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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.

SUBMITTER: Tsang YH

PROVIDER: S-EPMC4737758 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Functional annotation of rare gene aberration drivers of pancreatic cancer.

Tsang Yiu Huen YH Dogruluk Turgut T Tedeschi Philip M PM Wardwell-Ozgo Joanna J Lu Hengyu H Espitia Maribel M Nair Nikitha N Minelli Rosalba R Chong Zechen Z Chen Fengju F Chang Qing Edward QE Dennison Jennifer B JB Dogruluk Armel A Li Min M Ying Haoqiang H Bertino Joseph R JR Gingras Marie-Claude MC Ittmann Michael M Kerrigan John J Chen Ken K Creighton Chad J CJ Eterovic Karina K Mills Gordon B GB Scott Kenneth L KL

Nature communications 20160125

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 ge ...[more]

PMID: 26806015

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Project description:Breast cancer biological characteristics change as age advances. Today, there is a lack of knowledge regarding age-specific molecular alterations that characterize breast tumours, notably in elderly patients. The vast majority of studies that aimed at exploring breast cancer in function of age are based on clinico-pathological data. Gene-expression signatures (GES), which in some ways capture biological information in a non-reductionist manner, represent powerful tools able to explore tumour heterogeneity.Twenty-five GES were used for functional annotation of breast tumours in function of age: five for molecular subtyping, seven for immune response, three for metabolism, seven for critical pathways in cancer and three for prognosis. Affymetrix® genomics datasets were exclusively used to avoid cross-platform normalization issues. Available corresponding clinico-pathological data were also retrieved and analysed.Fifteen publicly available datasets were pooled for a total of 2378 breast cancer patients (whole cohort), out of whom 1413 were of Caucasian origin. Three age groups were defined: ? 40 years (AG1), > 40 to < 70 years (AG2) and ? 70 years (AG3). We confirmed that age influenced the incidence of molecular subtypes. We found a significant growing incidence of luminal B and a decreasing kinetics for basal-like in function of age. We showed that AG3 luminal B tumours were less aggressive than AG1 luminal B tumours based on different GES (iron metabolism, mitochondrial oxidative phosphorylation and reactive stroma), recurrence score prognostic GES and histological grade (SBR). Contrary to tumours of young patients, tumours of elderly patients concentrated favourable GES scores: high oestrogen receptor and mitochondrial oxidative phosphorylation, low proliferation, basal-like, glycolysis, chromosomal instability and iron metabolism, and low GES prognostic scores (van't Veer 70-GES, genomic grade index and recurrence score).Functional annotation of breast tumours by means of 25 GES demonstrated a decreasing aggressiveness of breast tumours in function of age. This strategy, which can be strengthened by increasing the number of representative GES to gain more insight into biological systems involved in this disease, provides a framework to develop rational therapeutic strategies in function of age.

Dataset Information

Functional annotation of rare gene aberration drivers of pancreatic cancer.

Publications

Functional annotation of rare gene aberration drivers of pancreatic cancer.

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