Proteogenomic Analysis of Salivary Adenoid Cystic Carcinomas Defines Molecular Subtypes and Identifies Therapeutic Targets.
Proteogenomic Analysis of Salivary Adenoid Cystic Carcinomas Defines Molecular Subtypes and Identifies Therapeutic Targets.
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DOI：
10.1158/1078-0432.ccr-20-1192
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发表时间：
2021-02-01
期刊：
影响因子：
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通讯作者：
El-Naggar AK
中科院分区：
文献类型：
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作者：
Ferrarotto R;Mitani Y;McGrail DJ;Li K;Karpinets TV;Bell D;Frank SJ;Song X;Kupferman ME;Liu B;Lee JJ;Glisson BS;Zhang J;Aster JC;Lin SY;Futreal PA;Heymach JV;El-Naggar AK
涎腺腺样囊性癌（ACC）具有异质性的临床行为。目前，所有患者的治疗是统一的，并没有标准的护理系统治疗转移性ACC. We进行了综合蛋白基因组学分析的ACC肿瘤，以确定失调的途径，并提出了一个分类与治疗意义。对38例54份快速冷冻的唾液腺腺样囊性癌标本进行RNA/DNA测序和反相蛋白阵列（RPPA）分析，并通过免疫印迹和/或免疫组化进行验证。三个独立的ACC队列用于验证。无偏RNA-seq和RPPA分析均揭示了两种分子亚型：ACC-I（37%）和ACC-II（63%）。ACC-I具有MYC、MYC靶基因和mRNA剪接的强烈上调、NOTCH激活突变的富集和显著更差的预后。ACC-II表现出TP 63和受体酪氨酸激酶（AXL、MET、EGFR）的上调，以及较低的侵袭性临床过程。TP 63和MYC足以将肿瘤分配给ACC亚型，这在一个独立队列中通过IHC和另外两个独立队列中通过RNAseq进行了验证。此外，MYC和P63蛋白水平的免疫组织化学染色可用于识别ACC亚型，从而能够快速临床部署以指导治疗决策。我们的数据表明，ACC-I由MYC信号通过NOTCH突变或直接扩增驱动，这反过来抑制了ACC-II中观察到的P63信号，从而为每种亚型产生独特的治疗漏洞。每种亚型中多个可操作的蛋白质/途径改变的同时发生表明了独特的治疗弱点和对这种研究不足和异质性疾病进行最佳联合治疗的机会。
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 ACC and reverse-phase protein array (RPPA) in 38 specimens were performed, with validation by western blot and/or immunohistochemistry. Three independent ACC cohorts were used for validation. Both unbiased RNA-seq and RPPA analysis revealed two molecular subtypes; ACC-I (37%) and ACC-II (63%). ACC-I had strong upregulation of MYC, MYC target genes, and mRNA splicing, enrichment of NOTCH activating mutations and dramatically worse prognosis. ACC-II exhibited upregulation of TP63 and receptor tyrosine kinases (AXL, MET, 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 RNAseq. Furthermore, immunohistochemical staining for MYC and P63 protein levels can be used to identify ACC subtypes, enabling rapid clinical deployment to guide therapeutic decisions. Our data suggests 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. Co-occurrence of multiple actionable protein/pathways alterations in each subtype indicate unique therapeutic vulnerabilities and opportunities for optimal combination therapy for this understudied and heterogeneous disease.