Functional annotation of rare gene aberration drivers of pancreatic cancer

Yiu Huen Tsang, Turgut Dogruluk, Philip M. Tedeschi, Joanna Wardwell-Ozgo, Hengyu Lu, Maribel Espitia, Nikitha Nair, Rosalba Minelli, Zechen Chong, Fengju Chen, Qing Edward Chang, Jennifer B. Dennison, Armel Dogruluk, Min Li, Haoqiang Ying, Joseph R. Bertino, Marie-Claude Gingras, Michael Ittmann, John Kerrigan, Ken Chen, Chad J. Creighton, Karina Eterovic, Gordon B. Mills and Kenneth L. Scott ()
Additional contact information
Yiu Huen Tsang: Baylor College of Medicine, One Baylor Plaza
Turgut Dogruluk: Baylor College of Medicine, One Baylor Plaza
Philip M. Tedeschi: Rutgers Cancer Institute of New Jersey
Joanna Wardwell-Ozgo: Baylor College of Medicine, One Baylor Plaza
Hengyu Lu: Baylor College of Medicine, One Baylor Plaza
Maribel Espitia: University of Texas M.D. Anderson Cancer Center
Nikitha Nair: Baylor College of Medicine, One Baylor Plaza
Rosalba Minelli: Baylor College of Medicine, One Baylor Plaza
Zechen Chong: University of Texas M.D. Anderson Cancer Center
Fengju Chen: Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza
Qing Edward Chang: University of Texas M.D. Anderson Cancer Center
Jennifer B. Dennison: University of Texas M.D. Anderson Cancer Center
Armel Dogruluk: Baylor College of Medicine, One Baylor Plaza
Min Li: The University of Oklahoma Health Sciences Center
Haoqiang Ying: University of Texas M.D. Anderson Cancer Center
Joseph R. Bertino: Rutgers Cancer Institute of New Jersey
Marie-Claude Gingras: Baylor College of Medicine, One Baylor Plaza
Michael Ittmann: Baylor College of Medicine, One Baylor Plaza
John Kerrigan: Rutgers Cancer Institute of New Jersey
Ken Chen: University of Texas M.D. Anderson Cancer Center
Chad J. Creighton: Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza
Karina Eterovic: University of Texas M.D. Anderson Cancer Center
Gordon B. Mills: University of Texas M.D. Anderson Cancer Center
Kenneth L. Scott: Baylor College of Medicine, One Baylor Plaza

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract As we enter the era of precision medicine, characterization of cancer genomes will directly influence therapeutic decisions in the clinic. Here we describe a platform enabling functionalization of rare gene mutations through their high-throughput construction, molecular barcoding and delivery to cancer models for in vivo tumour driver screens. We apply these technologies to identify oncogenic drivers of pancreatic ductal adenocarcinoma (PDAC). This approach reveals oncogenic activity for rare gene aberrations in genes including NAD Kinase (NADK), which regulates NADP(H) homeostasis and cellular redox state. We further validate mutant NADK, whose expression provides gain-of-function enzymatic activity leading to a reduction in cellular reactive oxygen species and tumorigenesis, and show that depletion of wild-type NADK in PDAC cell lines attenuates cancer cell growth in vitro and in vivo. These data indicate that annotating rare aberrations can reveal important cancer signalling pathways representing additional therapeutic targets.

Date: 2016
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DOI: 10.1038/ncomms10500

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