Pathogenic Germline Variants in 10,389 Adult Cancers.

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.

Phase transitions in evolutionary dynamics.

Sharp changes in state, such as transitions from survival to extinction, are hallmarks of evolutionary dynamics in biological systems. These transitions can be explored using the techniques of statistical physics and the physics of nonlinear and complex systems. For example, a survival-to-extinction transition can be characterized as a non-equilibrium phase transition to an absorbing state. Here, we review the literature on phase transitions in evolutionary dynamics. We discuss directed percolation transitions in cellular automata and evolutionary models, and models that diverge from the directed percolation universality class. We explore in detail an example of an absorbing phase transition in an agent-based model of evolutionary dynamics, including previously unpublished data demonstrating similarity to, but also divergence from, directed percolation, as well as evidence for phase transition behavior at multiple levels of the model system's evolutionary structure. We discuss phase transition models of the error catastrophe in RNA virus dynamics and phase transition models for transition from chemistry to biochemistry, i.e., the origin of life. We conclude with a review of phase transition dynamics in models of natural selection, discuss the possible role of phase transitions in unraveling fundamental unresolved questions regarding multilevel selection and the major evolutionary transitions, and assess the future outlook for phase transitions in the investigation of evolutionary dynamics.

Regulated Phosphosignaling Associated with Breast Cancer Subtypes and Druggability.

Aberrant phospho-signaling is a hallmark of cancer. We investigated kinase-substrate regulation of 33,239 phosphorylation sites (phosphosites) in 77 breast tumors and 24 breast cancer xenografts. Our search discovered 2134 quantitatively correlated kinase-phosphosite pairs, enriching for and extending experimental or binding-motif predictions. Among the 91 kinases with auto-phosphorylation, elevated EGFR, ERBB2, PRKG1, and WNK1 phosphosignaling were enriched in basal, HER2-E, Luminal A, and Luminal B breast cancers, respectively, revealing subtype-specific regulation. CDKs, MAPKs, and ataxia-telangiectasia proteins were dominant, master regulators of substrate-phosphorylation, whose activities are not captured by genomic evidence. We unveiled phospho-signaling and druggable targets from 113 kinase-substrate pairs and cascades downstream of kinases, including AKT1, BRAF and EGFR. We further identified kinase-substrate-pairs associated with clinical or immune signatures and experimentally validated activated phosphosites of ERBB2, EIF4EBP1, and EGFR. Overall, kinase-substrate regulation revealed by the largest unbiased global phosphorylation data to date connects driver events to their signaling effects.

GenomeVIP: a cloud platform for genomic variant discovery and interpretation.

Identifying genomic variants is a fundamental first step toward the understanding of the role of inherited and acquired variation in disease. The accelerating growth in the corpus of sequencing data that underpins such analysis is making the data-download bottleneck more evident, placing substantial burdens on the research community to keep pace. As a result, the search for alternative approaches to the traditional "download and analyze" paradigm on local computing resources has led to a rapidly growing demand for cloud-computing solutions for genomics analysis. Here, we introduce the Genome Variant Investigation Platform (GenomeVIP), an open-source framework for performing genomics variant discovery and annotation using cloud- or local high-performance computing infrastructure. GenomeVIP orchestrates the analysis of whole-genome and exome sequence data using a set of robust and popular task-specific tools, including VarScan, GATK, Pindel, BreakDancer, Strelka, and Genome STRiP, through a web interface. GenomeVIP has been used for genomic analysis in large-data projects such as the TCGA PanCanAtlas and in other projects, such as the ICGC Pilots, CPTAC, ICGC-TCGA DREAM Challenges, and the 1000 Genomes SV Project. Here, we demonstrate GenomeVIP's ability to provide high-confidence annotated somatic, germline, and de novo variants of potential biological significance using publicly available data sets.

CharGer: clinical Characterization of Germline variants.

SUMMARY: CharGer (Characterization of Germline variants) is a software tool for interpreting and predicting clinical pathogenicity of germline variants. CharGer gathers evidence from databases and annotations, provided by local tools and files or via ReST APIs, and classifies variants according to ACMG guidelines for assessing variant pathogenicity. User-designed pathogenicity criteria can be incorporated into CharGer's flexible framework, thereby allowing users to create a customized classification protocol. AVAILABILITY AND IMPLEMENTATION: Source code is freely available at https://github.com/ding-lab/CharGer and is distributed under the GNU GPL-v3.0 license. Software is also distributed through the Python Package Index (PyPI) repository. CharGer is implemented in Python 2.7 and is supported on Unix-based operating systems. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Database of evidence for precision oncology portal.

Summary: A database of curated genomic variants with clinically supported drug therapies and other oncological annotations is described. The accompanying web portal provides a search engine with two modes: one that allows users to query gene, cancer type, variant type or position for druggable mutations, and another to search for and to visualize, on three-dimensional protein structures, putative druggable sites that cluster with known druggable mutations. Availability and implementation: http://dinglab.wustl.edu/depo.

Spatially interacting phosphorylation sites and mutations in cancer.

Advances in mass-spectrometry have generated increasingly large-scale proteomics datasets containing tens of thousands of phosphorylation sites (phosphosites) that require prioritization. We develop a bioinformatics tool called HotPho and systematically discover 3D co-clustering of phosphosites and cancer mutations on protein structures. HotPho identifies 474 such hybrid clusters containing 1255 co-clustering phosphosites, including RET p.S904/Y928, the conserved HRAS/KRAS p.Y96, and IDH1 p.Y139/IDH2 p.Y179 that are adjacent to recurrent mutations on protein structures not found by linear proximity approaches. Hybrid clusters, enriched in histone and kinase domains, frequently include expression-associated mutations experimentally shown as activating and conferring genetic dependency. Approximately 300 co-clustering phosphosites are verified in patient samples of 5 cancer types or previously implicated in cancer, including CTNNB1 p.S29/Y30, EGFR p.S720, MAPK1 p.S142, and PTPN12 p.S275. In summary, systematic 3D clustering analysis highlights nearly 3,000 likely functional mutations and over 1000 cancer phosphosites for downstream investigation and evaluation of potential clinical relevance.

Multiple phase transitions in an agent-based evolutionary model with neutral fitness.

Null models are crucial for understanding evolutionary processes such as speciation and adaptive radiation. We analyse an agent-based null model, considering a case without selection-neutral evolution-in which organisms are defined only by phenotype. Universal dynamics has previously been demonstrated in a related model on a neutral fitness landscape, showing that this system belongs to the directed percolation (DP) universality class. The traditional null condition of neutral fitness (where fitness is defined as the number of offspring each organism produces) is extended here to include equal probability of death among organisms. We identify two types of phase transition: (i) a non-equilibrium DP transition through generational time (i.e. survival), and (ii) an equilibrium ordinary percolation transition through the phenotype space (based on links between mating organisms). Owing to the dynamical rules of the DP reaction-diffusion process, organisms can only sparsely fill the phenotype space, resulting in significant phenotypic diversity within a cluster of mating organisms. This highlights the necessity of understanding hierarchical evolutionary relationships, rather than merely developing taxonomies based on phenotypic similarity, in order to develop models that can explain phylogenetic patterns found in the fossil record or to make hypotheses for the incomplete fossil record of deep time.

Protein-structure-guided discovery of functional mutations across 19 cancer types.

Local concentrations of mutations are well known in human cancers. However, their three-dimensional spatial relationships in the encoded protein have yet to be systematically explored. We developed a computational tool, HotSpot3D, to identify such spatial hotspots (clusters) and to interpret the potential function of variants within them. We applied HotSpot3D to >4,400 TCGA tumors across 19 cancer types, discovering >6,000 intra- and intermolecular clusters, some of which showed tumor and/or tissue specificity. In addition, we identified 369 rare mutations in genes including TP53, PTEN, VHL, EGFR, and FBXW7 and 99 medium-recurrence mutations in genes such as RUNX1, MTOR, CA3, PI3, and PTPN11, all mapping within clusters having potential functional implications. As a proof of concept, we validated our predictions in EGFR using high-throughput phosphorylation data and cell-line-based experimental evaluation. Finally, mutation-drug cluster and network analysis predicted over 800 promising candidates for druggable mutations, raising new possibilities for designing personalized treatments for patients carrying specific mutations.