Comprehensive Genomic Profiling of Pancreatic Acinar Cell Carcinomas Identifies Recurrent RAF Fusions and Frequent Inactivation of DNA Repair Genes
Comprehensive Genomic Profiling of Pancreatic Acinar Cell Carcinomas Identifies Recurrent RAF Fusions and Frequent Inactivation of DNA Repair Genes
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DOI：
10.1158/2159-8290.cd-14-0617
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发表时间：
2014-12-01
期刊：
影响因子：
28.2
通讯作者：
Stephens, Philip J.
中科院分区：
文献类型：
--
作者：
Chmielecki, Juliann;Hutchinson, Katherine E.;Stephens, Philip J.
胰腺腺泡细胞癌（PACC）约占美国每年胰腺癌诊断的1%（约500例）。在这种疾病中，致癌治疗靶点已被证明是难以捉摸的，化疗和放疗对这些肿瘤的疗效有限。对大量PACCs（n = 44）的综合基因组分析发现，约23%的肿瘤中存在涉及BRAF和RAF 1（CRAF）的复发性重排。最普遍的融合，SND 1-BRAF，导致MAPK途径的激活，这是废除与MEK抑制。SND 1-BRAF转化细胞对MEK抑制剂曲美替尼处理敏感。缺乏RAF重排的PACCs显著富集基因组改变，导致DNA修复基因失活（45%）;这些基因组改变与对铂类治疗和PARP抑制剂的敏感性相关。总的来说，这些结果确定了潜在的可操作的基因组改变，在大多数的PACCs，并提供了一个理由，使用个性化的治疗在这种diseases.Significance：PACC是基因组不同于其他胰腺癌。RAF基因的融合和DNA修复基因的互斥失活代表了新的潜在治疗靶点，这些靶点在超过三分之二的肿瘤中发生了改变。(C)2014年AACR。
Pancreatic acinar cell carcinomas (PACC) account for approximately 1% (similar to 500 cases) of pancreatic cancer diagnoses annually in the United States. Oncogenic therapuetic targets have proven elusive in this disease, and chemotherapy and radiotherapy have demonstrated limited efficacy against these tumors. Comprehensive genomic profiling of a large series of PACCs (n = 44) identified recurrent rearrangements involving BRAF and RAF1 (CRAF) in approximately 23% of tumors. The most prevalent fusion, SND1-BRAF, resulted in activation of the MAPK pathway, which was abrogated with MEK inhibition. SND1-BRAF - transformed cells were sensitive to treatment with the MEK inhibitor trametinib. PACCs lacking RAF rearrangements were significantly enriched for genomic alterations, causing inactivation of DNA repair genes (45%); these genomic alterations have been associated with sensitivity to platinum-based therapies and PARP inhibitors. Collectively, these results identify potentially actionable genomic alterations in the majority of PACCs and provide a rationale for using personalized therapies in this disease.SIGNIFICANCE: PACC is genomically distinct from other pancreatic cancers. Fusions in RAF genes and mutually exclusive inactivation of DNA repair genes represent novel potential therapeutic targets that are altered in over two thirds of these tumors. (C) 2014 AACR.