The use of multidimensional data to identify the molecular biomarker for pancreatic ductal adenocarcinoma.
Zhuang Liwei,Qi Yue,Wu Yun,Liu Nannan,Fu Yili
BioMed research international
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, and the patient has an extremely poor overall survival with a less than 5% 5-year survival rate. Development of potential biomarkers provides a critical foundation for the diagnosis of PDAC. In this project, we have adopted an integrative approach to simultaneously identify biomarker and generate testable hypothesis from multidimensional omics data. We first examine genes for which expression levels are correlated with survival data. The gene list was screened with TF regulation, predicted miRNA targets information, and KEGG pathways. We identified that 273 candidate genes are correlated with patient survival data. 12 TF regulation gene sets, 11 miRNAs targets gene sets, and 15 KEGG pathways are enriched with these survival genes. Notably, CEBPA/miRNA32/PER2 signaling to the clock rhythm qualifies this pathway as a suitable target for therapeutic intervention in PDAC. PER2 expression was highly associated with survival data, thus representing a novel biomarker for earlier detection of PDAC.
10.1155/2013/798054
Defining the molecular pathology of pancreatic body and tail adenocarcinoma.
The British journal of surgery
BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease, with very little improvement in survival over the past 50 years. Recent large-scale genomic studies have improved understanding of the genomic and transcriptomic landscape of the disease, yet very little is known about molecular heterogeneity according to tumour location in the pancreas; body and tail PDACs especially tend to have a significantly worse prognosis. The aim was to investigate the molecular differences between PDAC of the head and those of the body and tail of the pancreas. METHODS:Detailed correlative analysis of clinicopathological variables, including tumour location, genomic and transcriptomic data, was performed using the Australian Pancreatic Cancer Genome Initiative (APGI) cohort, part of the International Cancer Genome Consortium study. RESULTS:Clinicopathological data were available for 518 patients recruited to the APGI, of whom 421 underwent genomic analyses; 179 of these patients underwent whole-genome and 96 RNA sequencing. Patients with tumours of the body and tail had significantly worse survival than those with pancreatic head tumours (12·1 versus 22·0 months; P = 0·001). Location in the body and tail was associated with the squamous subtype of PDAC. Body and tail PDACs enriched for gene programmes involved in tumour invasion and epithelial-to-mesenchymal transition, as well as features of poor antitumour immune response. Whether this is due to a molecular predisposition from the outset, or reflects a later time point on the tumour molecular clock, requires further investigation using well designed prospective studies in pancreatic cancer. CONCLUSION:PDACs of the body and tail demonstrate aggressive tumour biology that may explain worse clinical outcomes.
10.1002/bjs.10772
Advances in the epidemiology of pancreatic cancer: Trends, risk factors, screening, and prognosis.
Cai Jie,Chen Hongda,Lu Ming,Zhang Yuhan,Lu Bin,You Lei,Zhang Taiping,Dai Min,Zhao Yupei
Cancer letters
Pancreatic cancer is a malignancy with poor prognosis and high mortality. The recent increase in pancreatic cancer incidence and mortality has resulted in an increased number of studies on its epidemiology. This comprehensive and systematic literature review summarizes the advances in the epidemiology of pancreatic cancer, including its epidemiological trends, risk factors, risk prediction models, screening modalities, and prognosis. The risk factors for pancreatic cancers can be categorized as those related to individual characteristics, lifestyle and environment, and disease status. Several prediction models for pancreatic cancer have been developed in populations with new-onset diabetes or a family history of pancreatic cancer; however, these models require further validation. Despite recent progress in pancreatic cancer screening, the quantity and quality of related studies are also unsatisfactory, especially with respect to the identification of high-risk populations and development of effective screening modality. Apart from the populations with familial genetic risk and those at a high risk of sporadic pancreatic cancer, risk factors such as new-onset diabetes may be a new direction for timely intervention. We hope this work will provide new ideas for further prevention and treatment of pancreatic cancer.
10.1016/j.canlet.2021.06.027
Pancreatic Cancer: Changing Epidemiology and New Approaches to Risk Assessment, Early Detection, and Prevention.
Gastroenterology
Pancreatic cancer usually results in poor survival with limited options for treatment, as most affected individuals present with advanced disease. Early detection of preinvasive pancreatic neoplasia and identifying molecular therapeutic targets provide opportunities for extending survival. Although screening for pancreatic cancer is currently not recommended for the general population, emerging evidence indicates that pancreatic surveillance can improve outcomes for individuals in certain high-risk groups. Changes in the epidemiology of pancreatic cancer, experience from pancreatic surveillance, and discovery of novel biomarkers provide a roadmap for new strategies for pancreatic cancer risk assessment, early detection, and prevention.
10.1053/j.gastro.2023.02.012
Pancreatic Cancer: A Review of Risk Factors, Diagnosis, and Treatment.
Zhao ZhiYu,Liu Wei
Technology in cancer research & treatment
This review aims to summarize the latest knowledge on factors, diagnosis, and treatment of pancreatic cancer, and aims to promote further research on this under-studied malignant tumor. At present, we urgently need to identify high-risk patients with precancerous diseases through screening approaches, so that medical professionals and the general public may better understand prevention strategies or early detection measures. Pancreatic cancer is a highly invasive malignant tumor with a fatal risk, mainly seen in men and older adults (60-85 years old). Pancreatic cancer is now increasingly observed in young patients. Because the disease has no early symptoms and can quickly invade surrounding tissues and organs, it is one of the deadliest cancers. With a view to identify the important factors for the development of pancreatic cancer, previous studies have found that smoking, alcohol, and chronic pancreatitis are considered high-risk factors. Recent studies have shown that abnormal metabolism of human microorganisms, blood type, and glucose and lipid levels are also important factors in the development of pancreatic cancer. Identifying early diagnosis options is an important way to improve detection and survival rates of pancreatic cancer. None of the many tumor markers associated with pancreatic cancer are highly specific, which also indicates further research is required to improve the early detection rate. Future directions in terms of treatment evaluating the relationship between the microbiology-free system and immunotherapy will bring a major breakthrough and is expected to bring exciting clinical applications in improving the life-cycle of pancreatic cancer patients.
10.1177/1533033820962117
Pancreatic cancer.
Vincent Audrey,Herman Joseph,Schulick Rich,Hruban Ralph H,Goggins Michael
Lancet (London, England)
Substantial progress has been made in our understanding of the biology of pancreatic cancer, and advances in patients' management have also taken place. Evidence is beginning to show that screening first-degree relatives of individuals with several family members affected by pancreatic cancer can identify non-invasive precursors of this malignant disease. The incidence of and number of deaths caused by pancreatic tumours have been gradually rising, even as incidence and mortality of other common cancers have been declining. Despite developments in detection and management of pancreatic cancer, only about 4% of patients will live 5 years after diagnosis. Survival is better for those with malignant disease localised to the pancreas, because surgical resection at present offers the only chance of cure. Unfortunately, 80-85% of patients present with advanced unresectable disease. Furthermore, pancreatic cancer responds poorly to most chemotherapeutic agents. Hence, we need to understand the biological mechanisms that contribute to development and progression of pancreatic tumours. In this Seminar we will discuss the most common and deadly form of pancreatic cancer, pancreatic ductal adenocarcinoma.
10.1016/S0140-6736(10)62307-0
Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors.
Nature reviews. Gastroenterology & hepatology
Pancreatic cancer is a leading cause of cancer death worldwide and its global burden has more than doubled over the past 25 years. The highest incidence regions for pancreatic cancer include North America, Europe and Australia, and although much of this increase is due to ageing worldwide populations, there are key modifiable risk factors for pancreatic cancer such as cigarette smoking, obesity, diabetes and alcohol intake. The prevalence of these risk factors is increasing in many global regions, resulting in increasing age-adjusted incidence rates for pancreatic cancer, but the relative contribution from these risk factors varies globally due to variation in the underlying prevalence and prevention strategies. Inherited genetic factors, although not directly modifiable, are an important component of pancreatic cancer risk, and include pathogenic variants in hereditary cancer genes, genes associated with hereditary pancreatitis, as well as common variants identified in genome-wide association studies. Identification of the genetic changes that underlie pancreatic cancer not only provides insight into the aetiology of this cancer but also provides an opportunity to guide early detection strategies. The goal of this Review is to provide an up-to-date overview of the established modifiable and inherited risk factors for pancreatic cancer.
10.1038/s41575-021-00457-x
Development and validation of cuproptosis-related lncRNAs associated with pancreatic cancer immune microenvironment based on single-cell.
Frontiers in immunology
Background:Cuproptosis, a novel mode of cell death associated with the tricarboxylic acid (TCA) cycle, is relevant to the development of cancer. However, the impact of single-cell-based Cuproptosis-associated lncRNAs on the Tumor immune microenvironment (TIME) of Pancreatic adenocarcinoma (PAAD) and its potential value for individualized immunotherapy has not been clarified. Methods:14 immune-related CRGs were screened by exploring the interaction between differentially expressed Immune-Related Genes (IRGs) and Cuproptosis-Related Genes (CRGs) in PAAD. Next, the expression amount and expression distribution of CRGs in single-cell samples were analyzed by focusing on 7-CRGs with significant expressions. On the one hand, MAP2K2, SOD1, and VEGFA, which were significantly differentially expressed between PAAD sites and normal tissues adjacent to them, were subjected to immunohistochemical validation and immune landscape analysis. On the other hand, from these 7-CRGs, prognostic signatures of lncRNAs were established by co-expression and LASSO-COX regression analysis, and their prognostic value and immune relevance were assessed. In addition, this study not only validated the hub CRGs and the lncRNAs constituting the signature in a PAAD animal model treated with immunotherapy-based combination therapy using immunohistochemistry and qRT-PCR but also explored the potential value of the combination of targeted, chemotherapy and immunotherapy. Results:Based on the screening of 7-CRGs significantly expressed in a PAAD single-cell cohort and their co-expressed Cuproptosis-Related lncRNAs (CRIs), this study constructed a prognostic signature of 4-CRIs named CIR-score. A Nomogram integrating the CIR-score and clinical risk factors was constructed on this basis to predict the individualized survival of patients. Moreover, high and low-risk groups classified according to the median of signatures exhibited significant differences in clinical prognosis, immune landscape, bioenrichment, tumor burden, and drug sensitivity. And the immunohistochemical and qRT-PCR results of different mouse PAAD treatment strategies were consistent with the trend of inter-group variability in drug sensitivity of hub CRGs and CIR-score. The combination of immunotherapy, targeted therapy, and chemotherapy exhibited a better tumor suppression effect. Conclusion:CIR-score, as a Cuproptosis-related TIME-specific prognostic signature based on PAAD single cells, not only predicts the prognosis and immune landscape of PAAD patients but also provides a new strategy for individualized immunotherapy-based combination therapy.
10.3389/fimmu.2023.1220760
Comprehensive analysis of bulk and single-cell transcriptomic data reveals a novel signature associated with endoplasmic reticulum stress, lipid metabolism, and liver metastasis in pancreatic cancer.
Journal of translational medicine
BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with high probability of recurrence and distant metastasis. Liver metastasis is the predominant metastatic mode developed in most pancreatic cancer cases, which seriously affects the overall survival rate of patients. Abnormally activated endoplasmic reticulum stress and lipid metabolism reprogramming are closely related to tumor growth and metastasis. This study aims to construct a prognostic model based on endoplasmic reticulum stress and lipid metabolism for pancreatic cancer, and further explore its correlation with tumor immunity and the possibility of immunotherapy. METHODS:Transcriptomic and clinical data are acquired from TCGA, ICGC, and GEO databases. Potential prognostic genes were screened by consistent clustering and WGCNA methods, and the whole cohort was randomly divided into training and testing groups. The prognostic model was constructed by machine learning method in the training cohort and verified in the test, TCGA and ICGC cohorts. The clinical application of this model and its relationship with tumor immunity were analyzed, and the relationship between endoplasmic reticulum stress and intercellular communication was further explored. RESULTS:A total of 92 characteristic genes related to endoplasmic reticulum stress, lipid metabolism and liver metastasis were identified in pancreatic cancer. We established and validated a prognostic model for pancreatic cancer with 7 signatures, including ADH1C, APOE, RAP1GAP, NPC1L1, P4HB, SOD2, and TNFSF10. This model is considered to be an independent prognosticator and is a more accurate predictor of overall survival than age, gender, and stage. TIDE score was increased in high-risk group, while the infiltration levels of CD8 T cells and M1 macrophages were decreased. The number and intensity of intercellular communication were increased in the high ER stress group. CONCLUSIONS:We constructed and validated a novel prognostic model for pancreatic cancer, which can also be used as an instrumental variable to predict the prognosis and immune microenvironment. In addition, this study revealed the effect of ER stress on cell-cell communication in the tumor microenvironment.
10.1186/s12967-024-05158-y