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

被引：59

作者：

Liang, Winnie S. ^{[1
]}

Craig, David W. ^{[1
]}

Carpten, John ^{[1
]}

Borad, Mitesh J. ^{[2
]}

Demeure, Michael J. ^{[1
,3
]}

Weiss, Glen J. ^{[1
,3
]}

Izatt, Tyler ^{[1
]}

Sinari, Shripad ^{[1
]}

Christoforides, Alexis ^{[1
]}

Aldrich, Jessica ^{[1
]}

Kurdoglu, Ahmet ^{[1
]}

Barrett, Michael ^{[1
]}

Phillips, Lori ^{[1
]}

Benson, Hollie ^{[1
]}

Tembe, Waibhav ^{[1
]}

Braggio, Esteban ^{[2
]}

Kiefer, Jeffrey A. ^{[1
]}

Legendre, Christophe ^{[1
]}

Posner, Richard ^{[1
]}

Hostetter, Galen H. ^{[1
]}

Baker, Angela ^{[1
]}

Egan, Jan B. ^{[1
,2
]}

Han, Haiyong ^{[1
]}

Lake, Douglas ^{[4
]}

Stites, Edward C. ^{[1
]}

Ramanathan, Ramesh K. ^{[1
,3
]}

Fonseca, Rafael ^{[2
]}

Stewart, A. Keith ^{[2
]}

Von Hoff, Daniel ^{[1
,2
,3
]}

机构：

[1] Translat Genom Res Inst TGen, Phoenix, AZ USA

[2] Mayo Clin, Scottsdale, AZ USA

[3] Scottsdale Healthcare, Virginia G Piper Canc Ctr Clin Trials, Scottsdale, AZ USA

[4] Arizona State Univ, Tempe, AZ USA

来源：

PLOS ONE | 2012年 / 7卷 / 10期

基金：

美国国家卫生研究院;

关键词：

FREQUENT SOMATIC MUTATIONS; MESSENGER-RNA EXPRESSION; ACTIVATED RECEPTOR-GAMMA; GROWTH-FACTOR RECEPTOR; TUMOR-SUPPRESSOR GENE; OF-FUNCTION MUTATIONS; K-RAS MUTATIONS; CANCER-CELLS; COPY-NUMBER; PROGNOSTIC-SIGNIFICANCE;

D O I：

10.1371/journal.pone.0043192

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：20

共 126 条

[1] Genetic and immunohistochemical analysis of pancreatic acinar cell carcinoma -: Frequent allelic loss on chromosome 11p and alterations in the APC/β-catenin pathway [J].