Article

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

ABSTRACT

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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    • "Kras G12D ) (Pylayeva-Gupta et al., 2011). Kras mutations are found in over 90% of human PDA cases (Iacobuzio-Donahue et al., 2012). Kras G12D expression is necessary but not sufficient to initiate neoplasia; GTP binding is required to activate Kras G12D (Huang et al., 2014). "
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related deaths in the United States, and is projected to be second by 2025. It has the worst survival rate among all major cancers. Two pressing needs for extending life expectancy of affected individuals are the development of new approaches to identify improved therapeutics, addressed herein, and the identification of early markers. PDA advances through a complex series of intercellular and physiological interactions that drive cancer progression in response to organ stress, organ failure, malnutrition, and infiltrating immune and stromal cells. Candidate drugs identified in organ culture or cell-based screens must be validated in preclinical models such as KIC (p48Cre;LSL-KrasG12D;Cdkn2af/f) mice, a genetically engineered model of PDA in which large aggressive tumors develop by 4 weeks of age. We report a rapid, systematic and robust in vivo screen for effective drug combinations to treat Kras-dependent PDA. Kras mutations occur early in tumor progression in over 90% of human PDA cases. Protein kinase and G-protein coupled receptor (GPCR) signaling activates Kras. Regulators of G-protein signaling (RGS) proteins are coincidence detectors that can be induced by multiple inputs to feedback-regulate GPCR signaling. We crossed Rgs16::GFP bacterial artificial chromosome (BAC) transgenic mice with KIC mice and show that the Rgs16::GFP transgene is a KrasG12D-dependent marker of all stages of PDA, and increases proportionally to tumor burden in KIC mice. RNA sequencing (RNA-Seq) analysis of cultured primary PDA cells reveals characteristics of embryonic progenitors of pancreatic ducts and endocrine cells, and extraordinarily high expression of the receptor tyrosine kinase Axl, an emerging cancer drug target. In proof-of-principle drugscreens, we find that we anling KIC mice with PDA treated for 2 weeks with gemcitabine (with or without Abraxane) plus inhibitors of Axl signaling (warfarin and BGB324) have fewer tumor initiation sites and reduced tumor size compared with the standard-of-care treatment. Rgs16::GFP is therefore an in vivo reporter of PDA progression and sensitivity to new chemotherapeutic drug regimens such as Axl-targeted agents. This screening strategy can potentially be applied to identify improved therapeutics for other cancers.
    Full-text · Article · Oct 2015 · Disease Models and Mechanisms
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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, http://crdd.osdd.net/raghava/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.
    Full-text · Article · Feb 2014 · Scientific Reports
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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.
    Full-text · Article · Dec 2013 · Translational oncology
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