Genome-wide characterization of pancreatic adenocarcinoma patients using next generation sequencing.
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.
Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America.
Winnie S
WS
Liang
David W
DW
Craig
John
J
Carpten
Mitesh J
MJ
Borad
Michael J
MJ
Demeure
Glen J
GJ
Weiss
Tyler
T
Izatt
Shripad
S
Sinari
Alexis
A
Christoforides
Jessica
J
Aldrich
Ahmet
A
Kurdoglu
Michael
M
Barrett
Lori
L
Phillips
Hollie
H
Benson
Waibhav
W
Tembe
Esteban
E
Braggio
Jeffrey A
JA
Kiefer
Christophe
C
Legendre
Richard
R
Posner
Galen H
GH
Hostetter
Angela
A
Baker
Jan B
JB
Egan
Haiyong
H
Han
Douglas
D
Lake
Edward C
EC
Stites
Ramesh K
RK
Ramanathan
Rafael
R
Fonseca
A Keith
AK
Stewart
Daniel
D
Von Hoff
D000230:Adenocarcinoma / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics; D001483:Base Sequence; D004260:DNA Repair / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D017423:Sequence Analysis, RNA; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C117307:KRAS protein, human; C489427:MYC protein, human; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins