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; Kenneth L Scott

doi:10.1038/ncomms10500

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Functional annotation of rare gene aberration drivers of pancreatic cancer

Journal article

Open access

Peer reviewed

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, …

Nature communications, Vol.7(1), pp.10500-10500

01/25/2016

DOI: https://doi.org/10.1038/ncomms10500

PMCID: PMC4737758

PMID: 26806015

Abstract

Animals

Carcinogenesis

Cell Line, Tumor

Female

Humans

Mice

Mice, Nude

Pancreatic Neoplasms - enzymology

Pancreatic Neoplasms - genetics

Pancreatic Neoplasms - metabolism

Pancreatic Neoplasms - pathology

Phosphotransferases (Alcohol Group Acceptor) - genetics

Reactive Oxygen Species - metabolism

Mutation

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.

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Title: Functional annotation of rare gene aberration drivers of pancreatic cancer
Creators: Yiu Huen Tsang - Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
Turgut Dogruluk - Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
Philip M Tedeschi - Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, New Jersey 08903, USA
Joanna Wardwell-Ozgo - Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
Hengyu Lu - Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
Maribel Espitia - Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Nikitha Nair - Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
Rosalba Minelli - Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
Zechen Chong - Department of Bioinformatics and Computational Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Fengju Chen - Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
Qing Edward Chang - Department of Genomics Medicine, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Jennifer B Dennison - Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Armel Dogruluk - Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
Min Li - Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
Haoqiang Ying - Department of Genomics Medicine, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Joseph R Bertino - Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, New Jersey 08903, USA
Marie-Claude Gingras - Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
Michael Ittmann - Department of Pathology and Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
John Kerrigan - Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, New Jersey 08903, USA
Ken Chen - Department of Bioinformatics and Computational Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Chad J Creighton - Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
Karina Eterovic - Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Gordon B Mills - Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Kenneth L Scott - Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
Publication Details: Nature communications, Vol.7(1), pp.10500-10500
Date published: 01/25/2016
Grant note: R01CA138701 / NCI NIH HHS P30 CA016672 / NCI NIH HHS P30CA125123 / NCI NIH HHS P30 CA125123 / NCI NIH HHS R01 CA138701 / NCI NIH HHS U01 CA168394 / NCI NIH HHS U01CA168394 / NCI NIH HHS
Academic Unit: Graduate School of Biomedical Sciences - Newark; Bertino Office
Language: English
Resource Type: Journal article
Identifiers: 991031665734804646