A transcriptome and literature guided algorithm for reconstruction of pathways to assess activity of telomere maintenance mechanisms

Abstract

Activation of telomere maintenance mechanisms (TMMs) is a crucial factor for indefinite proliferation of cancer cells. The most common TMM is based on the action of telomerase, but in some cancers telomeres are elongated via homologous recombination based alternative mechanism (ALT). Despite their importance, little is known about TMM regulation and factors responsible for TMM phenotype choice in different cells. Currently, many studies address the involvement of few genes in TMMs, but a consensus unified picture of the full process is missing.We have developed a computational biology framework combining knowledge-and data-driven approaches to aid in understanding of TMMs. It is based on a greedy algorithm with three core modules: (1) knowledge-based construction/modification of molecular pathways for telomerase-dependent and alternative TMMs, (2) coupled with gene expression data-based validation with an in-house pathway signal flow (PSF) algorithm, and (3) iteration of these two coupled steps until converging at pathway topologies that best reflect state of the art knowledge and are in maximum accordance with the data. We have used gene expression data derived from cell lines and tumor tissues and have performed extensive literature search and multiple cycles of greedy iterations until reaching TMM assessment accuracy of 100% and 77%, respectively.Availability of TMM pathways that best reflect recent knowledge and data will facilitate better understanding of TMM processes. As novel experimental findings in TMM biology emerge, and new datasets are generated, our approach may be used to further expand/improve the pathways, possibly allowing for making distinctions not only between telomerase-dependent and ALT TMMs, but also among their different subtypes. Moreover, this method may be used

Telomere Length Maintenance and Its Transcriptional Regulation in Lynch Syndrome and Sporadic Colorectal Carcinoma

“…Concerted activation of TMM, mismatch-repair, cell cycle and apoptosis related gene sets in cells with high proliferative activity inherently imply that unsupervised analyses of gene expression, e.g., based on correlation with MTL, usually reveal not only canonical TMM genes, but also a large number of genes involved in other cellular programs. To avoid these interferences of mostly unknown background, we focus on a set of genes involved in TMM pathways which have previously been selected based on literature reports and reference gene expression data (53).…”

“…For detailed supervised analysis on telomere maintenance mechanisms, we make use of previously constructed TMM pathways describing (i) the “classical” TMM that is governed by the catalytic action of the telomerase enzyme (TEL), and (ii) the alternative TMM (ALT) which is realized through homologous recombination events [Supplementary Figure 7, (53) and references cited therein]. These pathways decompose into sub-processes that concertedly affect the activity of the TEL- or ALT-TMMs (Figures 3A,B).…”

“…Schematic representation of the TEL (A) and ALT (B) TMM pathways and their mean PSF-activation patterns averaged over the tumors of each CRC subtype (C–H) . The most relevant genes acting either as activators or suppressors are listed in each of the nodes [see (53) for details]. The color of the nodes in part (A,B) codes the respective genes and processes throughout the paper.…”

“…The activity of these pathways was estimated with the pathway signal flow (PSF) algorithm (53, 55, 56). The algorithm considers expression values of the genes and their mutual interactions to estimate the pathway activity in terms of PSF-scores in each the individual sample, as well as PSF-activities of each individual pathway node.…”

“…The genes and pathways involved in TEL and ALT TMM were taken from a literature search and pathway reconstruction approach using reference gene expression data in TEL- and ALT-positive cell systems [see (53, 54) and Supplementary Methods for details]. A list of TMM genes is provided in Supplementary Table 1 together with two independent verifications by means of enrichment analysis in gene ontology categories (Supplementary Table 2) and their characteristics as provided by TELNet telomere knowledge base (Supplementary Table 3).…”