naa a22 4500 528787012 20180924065502.0 cr unu---uuuuu 180924e20111101xx s 000 0 eng 10.3929/ethz-b-000041069 doi 10.1371/journal.pone.0027136 doi (ETHRESEARCH)oai:www.research-collection.ethz.ch:20.500.11850/41069 The Temporal Order of Genetic and Pathway Alterations in Tumorigenesis [Elektronische Daten] [Moritz Gerstung, Nicholas Eriksson, Jimmy Lin, Bert Vogelstein, Niko Beerenwinkel] PLoS ONE Open access ethresearch 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. Creative Commons Attribution 3.0 Unported http://creativecommons.org/licenses/by/3.0 ethresearch Gerstung Moritz joint author Eriksson Nicholas joint author Lin Jimmy joint author Vogelstein Bert joint author Beerenwinkel Niko joint author PLoS ONE Public Library of Science 6 (11), p. e27136 1932-6203 http://hdl.handle.net/20.500.11850/41069 text/html WWW-Backlink auf das Repository (Open access) 1 Journal Article ethresearch ETHRESEARCH 856 40 http://hdl.handle.net/20.500.11850/41069 text/html WWW-Backlink auf das Repository (Open access) ETHRESEARCH 700 1- Gerstung Moritz joint author ETHRESEARCH 700 1- Eriksson Nicholas joint author ETHRESEARCH 700 1- Lin Jimmy joint author ETHRESEARCH 700 1- Vogelstein Bert joint author ETHRESEARCH 700 1- Beerenwinkel Niko joint author ETHRESEARCH 773 0- PLoS ONE Public Library of Science 6 (11), p. e27136 1932-6203 BK010053 XK010053 XK010000 ETHRESEARCH ETHRESEARCH ETHRESEARCH Journal Article Open access