Genetic Basis of Pancreas Cancer Development and Progression: Insights from Whole-Exome and Whole-Genome Sequencing

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Clinical Cancer Research (Impact Factor: 8.72). 08/2012; 18(16):4257-65. DOI: 10.1158/1078-0432.CCR-12-0315
Source: PubMed


Pancreatic cancer is caused by inherited and acquired mutations in specific cancer-associated genes. The discovery of the most common genetic alterations in pancreatic cancer has provided insight into the fundamental pathways that drive the progression from a normal cell to noninvasive precursor lesions and finally to widely metastatic disease. In addition, recent genetic discoveries have created new opportunities to develop gene-based approaches for early detection, personalized treatment, and molecular classification of pancreatic neoplasms.

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    • "In the past, considerable efforts have been carried out to identify potential biomarkers that include aberrantly expressed genes, proteins, miRNA detectable through non-invasive techniques in cancerous tissue and body fluids34. In addition, mutations in few genes have also been identified to be associated with the progression of pancreatic cancer56. The involvement of DNA methylation, an epigenetic process, in carcinogenesis has been well established7. "
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    ABSTRACT: Pancreatic cancer is the fifth most aggressive malignancy and urgently requires new biomarkers to facilitate early detection. For providing impetus to the biomarker discovery, we have developed Pancreatic Cancer Methylation Database (PCMDB,, a comprehensive resource dedicated to methylation of genes in pancreatic cancer. Data was collected and compiled manually from published literature. PCMdb has 65907 entries for methylation status of 4342 unique genes. In PCMdb, data was compiled for both cancer cell lines (53565 entries for 88 cell lines) and cancer tissues (12342 entries for 3078 tissue samples). Among these entries, 47.22% entries reported a high level of methylation for the corresponding genes while 10.87% entries reported low level of methylation. PCMdb covers five major subtypes of pancreatic cancer; however, most of the entries were compiled for adenocarcinomas (88.38%) and mucinous neoplasms (5.76%). A user-friendly interface has been developed for data browsing, searching and analysis. We anticipate that PCMdb will be helpful for pancreatic cancer biomarker discovery.
    Scientific Reports 02/2014; 4:4197. DOI:10.1038/srep04197 · 5.58 Impact Factor
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    • "In 2013, it is estimated that a total of 45,220 patients will be diagnosed with pancreatic cancer and 38,460 will die of this disease in the United States [1]. Surgical resection through pancreatectomy remains the most viable curative option despite inroads into better understanding of the molecular biology of PDAC [2], emergence of targeted drugs [3] [4], intensity-modulated radiotherapy [5] [6] [7], and neoadjuvant chemotherapy regimen [8] [9]. "
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    ABSTRACT: The objective of this study is to assess lymphotropic nanoparticle-enhanced magnetic resonance imaging (LNMRI) in identifying malignant nodal involvement in patients with pancreatic ductal adenocarcinoma. Magnetic resonance imaging was performed in 13 patients with known or high index of suspicion of pancreatic cancer and who were scheduled for surgical resection. Protocols included T2*-weighted imaging before and after administration of Ferumoxytol (Feraheme) for the evaluation of lymph node involvement. Eleven of the 13 patients underwent a Whipple procedure and lymph node dissection. Nodes that lacked contrast uptake were deemed malignant, and those that demonstrated homogeneous uptake were deemed benign. A total of 264 lymph nodes were resection, of which 17 were malignant. The sensitivity and specificity of LNMRI was 76.5% and 98.4% at a nodal level and 83.3% and 80% at a patient level. LNMRI demonstrated high sensitivity and specificity in patients with pancreatic ductal adenocarcinoma.
    Translational oncology 12/2013; 6(6):670-5. DOI:10.1593/tlo.13400 · 2.88 Impact Factor
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    • "Pancreatic intraepithelial neoplasia (PanIN) is the most common pancreatic precursor lesion. Activating Kras mutations are almost uniformly present in the early stages of PanIN, whereas subsequent inactivating mutations in p16, p53, and Smad4 occur in advanced lesions [2] [3] [4] [5] [6] [7] [8]. However, because it is difficult to isolate and establish PanIN cell lines from the pancreatic tissue of pancreatic cancer patients, the previous studies of PanIN were mainly conducted using a hybrid of PanIN and pancreatic cancer tissues. "
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    ABSTRACT: Pancreatic intraepithelial neoplasia (PanIN) is the most common premalignant lesion of the pancreas. Further understanding of the biological behavior and molecular genetic alterations in the stepwise progression of PanINs is necessary toward the development of pancreatic ductal adenocarcinoma (PDAC) interventions. In this study, we analyzed the morphological characteristics, molecular alterations, and biological behavior of pancreatic wild-type and neoplasia tissues, including analysis of PanIN cell line SH-PAN (isolated from Pdx-1-Cre; LSL-Kras(G12D/+) mouse) and PDAC cell line DT-PCa (isolated from Pdx1-Cre; LSL-Kras(G12D/+); LSL-Tp53(R172H/+) mouse). Results show that Kras(G12D) induces ductal lesion PanINs. Increased expression of EGFR, Her-s/Neu, p-MAPK and β-Catenin was observed in low-grade PanINs. Tp53 was not expressed in wild-type and low-grade PanINs, however, increased expression was observed in high-grade PanINs. Furthermore, SH-PAN cells did not exhibit any colony formation and showed significantly lower migration and invasion ability compared with DT-PCa cells. Notably, we first found PPP2R2A (protein phosphatase 2, regulatory subunit B, alpha) expression was significantly higher in SH-PAN cells than DT-PCa cells, and was high in 96 of 172 peritumoral normal human pancreatic tissues and 20 of 36 human low- or middle-grade PanIN tissues, whereas, was weak or negligible in 12 of 20 human high-grade PanIN tissues and 124 of 172 human PDAC tissues post-operation. The expression of PPP2R2A appears to be correlated with clinical survival. Taken together, Kras(G12D)-driven PanIN showed the tumorigenic ability, however, did not undergo a malignant transformation, and decreased expression of PPP2R2A in PDACs may provided a new target for pancreatic carcinoma intervention.
    Cancer letters 07/2013; 339(1). DOI:10.1016/j.canlet.2013.07.010 · 5.62 Impact Factor
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