Whole genomes redefine the mutational landscape of pancreatic cancer

A Tumor Sorting Protocol that Enables Enrichment of Pancreatic Adenocarcinoma Cells and Facilitation of Genetic Analyses

Desmoplasia of Pancreatic Ductal Adenocarcinoma

Covering the Cover

Pancreatic Cancer: Novel Approaches to Diagnosis and Therapy

Background: Pancreatic cancer is associated with 6.9% and 4% of all cancer-related deaths in the United States and Brazil, respectively. Pancreatic ductal carcinoma comprises 90% of cases, the majority being of adenocarcinoma subtype. Approximately 12% of periampullary tumors are adenocarcinomas of Vater papilla (ampullary adenocarcinomas); ampullary tumors are often associated with a better prognosis than ductal adenocarcinomas. Although genetic alterations were previously identified in pancreatic carcinomas, there is still a lack of effective treatment strategies. Therefore, the identification of new biomarkers, such as alterations in non-coding RNAs, is urgently needed for the development of novel molecularly targeted therapies for these cancers. microRNAs (miRNAs) are frequently deregulated and contribute to cancer development and progression and have potential prognostic and predictive value. Global miRNA expression profiling analysis in pancreatic cancer, followed by the identification of miRNA target genes may lead to the identification of clinically applicable biomarkers. The novel aspect of our work is the investigation of pancreatic tumors from Brazilian patients, with the inclusion of ampullary adenocarcinomas, a rare subtype. Objectives: To identify global miRNA expression profiles and miRNA target genes in pancreatic ductal and ampullary adenocarcinomas compared to paired histologically normal pancreatic tissue. Patients and Methods: 30 formalin fixed, paraffin embedded (FFPE) pancreatic carcinoma samples were used, including 24 pancreatic ductal adenocarcinomas (PDAC) and 6 ampullary adenocarcinomas (AMP). Paired histologically normal pancreatic tissues were used as controls. All tumor and normal tissues were needle microdissected (Leica EZ4 stereomicroscope). Global miRNA expression profiles were determined using the TaqMan Array Human MicroRNA Cards (TLDA) (card A, v3.0) (Life Technologies) platform. Data analysis was performed using the ExpressionSuite Software v1.0.3. Statistical analysis was performed to correlate miRNA expression with relevant clinical data, using SAS 9.3 software. Computational bioinformatics analysis was performed to identify miRNA target genes, as well as to construct protein-protein interaction and miRNA-gene targets networks. Results and Discussion: We identified 63 significantly deregulated (FC≥2 and p<0.05) miRNAs in PDAC (33 over- and 30 under-expressed) compared to paired histologically normal pancreatic tissue. In AMP, a group of 7 miRNAs was significantly deregulated (4 over- and 3 under-expressed) compared to normal pancreas. Our results showed differentially expressed miRNAs and a complexity of miRNA changes potentially associated to PDAC and AMP tumorigenesis. 3/7 miRNAs (miR-222, 148a and 375) were commonly deregulated in PDAC and AMP tumors. Furthermore, miRNA-gene targets networks were distinct in these different histological subtypes of pancreatic carcinomas. Global miRNA expression profiles showed that PDAC have a significantly higher number of altered miRNAs and a higher number of predicted miRNA target genes than AMP tumors, which could be potentially associated to disease progression and tumor aggressiveness in PDAC compared to AMP. Although these tumors have biological differences, commonly deregulated miRNAs in PDAC and AMP suggest that PDAC and AMP tumorigenesis may share commonly deregulated pathways. Conclusion: miRNAs identified herein may be associated to the biology of PDAC and AMP. Among the miRNAs exclusively deregulated in PDAC, we identified known and not previously reported (novel) miRNAs. In addition, we identified several miRNA target genes associated with tumor invasion, metastasis and poor patient prognosis. Functional in vitro and in vivo validation studies may elucidate the role of identified miRNAs as modulators of oncogenesis mechanisms in PDAC and AMP. T. Felix was funded through São Paulo Research Foundation (FAPESP), MSc. fellowship (2014/00367-4) Citation Format: Tainara F. Felix, Tomas Tokar, Maria A. M. Rodrigues, Rogerio A. Oliveira, Claudia N. Hasimoto, Juan C. Llanos, Robson F. Carvalho, Silvia R. Rogatto, Wan Lam, Igor Jurisica, Sandra A. Drigo, Patricia P. Reis.{Authors}. Differentially expressed microRNA profiles in pancreatic ductal and ampullary adenocarcinomas. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A28.

A transposon-based tumor resection model of pancreatic ductal adenocarcinoma (PDAC) with extrahepatic distant metastases

ASGE guideline on screening for pancreatic cancer in individuals with genetic susceptibility: summary and recommendations

Recommendations for a More Organized and Effective Approach to the Early Detection of Pancreatic Cancer From the PRECEDE (Pancreatic Cancer Early Detection) Consortium

The effective treatment of pancreatic cancer relies on the diagnosis of the disease at an early stage, a difficult challenge. One major obstacle in the development of diagnostic biomarkers of early pancreatic cancer has been the dual expression of potential biomarkers in both chronic pancreatitis and cancer. To better understand the limitations of potential protein biomarkers, we used ICAT technology and tandem mass spectrometry-based proteomics to systematically study protein expression in chronic pancreatitis. Among the 116 differentially expressed proteins identified in chronic pancreatitis, most biological processes were responses to wounding and inflammation, a finding consistent with the underlining inflammation and tissue repair associated with chronic pancreatitis. Furthermore 40% of the differentially expressed proteins identified in chronic pancreatitis have been implicated previously in pancreatic cancer, suggesting some commonality in protein expression between these two diseases. Biological network analysis further identified c-MYC as a common prominent regulatory protein in pancreatic cancer and chronic pancreatitis. Lastly five proteins were selected for validation by Western blot and immunohistochemistry. Annexin A2 and insulin-like growth factor-binding protein 2 were overexpressed in cancer but not in chronic pancreatitis, making them promising biomarker candidates for pancreatic cancer. In addition, our study validated that cathepsin D, integrin beta1, and plasminogen were overexpressed in both pancreatic cancer and chronic pancreatitis. The positive involvement of these proteins in chronic pancreatitis and pancreatic cancer will potentially lower the specificity of these proteins as biomarker candidates for pancreatic cancer. Altogether our study provides some insights into the molecular events in chronic pancreatitis that may lead to diverse strategies for diagnosis and treatment of these diseases.

American Society for Gastrointestinal Endoscopy guideline on screening for pancreatic cancer in individuals with genetic susceptibility: methodology and review of evidence

BackgroundPancreatic cancers of the tail have an especially poor prognosis due to their late detection. An earlier diagnosis depends on a better understanding of the clinical course of the disease; however, much of the current literature focuses on pancreatic head adenocarcinomas owing to their higher incidence. Thus, we add our case report to the current literature of pancreatic tail cancers in the hope of aiding earlier detection. We present an interesting case of a patient who initially presented with innocuous abdominal pain and a single episode of vomiting who was subsequently diagnosed with metastatic pancreatic tail cancer.Case presentationA 56-year-old Hispanic man with a past medical history of alcohol and cocaine abuse was initially evaluated in our clinic after presenting to the emergency department with sudden onset of abdominal pain and one episode of emesis. On further questioning, he stated that he had been experiencing dull, intermittent left back pain for the past 2–3 years. Laboratory tests were performed, which showed that the patient had new-onset diabetes, and imaging revealed a pancreatic tail mass with metastases to the liver. Biopsy confirmed the diagnosis of stage IV metastatic pancreatic tail adenocarcinoma. During follow-up 1 month later, the patient reported that he had been largely asymptomatic since his hospital admission; however, his left back pain had increased in severity. He was then started on a FOLFIRINOX chemotherapy regimen (5-fluorouracil/leucovorin, irinotecan, and oxaliplatin).ConclusionsThere are many pitfalls in the diagnosis of pancreatic cancer, especially pancreatic tail cancer due to its vague symptoms. Thus, pancreatic cancer of the tail often presents late with a very poor prognosis. Because there is currently no widespread screening for pancreatic cancer, it is often difficult for practitioners to identify pancreatic tail cancers. Current research suggests that there is a strong association between new-onset diabetes after the age of 50 and pancreatic cancer, and tumors detected at the onset of diabetes are favorable to resection. Pancreatic cancer has also been shown to be associated with certain risk factors, such as smoking, high body mass index, chronic pancreatitis, and a family history of pancreatic cancer. Thus, when patients with presentations similar to our patient’s with new-onset diabetes after the age of 50, along with vague symptoms such as back or abdominal pain as well as the presence of risk factors, we suggest that it is beneficial for practitioners to maintain a high index of suspicion for pancreatic cancer.

Pancreatic cancer is a uniformly lethal disease that is difficult to diagnose at early stage and even more difficult to cure. In recent years, there has been a substantial interest in applying proteomics technologies to identify protein biomarkers for early detection of cancer. Quantitative proteomic profiling of body fluids, tissues, or other biological samples to identify differentially expressed proteins represents a very promising approach for improving the outcome of this disease. Proteins associated with pancreatic cancer identified through proteomic profiling technologies could be useful as biomarkers for the early diagnosis, therapeutic targets, and disease response markers. In this article, we discuss recent progress and challenges for applying quantitative proteomics technologies for biomarker discovery in pancreatic cancer.

Mechanistic Insights into Self-Reinforcing Processes Driving Abnormal Histogenesis During the Development of Pancreatic Cancer

Copy number variation is now recognized as an important class of risk factor for several child psychiatric disorders. In this article, we first explain what copy number variants (CNVs) are. We then consider key findings and what these have told us about the etiology of these conditions. Finally, we discuss whether these findings can yet translate into clinical practice.

Simulating Clinical Features of Pancreatic Cancer in a Mouse Model with Specific Genetic Alterations in Kras and p53