Journal Article

Genome-Wide Characterization of Pancreatic Adenocarcinoma Patients Using Next Generation Sequencing

Christoforides, Alexis, Craig, David W., Stites, Edward C., Posner, Richard, Stewart, A. Keith, Aldrich, Jessica, Liang, Winnie S., Phillips, Lori, Hostetter, Galen H., Braggio, Esteban, Carpten, John, Kurdoglu, Ahmet, Ramanathan, Ramesh K., Weiss, Glen J., Lake, Douglas, Von Hoff, Daniel, Tembe, Waibhav, Baker, Angela, Benson, Hollie, Han, Haiyong, Borad, Mitesh J., Legendre, Christophe, Egan, Jan B., Kiefer, Jeffrey A., Demeure, Michael J., Fonseca, Rafael, Izatt, Tyler, Sinari, Shripad, Barrett, Michael

2012

Overview

Pancreatic adenocarcinoma (PAC) is among the most lethal malignancies. While research has implicated multiple genes in disease pathogenesis, identification of therapeutic leads has been difficult and the majority of currently available therapies provide only marginal benefit. To address this issue, our goal was to genomically characterize individual PAC patients to understand the range of aberrations that are occurring in each tumor. Because our understanding of PAC tumorigenesis is limited, evaluation of separate cases may reveal aberrations, that are less common but may provide relevant information on the disease, or that may represent viable therapeutic targets for the patient. We used next generation sequencing to assess global somatic events across 3 PAC patients to characterize each patient and to identify potential targets. This study is the first to report whole genome sequencing (WGS) findings in paired tumor/normal samples collected from 3 separate PAC patients. We generated on average 132 billion mappable bases across all patients using WGS, and identified 142 somatic coding events including point mutations, insertion/deletions, and chromosomal copy number variants. We did not identify any significant somatic translocation events. We also performed RNA sequencing on 2 of these patients' tumors for which tumor RNA was available to evaluate expression changes that may be associated with somatic events, and generated over 100 million mapped reads for each patient. We further performed pathway analysis of all sequencing data to identify processes that may be the most heavily impacted from somatic and expression alterations. As expected, the KRAS signaling pathway was the most heavily impacted pathway (P<0.05), along with tumor-stroma interactions and tumor suppressive pathways. While sequencing of more patients is needed, the high resolution genomic and transcriptomic information we have acquired here provides valuable information on the molecular composition of PAC and helps to establish a foundation for improved therapeutic selection.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aberration / Adenocarcinoma / Adenocarcinoma - genetics / Analysis / Apoptosis / Base Sequence / Biology / BRCA2 Protein - genetics / Cancer genetics / Cancer therapies / Cell division / Chemotherapy / Clinical trials / Copy number / Deoxyribonucleic acid / DNA / DNA Repair - genetics / DNA sequencing / Evolution & development / Female / Gene Dosage / Gene expression / Gene mutation / Gene sequencing / Genes / Genetic aspects / Genome, Human / Genomes / Genomics / Health aspects / High-Throughput Nucleotide Sequencing / Humans / Identification / K-Ras protein / Kinases / Male / Medical prognosis / Medical research / Medicine / Metabolic Networks and Pathways - genetics / Metastasis / Mutation / Pancreas / Pancreatic cancer / Pancreatic Neoplasms - genetics / Pathogenesis / Patients / Proteins / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins c-myc - genetics / Proto-Oncogene Proteins p21(ras) / ras Proteins - genetics / Ribonucleic acid / RNA / RNA sequencing / Sequence Analysis, RNA / Signal transduction / Signaling / Stroma / Target recognition / Transcriptome / Translocation / Tumor Suppressor Protein p53 - genetics / Tumorigenesis / Tumors