Nat Commun. 2016 Jan 25;7:10500. doi: 10.1038/ncomms10500.

Functional annotation of rare gene aberration drivers of pancreatic cancer.

Tsang YH¹, Dogruluk T¹, Tedeschi PM², Wardwell-Ozgo J¹, Lu H¹, Espitia M³, Nair N¹, Minelli R¹, Chong Z⁴, Chen F⁵, Chang QE⁶, Dennison JB³, Dogruluk A¹, Li M⁷, Ying H⁶, Bertino JR², Gingras MC^1,⁸, Ittmann M⁹, Kerrigan J², Chen K⁴, Creighton CJ^5,¹⁰, Eterovic K³, Mills GB³, Scott KL^1,⁵.

Author information

1: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
2: Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, New Jersey 08903, USA.
3: Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
4: Department of Bioinformatics and Computational Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
5: Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
6: Department of Genomics Medicine, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
7: Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
8: Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
9: Department of Pathology and Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
10: Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.

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.