Altered Gene Expression along the Glycolysis-Cholesterol Synthesis Axis Is Associated with Outcome in Pancreatic Cancer

被引：153

作者：

Karasinska, Joanna M. ^{[1
]}

Topham, James T. ^{[1
]}

Kalloger, Steve E. ^{[1
,2
]}

Jang, Gun Ho ^{[3
]}

Denroche, Robert E. ^{[3
]}

Culibrk, Luka ^{[4
]}

Williamson, Laura M. ^{[4
]}

Wong, Hui-Li ^{[5
]}

Lee, Michael K. C. ^{[5
]}

O'Kane, Grainne M. ^{[6
]}

Moore, Richard A. ^{[4
]}

Mungall, Andrew J. ^{[4
]}

Moore, Malcolm J. ^{[5
]}

Warren, Cassia ^{[1
]}

Metcalfe, Andrew ^{[1
]}

Notta, Faiyaz ^{[3
]}

Knox, Jennifer J. ^{[6
]}

Gallinger, Steven ^{[3
,6
]}

Laskin, Janessa ^{[4
,5
]}

Marra, Marco A. ^{[4
,7
]}

Jones, Steven J. M. ^{[4
,7
]}

Renouf, Daniel J. ^{[1
,5
,8
]}

Schaeffer, David F. ^{[1
,2
,9
]}

机构：

[1] Pancreas Ctr BC, Vancouver, BC, Canada

[2] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC, Canada

[3] Ontario Inst Canc Res, Toronto, ON, Canada

[4] Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada

[5] BC Canc, Div Med Oncol, Vancouver, BC, Canada

[6] Univ Toronto, Univ Hlth Network, Toronto, ON, Canada

[7] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada

[8] Univ British Columbia, Dept Med, Vancouver, BC, Canada

[9] Vancouver Gen Hosp, Div Anat Pathol, Vancouver, BC, Canada

来源：

CLINICAL CANCER RESEARCH | 2020年 / 26卷 / 01期

基金：

加拿大创新基金会;

关键词：

MITOCHONDRIAL PYRUVATE CARRIER; STATIN USE; MUTATIONAL LANDSCAPE; METABOLISM; SUBTYPES; TUMOR; PATHWAY; GROWTH; DEFINES; RISK;

D O I：

10.1158/1078-0432.CCR-19-1543

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：135 / 146

页数：12

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