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

Winnie S. Liang, David W. Craig, John Carpten, Mitesh J. Borad, Michael J. Demeure, Glen J. Weiss, Tyler Izatt, Shripad Sinari, Alexis Christoforides, Jessica Aldrich, Ahmet Kurdoglu, Michael Barrett, Lori Phillips, Hollie Benson, Waibhav Tembe, Esteban Braggio, Jeffrey A. Kiefer, Christophe Legendre, Richard G Posner, Galen H. Hostetter & 9 others Angela Baker, Jan B. Egan, Haiyong Han, Douglas Lake, Edward C. Stites, Ramesh K. Ramanathan, Rafael Fonseca, A. Keith Stewart, Daniel von Hoff

Research output: Contribution to journalArticle

49 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere43192
JournalPLoS One
Volume7
Issue number10
DOIs
StatePublished - Oct 10 2012
Externally publishedYes

Fingerprint

adenocarcinoma
Tumors
Adenocarcinoma
Genes
Genome
genome
neoplasms
Aberrations
Neoplasms
therapeutics
RNA
RNA Sequence Analysis
Therapeutics
point mutation
transcriptomics
lethal genes
Point Mutation
carcinogenesis
Carcinogenesis
pathogenesis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Liang, W. S., Craig, D. W., Carpten, J., Borad, M. J., Demeure, M. J., Weiss, G. J., ... von Hoff, D. (2012). Genome-Wide Characterization of Pancreatic Adenocarcinoma Patients Using Next Generation Sequencing. PLoS One, 7(10), [e43192]. https://doi.org/10.1371/journal.pone.0043192

Genome-Wide Characterization of Pancreatic Adenocarcinoma Patients Using Next Generation Sequencing. / Liang, Winnie S.; Craig, David W.; Carpten, John; Borad, Mitesh J.; Demeure, Michael J.; Weiss, Glen J.; Izatt, Tyler; Sinari, Shripad; Christoforides, Alexis; Aldrich, Jessica; Kurdoglu, Ahmet; Barrett, Michael; Phillips, Lori; Benson, Hollie; Tembe, Waibhav; Braggio, Esteban; Kiefer, Jeffrey A.; Legendre, Christophe; Posner, Richard G; Hostetter, Galen H.; Baker, Angela; Egan, Jan B.; Han, Haiyong; Lake, Douglas; Stites, Edward C.; Ramanathan, Ramesh K.; Fonseca, Rafael; Stewart, A. Keith; von Hoff, Daniel.

In: PLoS One, Vol. 7, No. 10, e43192, 10.10.2012.

Research output: Contribution to journalArticle

Liang, WS, Craig, DW, Carpten, J, Borad, MJ, Demeure, MJ, Weiss, GJ, Izatt, T, Sinari, S, Christoforides, A, Aldrich, J, Kurdoglu, A, Barrett, M, Phillips, L, Benson, H, Tembe, W, Braggio, E, Kiefer, JA, Legendre, C, Posner, RG, Hostetter, GH, Baker, A, Egan, JB, Han, H, Lake, D, Stites, EC, Ramanathan, RK, Fonseca, R, Stewart, AK & von Hoff, D 2012, 'Genome-Wide Characterization of Pancreatic Adenocarcinoma Patients Using Next Generation Sequencing', PLoS One, vol. 7, no. 10, e43192. https://doi.org/10.1371/journal.pone.0043192
Liang, Winnie S. ; Craig, David W. ; Carpten, John ; Borad, Mitesh J. ; Demeure, Michael J. ; Weiss, Glen J. ; Izatt, Tyler ; Sinari, Shripad ; Christoforides, Alexis ; Aldrich, Jessica ; Kurdoglu, Ahmet ; Barrett, Michael ; Phillips, Lori ; Benson, Hollie ; Tembe, Waibhav ; Braggio, Esteban ; Kiefer, Jeffrey A. ; Legendre, Christophe ; Posner, Richard G ; Hostetter, Galen H. ; Baker, Angela ; Egan, Jan B. ; Han, Haiyong ; Lake, Douglas ; Stites, Edward C. ; Ramanathan, Ramesh K. ; Fonseca, Rafael ; Stewart, A. Keith ; von Hoff, Daniel. / Genome-Wide Characterization of Pancreatic Adenocarcinoma Patients Using Next Generation Sequencing. In: PLoS One. 2012 ; Vol. 7, No. 10.
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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.",
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AU - Liang, Winnie S.

AU - Craig, David W.

AU - Carpten, John

AU - Borad, Mitesh J.

AU - Demeure, Michael J.

AU - Weiss, Glen J.

AU - Izatt, Tyler

AU - Sinari, Shripad

AU - Christoforides, Alexis

AU - Aldrich, Jessica

AU - Kurdoglu, Ahmet

AU - Barrett, Michael

AU - Phillips, Lori

AU - Benson, Hollie

AU - Tembe, Waibhav

AU - Braggio, Esteban

AU - Kiefer, Jeffrey A.

AU - Legendre, Christophe

AU - Posner, Richard G

AU - Hostetter, Galen H.

AU - Baker, Angela

AU - Egan, Jan B.

AU - Han, Haiyong

AU - Lake, Douglas

AU - Stites, Edward C.

AU - Ramanathan, Ramesh K.

AU - Fonseca, Rafael

AU - Stewart, A. Keith

AU - von Hoff, Daniel

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