A Lipid Metabolomics Study Of Pancreatic Cancer Based On UPLC-TOF/MS Approach

Background and Objective Pancreatic ductal adenocarcinoma(PDAC)is a type of highly malignant tumor with insidious onset,rapid progression,and poor prognosis.Most patients with PDAC are at an advanced stage at the time of diagnosis and lose the chance for curative surgery.Only approximately 20% of the patients can get appropriate resection,and the 5-year survival rate is less than 5%.At present,there is still lack of specificity in the early diagnosis of pancreatic cancer.The "metabolomics" was proposed by Nicholson et al.in 1999,and it is a new branch of science,compared with genomics,transcriptomics,proteomics.It focuses on the phenotype of the organisms,changes in the levels of all metabolites produced by external stimuli in cells,tissues,and organisms.It achieves identification and quantification of a small amount of substance that is contained in the metabolism of an organism during specific time and specific environment.It is also one of the most promising techniques for the screening of potential biomarkers.In recent years has become a hot topic in the research of the pathogenesis of tumor and tumor biomarkers.As an important branch of metabolomics,lipidomics was formally proposed by Han et al.in 2003 to detect the whole lipids in organisms and study their roles in gene regulation and protein expression.It can be used to determine the lipid molecules ofabnormal levels associated with diseases,as well as the changes during disease progression and their interactions with other biomolecules.Pancreas is an important organ that regulates the lipid level in body.At present,there is still a lack of the comprehensive research on the lipid profile of pancreatic cancer.In this study,we analyzed the differences in plasma lipid metabolism in patients with PDAC(P group),chronic pancreatitis(C group)and healthy people(H group)by using metabolomics analysis method,aiming to find a specific biomarker for the diagnosis of pancreatic cancer.Materials and Methods 5 samples from each group were examined by ultra high performance liquid chromatography-time of flight mass spectrometry(UPLC-TOF/MS).The original data were collected and analyzed after adjustment based on the internal standard.EZinfo,Hem I,Simca-P and other software were used for multivariate analysis and building the PCA and OPLS-DA model.Variable importance factor(VIP)>1 and S-Plot plots were compared between different groups.VENN was used to screen the specific lipid components and the relative substances were found in the lipid database.Results 1.After a series of tests,669 kinds of lipid components were identified.Integrated H,C,P group pie chart,lipid component ratio had no significant difference under the overall condition,the order from the maximal to the minimal parts is TG(33%-34%),others(30%-31%,composed of different lipid),phospholipids(29%)and DG(7%).2.In the analysis of the PCA and OPLS-DA model,the distribution of H group and C group was in the relative area,which indicated the difference and availability of the data;there are 46 and 27 lipid elements that are higher and lower,respectively,in the C group in comparison with the H group.3.H and P groups are also different based on the analysis of PCA and OPLS-DA in the model group.The two component distribution in the relative area showed the differences of data and availability;P group had 43 and 17 lipid fractions that were either higher or lower than H group.4.In the VENN plot,there were two common lipid components in the overlapping area of yellow and green,which were lower in the C group than in the H group,higher in the P group than in the H group.These two lipids are TG(16:0/18:2(9Z,12Z)/20:3(8Z,11 Z,14Z))[iso6] molecular formula is C57H100O6 and TG(17:2(9Z,12Z)/17:2(9Z,12Z)/20:0 [iso3] molecular formula is C57H102O6.Conclusion 1.Compared with H group,there are many parameters in C and P groups up-or down-regulated respectively.These deregulated elements have the potential to be used as biomarker to differentiate healthy persons and individuals with pancreatic disease.2.In this study,We found two TG elements that are conversely regulated in C and P groups,which are TG(16:0/18:2(9Z,12Z)/20:3(8Z,11 Z,14Z))[iso6] and TG(17:2(9Z,12Z)/17:2(9Z,12Z)/20:0 [iso3];this finding provides a new perspective and parameters for distinguishing chronic pancreatitis and pancreatic ductal adenocarcinoma,especially for clinical monitoring the progress of chronic pancreatitis and predict the occurrence of pancreatic cancer.