title: Functional annotation of rare gene aberration drivers of pancreatic cancer.
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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Yiu Huen
authors.initials: YH
authors.lastname: Tsang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Turgut
authors.initials: T
authors.lastname: Dogruluk
authors.affiliation: Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, New Jersey 08903, USA.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Tedeschi
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Wardwell-Ozgo
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Hengyu
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Maribel
authors.initials: M
authors.lastname: Espitia
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Nikitha
authors.initials: N
authors.lastname: Nair
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Minelli
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Zechen
authors.initials: Z
authors.lastname: Chong
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Fengju
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Genomics Medicine, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Qing Edward
authors.initials: QE
authors.lastname: Chang
authors.affiliation: Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Dennison
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Armel
authors.initials: A
authors.lastname: Dogruluk
authors.affiliation: Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Genomics Medicine, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Haoqiang
authors.initials: H
authors.lastname: Ying
authors.affiliation: Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, New Jersey 08903, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Bertino
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gingras
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ittmann
authors.affiliation: Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, New Jersey 08903, USA.
authors.forename: John
authors.initials: J
authors.lastname: Kerrigan
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Chen
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Karina
authors.initials: K
authors.lastname: Eterovic
authors.affiliation: Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Scott
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D017853:Phosphotransferases (Alcohol Group Acceptor); C021844:NAD kinase