Abstract
Massive genome sequencing data have inspired new challenges in personalized treatments and facilitated oncological drug discovery. We present a comprehensive database, My Personal Mutanome (MPM), for accelerating the development of precision cancer medicine protocols. MPM contains 490,245 mutations from over 10,800 tumor exomes across 33 cancer types in The Cancer Genome Atlas mapped to 94,563 structure-resolved/predicted protein-protein interaction interfaces (“edgetic”) and 311,022 functional sites (“nodetic”), including ligand-protein binding sites and 8 types of protein posttranslational modifications. In total, 8884 survival results and 1,271,132 drug responses are obtained for these mapped interactions. MPM is available at https://mutanome.lerner.ccf.org.
Highlights
Recent advances in high-throughput sequencing have led to the availability of hundreds of thousands of exomes and genomes, which contain billions of singlenucleotide variants including millions of missense variants [1, 2]
Database overview We have assembled and processed all the data, including 21,759 proteins, 490,245 somatic mutations, and 544,692 mutation cases, 121,172 protein-protein interactions (PPIs), drug responses of 251 drugs tested in 1074 cancer cell lines, 41,843 PDBs, and 535,182 protein functional sites for protein-ligand binding and across 7 types of protein post-translational modifications (PTMs): acetylation, malonylation, methylation, o-linked glycosylation, phosphorylation, succinylation, ubiquitination (Table 1)
We found that somatic missense mutations are significantly enriched in ligandbinding sites (Additional file 1: Fig. S2) and phosphorylation sites (Additional file 1: Fig. S3) compared to non-ligand-binding sites and non-phosphorylation sites, respectively, across all 33 cancer types/subtypes, which are consistent with our previous findings [12,13,14]
Summary
Recent advances in high-throughput sequencing have led to the availability of hundreds of thousands of exomes and genomes, which contain billions of singlenucleotide variants including millions of missense variants [1, 2]. Recent ongoing community efforts have completed the mapping of the human interactome and provided the increasing availability of structural genomic information on PPIs from diverse sources including the PDB [16], Interactome INSIDER [17], and Interactome3D [18] These protein structural genomic resources offer unexpected opportunities for accelerating interpretation of biological and functional consequences of cancer mutations for precision cancer medicine from systems biology perspectives [6, 19]. MPM offers three interactive visualization tools that provide 3D views of somatic mutations in the context of the human interactome network (nodetic and edgetic) with their clinical (survival) and drug responses. MPM is expected to facilitate the identification of actionable mutations for tumorigenesis and personalized treatments at the human interactome level It offers network-based diagnosis and pharmacogenomics approaches to understand complex genotype-phenotype relationships and therapeutic responses in the clinical settings.
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