5,181 research outputs found

    Typing tumors using pathways selected by somatic evolution.

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    Many recent efforts to analyze cancer genomes involve aggregation of mutations within reference maps of molecular pathways and protein networks. Here, we find these pathway studies are impeded by molecular interactions that are functionally irrelevant to cancer or the patient's tumor type, as these interactions diminish the contrast of driver pathways relative to individual frequently mutated genes. This problem can be addressed by creating stringent tumor-specific networks of biophysical protein interactions, identified by signatures of epistatic selection during tumor evolution. Using such an evolutionarily selected pathway (ESP) map, we analyze the major cancer genome atlases to derive a hierarchical classification of tumor subtypes linked to characteristic mutated pathways. These pathways are clinically prognostic and predictive, including the TP53-AXIN-ARHGEF17 combination in liver and CYLC2-STK11-STK11IP in lung cancer, which we validate in independent cohorts. This ESP framework substantially improves the definition of cancer pathways and subtypes from tumor genome data

    Algorithmic methods to infer the evolutionary trajectories in cancer progression

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    The genomic evolution inherent to cancer relates directly to a renewed focus on the voluminous next-generation sequencing data and machine learning for the inference of explanatory models of how the (epi)genomic events are choreographed in cancer initiation and development. However, despite the increasing availability of multiple additional -omics data, this quest has been frustrated by various theoretical and technical hurdles, mostly stemming from the dramatic heterogeneity of the disease. In this paper, we build on our recent work on the 'selective advantage' relation among driver mutations in cancer progression and investigate its applicability to the modeling problem at the population level. Here, we introduce PiCnIc (Pipeline for Cancer Inference), a versatile, modular, and customizable pipeline to extract ensemble-level progression models from cross-sectional sequenced cancer genomes. The pipeline has many translational implications because it combines state-of-the-art techniques for sample stratification, driver selection, identification of fitness-equivalent exclusive alterations, and progression model inference. We demonstrate PiCnIc's ability to reproduce much of the current knowledge on colorectal cancer progression as well as to suggest novel experimentally verifiable hypotheses

    Automatic categorization of abstracts through Bayesian networks

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    This thesis presents a method for assigning abstracts of Artificial Intelligence papers to their area of the field. The technique is implemented by the use of a Bayesian network where relevant keywords extracted from the abstract being categorized, are entered as evidence and inferencing is made to determine potential subject areas. The structure of the Bayesian network represents the causal relationship between Artificial Intelligence keywords and subject areas. Keyword components of the network are selected from precategorized abstracts. The work reported here is part of a larger project to automatically assign papers to reviewers for Artificial Intelligence conferences. The process of assigning papers to reviewers begins by using the inference system reported here to derive Artificial Intelligence subject areas for such papers. Based on those subjects, another module can select reviewers according to their specialization and limited by conflicts of interest
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