Genomic and Epigenomic Landscaping Defines New Therapeutic Targets for Adenosquamous Carcinoma of the Pancreas.
Genomic and Epigenomic Landscaping Defines New Therapeutic Targets for Adenosquamous Carcinoma of the Pancreas.
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DOI：
10.1158/0008-5472.can-20-0078
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发表时间：
2020-10-15
期刊：
影响因子：
11.2
通讯作者：
Barrett MT
中科院分区：
文献类型：
--
作者：
Lenkiewicz E;Malasi S;Hogenson TL;Flores LF;Barham W;Phillips WJ;Roesler AS;Chambers KR;Rajbhandari N;Hayashi A;Antal CE;Downes M;Grandgenett PM;Hollingsworth MA;Cridebring D;Xiong Y;Lee JH;Ye Z;Yan H;Hernandez MC;Leiting JL;Evans RM;Ordog T;Truty MJ;Borad MJ;Reya T;Von Hoff DD;Fernandez-Zapico ME;Barrett MT
胰腺腺鳞癌（ASCP）是胰腺癌的一种亚型，与更常见的胰腺导管腺癌（PDAC）亚型相比，其预后更差，转移潜力更大。为了区分ASCP的基因组图谱并确定这种致命癌症的可操作靶点，我们对15个肿瘤样本进行了DNA含量流式细胞术检测，其中包括5个患者来源的异种移植物（PDXs）。我们用全基因组拷贝数变异（CNV）、全外显子组测序（WES）和ATAC-seq分析从这些样本中纯化的分类肿瘤组分。这些研究发现了ASCP基因组中针对染色质调节因子的各种体细胞基因组病变，这些病变叠加在特征明确的基因组病变上，包括TP53（87%）和KRAS（73%）突变、MYC扩增（47%）和CDKN2A纯合缺失（40%），这些病变在pdac中很常见。此外，使用流式分类PDX模型对三个ASCP和三个PDAC基因组的ATAC-seq谱进行比较，鉴定出ASCP基因组特有的可接近染色质的基因，包括所有三个ASCP中赖氨酸甲基转移酶SMYD2和胰腺癌干细胞调节因子RORC，以及单个ASCP中两个基因中与局灶性CNVs相关的FGFR1-ERLIN2融合。最后，我们证明了泛FGFR抑制剂对来自FGFR1-ERLIN2融合阳性ASCP PDX模型的类器官的显著活性。我们的研究结果表明，ASCP的基因组和表观基因组图谱为靶向这种侵袭性胰腺癌亚型提供了新的策略。
Adenosquamous cancer of the pancreas (ASCP) is a subtype of pancreatic cancer that has a worse prognosis and greater metastatic potential than the more common pancreatic ductal adenocarcinoma (PDAC) subtype. In order to distinguish the genomic landscape of ASCP and identify actionable targets for this lethal cancer we applied DNA content flow cytometry to a series of 15 tumor samples including five patient derived xenografts (PDXs). We interrogated purified sorted tumor fractions from these samples with whole genome copy number variant (CNV), whole exome sequencing (WES) and ATAC-seq analyses. These identified a variety of somatic genomic lesions targeting chromatin regulators in ASCP genomes that were superimposed on well characterized genomic lesions including mutations in TP53 (87%) and KRAS (73%), amplification of MYC (47%), and homozygous deletion of CDKN2A (40%) that are common in PDACs. Furthermore, a comparison of ATAC-seq profiles of three ASCP and three PDAC genomes using flow-sorted PDX models identified genes with accessible chromatin unique to the ASCP genomes, including the lysine methyltransferase SMYD2 and the pancreatic cancer stem cell regulator RORC in all three ASCPs, and a FGFR1-ERLIN2 fusion associated with focal CNVs in both genes in a single ASCP. Finally, we demonstrate significant activity of a pan FGFR inhibitor against organoids derived from the FGFR1-ERLIN2 fusion-positive ASCP PDX model. Our results suggest that the genomic and epigenomic landscape of ASCP provide new strategies for targeting this aggressive subtype of pancreatic cancer.