Dataset Information

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types.

ABSTRACT: Protein ubiquitination is a dynamic and reversible process of adding single ubiquitin molecules or various ubiquitin chains to target proteins. Here, using multidimensional omic data of 9,125 tumor samples across 33 cancer types from The Cancer Genome Atlas, we perform comprehensive molecular characterization of 929 ubiquitin-related genes and 95 deubiquitinase genes. Among them, we systematically identify top somatic driver candidates, including mutated FBXW7 with cancer-type-specific patterns and amplified MDM2 showing a mutually exclusive pattern with BRAF mutations. Ubiquitin pathway genes tend to be upregulated in cancer mediated by diverse mechanisms. By integrating pan-cancer multiomic data, we identify a group of tumor samples that exhibit worse prognosis. These samples are consistently associated with the upregulation of cell-cycle and DNA repair pathways, characterized by mutated TP53, MYC/TERT amplification, and APC/PTEN deletion. Our analysis highlights the importance of the ubiquitin pathway in cancer development and lays a foundation for developing relevant therapeutic strategies.

SUBMITTER: Ge Z

PROVIDER: S-EPMC5916807 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types.

Ge Zhongqi Z Leighton Jake S JS Wang Yumeng Y Peng Xinxin X Chen Zhongyuan Z Chen Hu H Sun Yutong Y Yao Fan F Li Jun J Zhang Huiwen H Liu Jianfang J Shriver Craig D CD Hu Hai H Piwnica-Worms Helen H Ma Li L Liang Han H

Cell reports 20180401 1

Protein ubiquitination is a dynamic and reversible process of adding single ubiquitin molecules or various ubiquitin chains to target proteins. Here, using multidimensional omic data of 9,125 tumor samples across 33 cancer types from The Cancer Genome Atlas, we perform comprehensive molecular characterization of 929 ubiquitin-related genes and 95 deubiquitinase genes. Among them, we systematically identify top somatic driver candidates, including mutated FBXW7 with cancer-type-specific patterns ...[more]

PMID: 29617661

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Project description:According to the National Comprehensive Cancer Network and the American Society of Clinical Oncology, the standard treatment for pancreatic cancer (PC) is gemcitabine and fluorouracil. Other chemotherapeutic agents have been widely combined. However, drug resistance remains a huge challenge, leading to the ineffectiveness of cancer therapy. Therefore, we are trying to discover new treatments for PC by utilizing genomic information to identify PC-associated genes as well as drug target genes for drug repurposing. Genomic information from a public database, the cBio Cancer Genomics Portal, was employed to retrieve the somatic mutation genes of PC. Five functional annotations were applied to prioritize the PC risk genes: Kyoto Encyclopedia of Genes and Genomes; biological process; knockout mouse; Gene List Automatically Derived For You; and Gene Expression Omnibus Dataset. DrugBank database was utilized to extract PC drug targets. To narrow down the most promising drugs for PC, CMap Touchstone analysis was applied. Finally, ClinicalTrials.gov and a literature review were used to screen the potential drugs under clinical and preclinical investigation. Here, we extracted 895 PC-associated genes according to the cBioPortal database and prioritized them by using five functional annotations; 318 genes were assigned as biological PC risk genes. Further, 216 genes were druggable according to the DrugBank database. CMap Touchstone analysis indicated 13 candidate drugs for PC. Among those 13 drugs, 8 drugs are in the clinical trials, 2 drugs were supported by the preclinical studies, and 3 drugs are with no evidence status for PC. Importantly, we found that midostaurin (targeted PRKA) and fulvestrant (targeted ESR1) are promising candidate drugs for PC treatment based on the genomic-driven drug repurposing pipelines. In short, integrated analysis using a genomic information database demonstrated the viability for drug repurposing. We proposed two drugs (midostaurin and fulvestrant) as promising drugs for PC.

Dataset Information

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types.

Publications

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types.

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