A comprehensive overview of oncogenic pathways in human cancer

Alterations of biological pathways can lead to oncogenesis. An overview of these oncogenic pathways would be highly valuable for researchers to reveal the pathogenic mechanism and develop novel therapeutic approaches for cancers. Here, we reviewed approximately 8500 literatures and documented experimentally validated cancer-pathway associations as benchmarking data set. This data resource includes 4709 manually curated relationships between 1557 paths and 49 cancers with 2427 upstream regulators in 7 species. Based on this resource, we first summarized the cancer-pathway associations and revealed some commonly deregulated pathways across tumor types. Then, we systematically analyzed these oncogenic pathways by integrating TCGA pan-cancer data sets. Multi-omics analysis showed oncogenic pathways may play different roles across tumor types under different omics contexts. We also charted the survival relevance landscape of oncogenic pathways in 26 tumor types, identified dominant omics features and found survival relevance for oncogenic pathways varied in tumor types and omics levels. Moreover, we predicted upstream regulators and constructed a hierarchical network model to understand the pathogenic mechanism of human cancers underlying oncogenic pathway context. Finally, we developed `CPAD' (freely available at http://bio-bigdata.hrbmu.edu.cn/CPAD/), an online resource for exploring oncogenic pathways in human cancers, that integrated manually curated cancer-pathway associations, TCGA pan-cancer multi-omics data sets, drug-target data, drug sensitivity and multi-omics data for cancer cell lines. In summary, our study provides a comprehensive characterization of oncogenic pathways and also presents a valuable resource for investigating the pathogenesis of human cancer.

[1]  Russ B. Altman,et al.  Missing value estimation methods for DNA microarrays , 2001, Bioinform..

[2]  Kaleigh Fernald,et al.  Evading apoptosis in cancer. , 2013, Trends in cell biology.

[3]  Howard Y. Chang,et al.  Long Noncoding RNAs in Cancer Pathways. , 2016, Cancer cell.

[4]  Kun-Liang Guan,et al.  Mechanisms of Hippo pathway regulation , 2016, Genes & development.

[5]  Michal Sheffer,et al.  Pathway-based personalized analysis of cancer , 2013, Proceedings of the National Academy of Sciences.

[6]  Rebecca L. Siegel Mph,et al.  Cancer statistics, 2018 , 2018 .

[7]  Susumu Goto,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 2000, Nucleic Acids Res..

[8]  Weiying Zhou,et al.  Breast cancer-secreted miR-122 reprograms glucose metabolism in pre-metastatic niche to promote metastasis , 2015, Nature Cell Biology.

[9]  Gregory P. Way,et al.  Machine Learning Detects Pan-cancer Ras Pathway Activation in The Cancer Genome Atlas , 2018, Cell reports.

[10]  Mark A Feitelson,et al.  Sustained proliferation in cancer: Mechanisms and novel therapeutic targets. , 2015, Seminars in cancer biology.

[11]  Adam A. Margolin,et al.  The Cancer Cell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity , 2012, Nature.

[12]  Yun Ye,et al.  Construction and analysis of mRNA, miRNA, lncRNA, and TF regulatory networks reveal the key genes associated with prostate cancer , 2018, PloS one.

[13]  William C Reinhold,et al.  CellMiner: a relational database and query tool for the NCI-60 cancer cell lines , 2009, BMC Genomics.

[14]  Hiroko K. Solvang,et al.  Linear and non-linear dependencies between copy number aberrations and mRNA expression reveal distinct molecular pathways in breast cancer , 2011, BMC Bioinformatics.

[15]  Yuan Yuan,et al.  MicroRNA‐590‐5p functions as a tumor suppressor in breast cancer conferring inhibitory effects on cell migration, invasion, and epithelial–mesenchymal transition by downregulating the Wnt–β‐catenin signaling pathway , 2018, Journal of cellular physiology.

[16]  Brämer Gr.  International statistical classification of diseases and related health problems. Tenth revision. , 1988, World health statistics quarterly. Rapport trimestriel de statistiques sanitaires mondiales.

[17]  Ugur Dogrusoz,et al.  PathwayMapper: a collaborative visual web editor for cancer pathways and genomic data , 2017, Bioinform..

[18]  David S. Wishart,et al.  DrugBank 5.0: a major update to the DrugBank database for 2018 , 2017, Nucleic Acids Res..

[19]  Andrew E. Teschendorff,et al.  Tissue-independent and tissue-specific patterns of DNA methylation alteration in cancer , 2016, Epigenetics & Chromatin.

[20]  Ervin H. Epstein,et al.  Posaconazole, a Second-Generation Triazole Antifungal Drug, Inhibits the Hedgehog Signaling Pathway and Progression of Basal Cell Carcinoma , 2016, Molecular Cancer Therapeutics.

[21]  Yibo Wu,et al.  GOSemSim: an R package for measuring semantic similarity among GO terms and gene products , 2010, Bioinform..

[22]  O. Franco,et al.  Optimal database combinations for literature searches in systematic reviews: a prospective exploratory study , 2017, Systematic Reviews.

[23]  Steven J. M. Jones,et al.  Oncogenic Signaling Pathways in The Cancer Genome Atlas. , 2018, Cell.

[24]  Min Shi,et al.  Long noncoding RNA DGCR5 represses hepatocellular carcinoma progression by inactivating Wnt signaling pathway , 2018, Journal of cellular biochemistry.

[25]  Taesung Park,et al.  Association between mutations of critical pathway genes and survival outcomes according to the tumor location in colorectal cancer , 2017, Cancer.

[26]  William C Reinhold,et al.  Integrating data on DNA copy number with gene expression levels and drug sensitivities in the NCI-60 cell line panel , 2006, Molecular Cancer Therapeutics.

[27]  Hu Chen,et al.  Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types. , 2018, Cell reports.

[28]  Margit Rosner,et al.  Human stem cells alter the invasive properties of somatic cells via paracrine activation of mTORC1 , 2017, Nature Communications.

[29]  Leng Han,et al.  Comprehensive Molecular Characterization of the Hippo Signaling Pathway in Cancer , 2018, Cell reports.

[30]  Ilya Mazo,et al.  Clustering Gene Expression Regulators: New Approach to Disease Subtyping , 2014, PloS one.

[31]  Lovelace J. Luquette,et al.  A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations. , 2017, Cancer cell.

[32]  Fang Wang,et al.  Inhibitory role of large intergenic noncoding RNA‐ROR on tamoxifen resistance in the endocrine therapy of breast cancer by regulating the PI3K/Akt/mTOR signaling pathway , 2018, Journal of cellular physiology.

[33]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[34]  P. Iengar.  Identifying pathways affected by cancer mutations. , 2017, Genomics.

[35]  A. Jemal,et al.  Cancer statistics, 2018 , 2018, CA: a cancer journal for clinicians.

[36]  David García-Dorado,et al.  TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. , 2009, Cancer cell.

[37]  Ming Lei,et al.  Triptolide Inhibits the AR Signaling Pathway to Suppress the Proliferation of Enzalutamide Resistant Prostate Cancer Cells , 2017, Theranostics.

[38]  Min Pan,et al.  A miRNA-regulatory network explains how dysregulated miRNAs perturb oncogenic processes across diverse cancers , 2012, Genome research.