Molecular Diagnostics and Treatment of Pancreatic Cancer

Systems and Network Biology Approaches

Asfar Azmi

• Publisher: Academic Press
• Year: 2014
• Print ISBN: 9780124081031
• eBook ISBN: 9780124079465
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

Molecular Diagnostics and Treatment of Pancreatic Cancer describes the different emerging applications of systems biology and how it is shaping modern pancreatic cancer research. This book begins by introducing the current state of the art knowledge, trends in diagnostics, progress in disease model systems as well as new treatment and palliative care strategies in pancreatic cancer. Specific sections are dedicated to enlighten the readers to newer discoveries that have emerged from gene expression profiling, proteomics, metabolomics and systems level analyses of pancreatic cancer datasets. First of a kind and novel network strategies to understand oncogenic Kras signaling in pancreatic tumors are presented. The attempts to computationally model and prioritize microRNAs that cause pancreatic cancer resistance are also highlighted.Addressing this important area, Molecular Diagnostics and Treatment of Pancreatic Cancer provides insights into important network evaluation methodologies related to pancreatic cancer related microRNAs targetome. There are dedicated chapters on critical aspects of the evolving yet controversial field of pancreatic cancer stems cells. The work concludes by discussing the applications of network sciences in pancreatic cancer drug discovery and clinical trial design.- Encompasses discussion of innovative tools including expression signatures in cell lines, 3D models, animal xenograft models, primary models and patient derived samples, aiding subversion of traditional biology paradigms, and enhancing comprehension across conventional length and temporal scales- Coverage includes novel applications in targeted drugs, polypharmacology, network pharmacology and other related drug development arenas – helping researchers in pancreatic cancer drug discovery- Summarizes many relevant computational and clinical references from fast-evolving literature- Comprehensive glossary helps newer readers understand technical terms and specialized nomenclature

Section II

Gene Expression Profiling and Bioinformatics Analysis in Pancreatic Cancer

Outline

Chapter 5. Bioinformatics Analysis of Pancreas Cancer Genome in High-Throughput Genomic Technologies

Chapter 6. Statistical Analysis of High-Dimensional Data for Pancreatic Cancer

Chapter 7. Gene Expression Profiling in Pancreatic Cancer

Chapter 8. Genetic Susceptibility and Risk of Pancreatic Cancer

Chapter 5

Bioinformatics Analysis of Pancreas Cancer Genome in High-Throughput Genomic Technologies

Enrique Carrillo-de Santa Pau, Francisco X. Real, and Alfonso Valencia Spanish National Cancer Research Center (CNIO), Madrid, Spain

Abstract

The technology revolution propelled by the Human Genome Project is about to transform medicine, especially cancer treatment. Bioinformatics is essential for the interpretation of the genomic information and, as such, a fundamental element in the study of the molecular causes of pancreatic cancer pathophysiology. The aim of this chapter is to provide an overview of the bioinformatics analysis that currently is being applied to genome-wide studies in the field of pancreatic cancer. The bioinformatics methodologies cover a wide range of topics from data organization to the assessment of sample quality, the analysis of sequencing data, and the prediction of cancer driver genes and processes. This chapter illustrates the various stages of the bioinformatics analysis with actual examples taken from pancreatic cancer genome projects and includes a description of the available technologies and resources in each case. The current limitations in the interpretation of cancer genome data, difficulties in the integration of clinical and genomic data, and challenges in the interpretation of the genomic information in clinical settings are highlighted.

Keywords

Bioinformatics; Cancer; Genomics; Microarrays; Next-generation sequencing; Pancreas

Contents

Introduction 94

Heterogeneity and Quality of Samples for High-Throughput Genomic Technologies 95

Microarrays 96

Technique 96

Bioinformatic Analysis 96

Microarrays in the Pancreas 99

Expression Microarrays 99

Genotyping Microarrays 100

Next-Generation Sequencing 101

ChIP-seq 101

Technique 101

ChIP-seq Encyclopedia of DNA Elements Guidelines 102

Bioinformatics Analysis 102

Further ChIP-seq Applications 105

ChIP-seq Analysis of Pancreatic Cancer 107

RNA-seq 107

Technique 107

RNA-seq ENCODE Guidelines 108

Bioinformatic Analysis 108

RNA-seq in the Pancreas 110

Cancer Genome Sequencing 111

Genome–Exome Sequencing Studies in the Pancreas 114

Databases and Resources 115

Sequence Read Archive 116

GenBank and the European Nucleotide Archive 116

The ENCODE Project 116

Gene Expression Omnibus 117

Array-Express 117

Oncomine118

IntOGen 122

The Gene Expression Barcode 122

The Single-Nucleotide Polymorphism Database 122

The Catalogue of Somatic Mutations in Cancer 122

The cBioPortal for Cancer Genomics 123

The Cancer Genome Atlas 124

The International Cancer Genome Consortium 124

The 1000 Genomes Project 124

The Cancer Cell Line Encyclopedia 125

The Pancreatic Expression Database 125

Conclusion and Future Perspectives 125

References 126

Introduction

The technology revolution by the Human Genome Project from 1986 to 2003 [1] has propelled the field of bioinformatics into a new era, with the formidable challenge of organizing, classifying, making available, and interpreting complex genomic data within the context of large biological databases and repositories containing the accumulated information.

The major advances in experimental methods for genome characterization based on deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) microarrays and DNA sequencing—for example, capillary-based DNA Sanger sequencing and, more recently, next-generation sequencing (NGS)—make analysis mutations, gene expression, and copy number alterations possible in a large number of cancer genomes [2]. Indeed, 21st-century sequencing-based experiments generate substantially more data and are more broadly applicable than microarray technology, allowing for various novel functional assays, including quantification of protein–DNA binding or histone modifications (chromatin immunoprecipitation followed by sequencing, ChIP-seq), transcript levels using RNA sequencing (RNA-seq), and genome (WGS) and exome sequencing (WES) variant discovery.

New genomic technology has come at a cost, however, resulting in a greater challenge for associated bioinformatics analyses. The fast development of bioinformatics and the complex combination of related biology, computer science, and information technology often make it difficult for biomedical researchers to use the available technology to its fullest and, in many cases, even to select the appropriate tools and computational resources.

This chapter provides an overview of the high-throughput genomics technologies (with an emphasis in NGS), the data currently available (cancer...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Preface
• Acknowledgments
• Contributors
• Section I. Current Trends and Advances in Pancreatic Cancer
• Section II. Gene Expression Profiling and Bioinformatics Analysis in Pancreatic Cancer
• Section III. Pancreatic Cancer Proteomics
• Section IV. Systems and Network Understanding of Pancreatic Cancer Signaling
• Section V. Systems Approaches to Pancreatic Cancer Therapeutics
• Index