Identification of conserved evolutionary trajectories in tumors.

MOTIVATION: As multi-region, time-series and single-cell sequencing data become more widely available; it is becoming clear that certain tumors share evolutionary characteristics with others. In the last few years, several computational methods have been developed with the goal of inferring the subclonal composition and evolutionary history of tumors from tumor biopsy sequencing data. However, the phylogenetic trees that they report differ significantly between tumors (even those with similar characteristics). RESULTS: In this article, we present a novel combinatorial optimization method, CONETT, for detection of recurrent tumor evolution trajectories. Our method constructs a consensus tree of conserved evolutionary trajectories based on the information about temporal order of alteration events in a set of tumors. We apply our method to previously published datasets of 100 clear-cell renal cell carcinoma and 99 non-small-cell lung cancer patients and identify both conserved trajectories that were reported in the original studies, as well as new trajectories. AVAILABILITY AND IMPLEMENTATION: CONETT is implemented in C++ and available at https://github.com/ehodzic/CONETT. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

HIT'nDRIVE: patient-specific multidriver gene prioritization for precision oncology.

Prioritizing molecular alterations that act as drivers of cancer remains a crucial bottleneck in therapeutic development. Here we introduce HIT'nDRIVE, a computational method that integrates genomic and transcriptomic data to identify a set of patient-specific, sequence-altered genes, with sufficient collective influence over dysregulated transcripts. HIT'nDRIVE aims to solve the "random walk facility location" (RWFL) problem in a gene (or protein) interaction network, which differs from the standard facility location problem by its use of an alternative distance measure: "multihitting time," the expected length of the shortest random walk from any one of the set of sequence-altered genes to an expression-altered target gene. When applied to 2200 tumors from four major cancer types, HIT'nDRIVE revealed many potentially clinically actionable driver genes. We also demonstrated that it is possible to perform accurate phenotype prediction for tumor samples by only using HIT'nDRIVE-seeded driver gene modules from gene interaction networks. In addition, we identified a number of breast cancer subtype-specific driver modules that are associated with patients' survival outcome. Furthermore, HIT'nDRIVE, when applied to a large panel of pan-cancer cell lines, accurately predicted drug efficacy using the driver genes and their seeded gene modules. Overall, HIT'nDRIVE may help clinicians contextualize massive multiomics data in therapeutic decision making, enabling widespread implementation of precision oncology.

Mutational Signatures as Sensors of Environmental Exposures: Analysis of Smoking-Induced Lung Tissue Remodeling.

Smoking is a widely recognized risk factor in the emergence of cancers and other lung diseases. Studies of non-cancer lung diseases typically investigate the role that smoking has in chronic changes in lungs that might predispose patients to the diseases, whereas most cancer studies focus on the mutagenic properties of smoking. Large-scale cancer analysis efforts have collected expression data from both tumor and control lung tissues, and studies have used control samples to estimate the impact of smoking on gene expression. However, such analyses may be confounded by tumor-related micro-environments as well as patient-specific exposure to smoking. Thus, in this paper, we explore the utilization of mutational signatures to study environment-induced changes of gene expression in control lung tissues from lung adenocarcinoma samples. We show that a joint computational analysis of mutational signatures derived from sequenced tumor samples, and the gene expression obtained from control samples, can shed light on the combined impact that smoking and tumor-related micro-environments have on gene expression and cell-type composition in non-neoplastic (control) lung tissue. The results obtained through such analysis are both supported by experimental studies, including studies utilizing single-cell technology, and also suggest additional novel insights. We argue that the study provides a proof of principle of the utility of mutational signatures to be used as sensors of environmental exposures not only in the context of the mutational landscape of cancer, but also as a reference for changes in non-cancer lung tissues. It also provides an example of how a database collected with the purpose of understanding cancer can provide valuable information for studies not directly related to the disease.

Combinatorial Detection of Conserved Alteration Patterns for Identifying Cancer Subnetworks.

BACKGROUND: Advances in large-scale tumor sequencing have led to an understanding that there are combinations of genomic and transcriptomic alterations specific to tumor types, shared across many patients. Unfortunately, computational identification of functionally meaningful and recurrent alteration patterns within gene/protein interaction networks has proven to be challenging. FINDINGS: We introduce a novel combinatorial method, cd-CAP (combinatorial detection of conserved alteration patterns), for simultaneous detection of connected subnetworks of an interaction network where genes exhibit conserved alteration patterns across tumor samples. Our method differentiates distinct alteration types associated with each gene (rather than relying on binary information of a gene being altered or not) and simultaneously detects multiple alteration profile conserved subnetworks. CONCLUSIONS: In a number of The Cancer Genome Atlas datasets, cd-CAP identified large biologically significant subnetworks with conserved alteration patterns, shared across many tumor samples.