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Pancreatic Cancer

Drug Resistance Analysis of Pancreatic Cancer Based on Universally Differentially Expressed Genes


Pancreatic ductal adenocarcinoma (PDAC) is considered one of the most aggressive malignant neoplasms, with a 12.8% five-year survival rate according to National Cancer Institute statistics. Complete surgery resection is the only possible cure for resectable PDAC, but most patients are already in an advanced stage at diagnosis. Chemotherapy with/without radiotherapy has been a mainstay strategy for treating PDAC, but it only provides a modest improvement in survival. Only 3% to 11% of patients have pathological complete responses after receiving chemotherapy with/without radiation therapy, which may be due to the high heterogeneity between patients and the ubiquitous drug resistance of PDAC.

Immune checkpoint blockade (ICB) has changed the standard of care for multiple cancers and has brought hope to pancreatic cancer patients; however, almost all tentative trials have had little effect or failed before clinical application. The most common reason for failure was the immunosuppressive tumor microenvironment (TME) resulting in low effector T cell infiltration, which is unfavorable for the immune response. We suspect that there are some common features underlying the high heterogeneity of pancreatic cancer, which could be closely related to the mechanism underlying the ineffectiveness of current therapies. It is essential to identify and target these mechanisms to improve the early diagnosis rate and therapeutic efficiency.

Conventional differentially expressed gene (DEG) screening methods for bulk tissues only compare the average expression levels between disease and control groups, which cannot show the dysregulation status of each gene in a single disease sample or the frequency of differential expression of genes in all disease samples. The gold standard for individualized DEG screening is comparing the expression levels between paired tumor and adjacent normal samples from the same patient. However, the late diagnosis and difficulty of sampling pathologically normal samples in the complicated structure of the pancreas has led to few paired samples.

To solve this problem, a robust individual DEG screening method, RankComp, has been developed to detect the dysregulation of genes in a single tumor sample relative to the normal background derived from normal samples from different studies. Thus, we can identify individual-level DEGs for unpaired tumor samples based on the aggregation of normal samples using this method. Here, we made full use of paired and unpaired PDAC samples to identify common molecular characteristics of PDAC patients to construct a robust early diagnosis model and determine the mechanisms underlying the resistance to current therapies.

In this study, using transcription profiles of paired and unpaired PDAC bulk samples, we identified individual-level DEGs in the PDAC samples and defined the genes that were dysregulated in at least 85% of the PDAC samples as universally differentially expressed genes (UDEGs). Bulk assays represent a population average, which masks the heterogeneity that exists at the single-cell level . Thus, we analyzed the expression of the UDEGs at the single-cell level to explore their roles in the formation of tumors. Finally, we investigated the potential association between the UDEGs and overall drug resistance based on GDSC resistance data, as well as their correlation with responsiveness to immunotherapy using reported immunotherapy biomarkers.

Pancreatic cancer, Pancreatitis, Pancreatic ductal adenocarcinoma, Tumor markers, CA 19-9, Chronic pancreatitis, Acute pancreatitis, Diabetes mellitus, Jaundice, Abdominal pain, Chemotherapy, Radiation therapy, Genetic mutations, KRAS mutation, Metastasis, Whipple procedure, Immunotherapy, Biliary obstruction, Pancreatic cysts, Early detection

#PancreaticCancer, #Pancreatitis, #PDAC, #TumorMarkers, #CA199, #ChronicPancreatitis, #AcutePancreatitis, #PancreaticHealth, #DiabetesAndCancer, #CancerAwareness, #PancreaticPain, #CancerResearch, #KRASMutation, #PancreaticTumor, #CancerMetastasis, #WhippleSurgery, #Immunotherapy, #CancerDiagnosis, #PancreaticScreening, #OncologyCare

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