Altered Gene Expression along the Glycolysis-Cholesterol Synthesis Axis Is Associated with Outcome in Pancreatic Cancer
Altered Gene Expression along the Glycolysis-Cholesterol Synthesis Axis Is Associated with Outcome in Pancreatic Cancer
复制标题
DOI：
10.1158/1078-0432.ccr-19-1543
复制
发表时间：
2020-01-01
影响因子：
11.5
通讯作者：
Schaeffer, David F.
中科院分区：
文献类型：
--
作者：
Karasinska, Joanna M.;Topham, James T.;Schaeffer, David F.
目的：确定胰腺导管腺癌（PDAC）的临床可操作分子亚型是改善患者预后的关键。肿瘤间代谢异质性有助于癌症生存，不同代谢途径之间的平衡可能会影响PDAC结果。我们假设，PDAC可以分为预后代谢亚组的基础上参与糖酵解和胆固醇synthesis.Experimental设计的基因表达的改变：我们进行了生物信息学分析的基因组，转录组学，和临床数据在一个综合的队列325可切除和不可切除的PDAC。可切除数据集包括回顾性癌症基因组图谱（TCGA）和国际癌症基因组联盟（ICGC）队列。不可切除PDAC队列研究包括前瞻性COMPASS、PanGen和BC Cancer Personalized OncoGenomics program（POG）。结果：根据糖酵解和胆固醇生成基因的中位标准化表达，确定了4个亚组：静止、糖酵解、胆固醇生成和混合。糖溶性肿瘤与可切除（对数秩检验P = 0.018）和转移性（对数秩检验P = 0.027）中位生存期最短相关。胆固醇源性肿瘤患者的中位生存期最长。KRAS和MYC扩增肿瘤的糖酵解基因表达高于癌基因拷贝正常或丢失的肿瘤（Wilcoxon秩和检验P = 0.015）。糖酵解肿瘤中线粒体丙酮酸载体MPC 1和MPC 2的表达最低。糖酵解和胆固醇生成基因表达与预后PDAC亚型classifier genes.Conclusions的表达相关：特定于糖酵解和胆固醇生成途径的代谢分类为先前建立的PDAC亚型提供了新的生物学见解，并可能有助于开发针对独特肿瘤代谢特征的个性化治疗。
Purpose: Identification of clinically actionable molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcome. Intertumoral metabolic heterogeneity contributes to cancer survival and the balance between distinct metabolic pathways may influence PDAC outcome. We hypothesized that PDAC can be stratified into prognostic metabolic subgroups based on alterations in the expression of genes involved in glycolysis and cholesterol synthesis.Experimental Design: We performed bioinformatics analysis of genomic, transcriptomic, and clinical data in an integrated cohort of 325 resectable and nonresectable PDAC. The resectable datasets included retrospective The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) cohorts. The nonresectable PDAC cohort studies included prospective COMPASS, PanGen, and BC Cancer Personalized OncoGenomics program (POG).Results: On the basis of the median normalized expression of glycolytic and cholesterogenic genes, four subgroups were identified: quiescent, glycolytic, cholesterogenic, and mixed. Glycolytic tumors were associated with the shortest median survival in resectable (log-rank test P = 0.018) and metastatic settings (log-rank test P = 0.027). Patients with cholesterogenic tumors had the longest median survival. KRAS and MYC-amplified tumors had higher expression of glycolytic genes than tumors with normal or lost copies of the oncogenes (Wilcoxon rank sum test P = 0.015). Glycolytic tumors had the lowest expression of mitochondrial pyruvate carriers MPC1 and MPC2. Glycolytic and cholesterogenic gene expression correlated with the expression of prognostic PDAC subtype classifier genes.Conclusions: Metabolic classification specific to glycolytic and cholesterogenic pathways provides novel biological insight into previously established PDAC subtypes and may help develop personalized therapies targeting unique tumor metabolic profiles.