The Temporal Order of Genetic and Pathway Alterations in Tumorigenesis

Abstract

Cancer evolves through the accumulation of mutations, but the order in which mutations occur is poorly understood. Inference of a temporal ordering on the level of genes is challenging because clinically and histologically identical tumors often have few mutated genes in common. This heterogeneity may at least in part be due to mutations in different genes having similar phenotypic effects by acting in the same functional pathway. We estimate the constraints on the order in which alterations accumulate during cancer progression from cross-sectional mutation data using a probabilistic graphical model termed Hidden Conjunctive Bayesian Network (H-CBN). The possible orders are analyzed on the level of genes and, after mapping genes to functional pathways, also on the pathway level. We find stronger evidence for pathway order constraints than for gene order constraints, indicating that temporal ordering results from selective pressure acting at the pathway level. The accumulation of changes in core pathways differs among cancer types, yet a common feature is that progression appears to begin with mutations in genes that regulate apoptosis pathways and to conclude with mutations in genes involved in invasion pathways. H-CBN models provide a quantitative and intuitive model of tumorigenesis showing that the genetic events can be linked to the phenotypic progression on the level of pathways.

Oncogenic Ras stimulates Eiger/TNF exocytosis to promote growth

“…This is consistent with accumulating data from rodents and patients indicating that signaling events emanating from host/stromal cells promote tumor development (Bremnes et al, 2011;Lu et al, 2013;Mueller and Fusenig, 2004;Sounni and Noel, 2012). Additional significance is derived from recent studies of various solid tumors showing heterogeneity within each tumor (Diaz et al, 2012;Gerlinger et al, 2012;Gerstung et al, 2011;Marusyk and Polyak, 2010).…”

The p53 Protein Does Not Facilitate Adenovirus Type 5 Replication in Normal Human Cells

“…In contrast to these findings, host cell p53 status was not observed to have an effect on Ad5 replication and appearance of CPE when infections of p53 wt (WI38 and HNK [human natural killer]) and p53-null (SK-OV-3 and H1299) cell lines were compared (16). Interpretation of many such studies is complicated by the use of nonisogenic, tumor-derived cell lines that carry numerous, nonequivalent genetic alterations affecting stress responses, cell cycle regulation, and metabolism (17). Furthermore, generation of cells devoid of functional p53 and matched to isogenic parental cells by overproduction of dominant-negative mutant p53 would not be expected to simulate accurately the absence of p53 from the virus's natural host cells.…”

Network-Based Method for Inferring Cancer Progression at the Pathway Level from Cross-Sectional Mutation Data

“…Second, how to detect driver pathways, which are frequently perturbed with a large number of tumor cells, and give rise to the product of tumorigenic properties, such as cell angiogenesis, proliferation or metastasis [1], [2], [3], [12], [13], [14], [15], [16], [17]. Third, how to determine temporal orders of the driver mutations in cancer patients [18], [19], [20], [21], [22]. The first question can usually be solved by comparing mutation frequencies across different individuals [6], [7], [8], [9], [10], [11].…”