the temporal order of genetic and pathway alterations in tumorigenesis的时间顺序基因和通路在肿瘤发生改变.pdfVIP

The Temporal Order of Genetic and Pathway Alterations in Tumorigenesis 1,2 3¤ 4 4 1,2 Moritz Gerstung , Nicholas Eriksson , Jimmy Lin , Bert Vogelstein , Niko Beerenwinkel * 1 Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland, 2 Swiss Institute of Bioinformatics (SIB), Basel, Switzerland, 3 Department of Statistics, University of Chicago, Chicago, Illinois, United States of America, 4 Ludwig Center and Howard Hughes Medical Institute, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, United States of America 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