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. 2012;7(10):e43192.
doi: 10.1371/journal.pone.0043192. Epub 2012 Oct 10.

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

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Free PMC article

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

Winnie S Liang et al. PLoS One. .
Free PMC article

Abstract

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Patient 1 Circos Plot.
This plot summarizes all significant genomic events that were identified in patient 1 using WGS. Copy number changes are shown in the inner circle plot with red marking amplifications and green marking deletions. SNVs are indicated with dark blue tick marks and indels are indicated with light blue tick marks.
Figure 2
Figure 2. Patient 2 Circos Plot.
This plot summarizes all significant genomic events that were identified in patient 2 using WGS. Copy number changes are shown in the inner circle plot with red marking amplifications and green marking deletions. SNVs are indicated with dark blue tick marks and indels are indicated with light blue tick marks.
Figure 3
Figure 3. Patient 3 Circos Plot.
This plot summarizes all significant genomic events that were identified in patient 3 using WGS. Copy number changes are shown in the inner circle plot with red marking amplifications and green marking deletions. SNVs are indicated with dark blue tick marks and indels are indicated with light blue tick marks.
Figure 4
Figure 4. Pathway analysis of WGS and RNAseq results.
Whole genome and RNAseq data were integrated and analyzed using GeneGo's Metaminer Pancreatic Cancer Disease module to identify pathways that may be affected by mutations and/or significant expression changes (q-value<0.05, corrected). The top pathways (minimum mapping p-value across all WGS and RNAseq datasets <0.05) are summarized based off of GeneGo maps. Breakdown of affected pathways in each patient are shown in Table S4.

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