚型：ACC-I（37%）和 ACC-II（63%）。ACC-I 具有强烈的上调 、MYC 靶基因和 mRNA 剪接、 -激活突变的富集以及显著更差的预后。ACC-II 表现出上调和受体酪氨酸激酶（AXL、MET 和 EGFR），且临床过程较不具侵袭性。TP63 和 MYC 足以将肿瘤分配到 ACC 亚型，这在一个独立队列中通过 IHC 和另外两个独立队列通过 RNA-seq 得到验证。此外，MYC 和 P63 蛋白水平的 IHC 染色可用于识别 ACC 亚型，从而快速临床应用于指导治疗决策。我们的数据表明，在 MYC 信号通路中，ACC-I 是由 NOTCH 突变或直接扩增驱动的，这反过来又抑制了在 ACC-II 中观察到的 P63 信号，从而为每种亚型产生独特的治疗弱点。
每种亚型中多个可操作的蛋白/途径改变的共存表明存在独特的治疗弱点和机会，可用于为这种研究不足和异质性疾病进行最佳联合治疗。
