Tissue-Specific Signaling Networks Rewired by Major Somatic Mutations in Human Cancer Revealed by Proteome-Wide Discovery

Abstract

Massive somatic mutations discovered by large cancer genome sequencing projects provide unprecedented opportunities in the development of precision oncology. However, deep understanding of functional consequences of somatic mutations and identifying actionable mutations and the related drug responses currently remain formidable challenges. Dysfunction of protein post-translational modification plays critical roles in tumorigenesis and drug responses. In this study, we proposed a novel computational oncoproteomics approach, named kinome-wide network module for cancer pharmacogenomics (KNMPx), for identifying actionable mutations that rewired signaling networks and further characterized tumorigenesis and anticancer drug responses. Specifically, we integrated 746,631 missense mutations in 4,997 tumor samples across 16 major cancer types/subtypes from The Cancer Genome Atlas into over 170,000 carefully curated non-redundant phosphorylation sites covering 18,610 proteins. We found 47 mutated proteins (e.g., ERBB2, TP53, and CTNNB1) that had enriched missense mutations at their phosphorylation sites in pan-cancer analysis. In addition, tissue-specific kinase-substrate interaction modules altered by somatic mutations identified by KNMPx were significantly associated with patient survival. We further reported a kinome-wide landscape of pharmacogenomic interactions by incorporating somatic mutation-rewired signaling networks in 1,001 cancer cell lines via KNMPx. Interestingly, we found that cell lines could highly reproduce oncogenic phosphorylation site mutations identified in primary tumors, supporting the confidence in their associations with sensitivity/resistance of inhibitors targeting EGF, MAPK, PI3K, mTOR, and Wnt signaling pathways. In summary, our KNMPx approach is powerful for identifying oncogenic alterations via rewiring phosphorylation-related signaling networks and drug sensitivity/resistance in the era of precision oncology.

Conformational Dynamics and Allosteric Regulation Landscapes of Germline PTEN Mutations Associated with Autism Compared to Those Associated with Cancer

“…We collected significantly somatically mutated genes from The Cancer Genome Atlas (TCGA) projects, as described in the previous studies. 38,42 In addition, we collected known cancerassociated genes (germline-mutation-related) from four public databases: the Online Mendelian Inheritance in Man (OMIM) database, 43 the HuGE Navigator, 44 PharmGKB, 45 and the Comparative Toxicogenomics Database (CTD), 46 as described in our recent study. 39 Here, we used a network proximity measure for quantifying network-based relationships between PTEN influencers and ASDrelated genes or cancer genes from the human protein-protein interactome.…”

Distinct telomere length and molecular signatures in seminoma and non-seminoma of testicular germ cell tumor

“…The significance level of pathways was set to FDR (Benjamini-Hochberg) < 0.05. For the candidates of TL-associated genes, we executed Reactome Analyze Data tool (http://reactome.org/PathwayBrowser/#TOOL¼AT) to define related pathways based on Reactome pathway database (version 61), and pathways with FDR (Benjamini-Hochberg) < 0.05 were considered significant [23].…”

An integrative functional genomics framework for effective identification of novel regulatory variants in genome–phenome studies

“…We also collected human phosphorylation site information from the PhosphoSitePlus [ 26 ] and dbPTM3 databases [ 27 ]. The detailed data preparation for phosphorylation sites was described in our previous studies [ 28 , 29 ]. In total, we obtained 173,460 non-redundant phosphorylation sites on 18,610 proteins.…”