Preferred Sequences of Genetic Events in Carcinogenesis: Quantitative Aspects of the Problem

Abstract

In this paper we discuss some natural limitations in quantitative inference about the frequency, correlation and ordering of genetic events occurring in the course of tumor development. We consider a simple, yet frequently used experimental design, under which independent tumors are examined once for the presence/absence of specific mutations of interest. The most typical factors that affect the inference on the chronological order of genetic events are: a possible dependence of mutation rates, the sampling bias that arises from the observation process and small sample sizes. Our results clearly indicate that just these three factors alone may dramatically distort the outcome of data analysis, thereby leading to estimates of limited utility as an underpinning for mechanistic models of carcinogenesis.

Accurate Reconstruction of the Temporal Order of Mutations in Neoplastic Progression

“…Using a probabilistic framework, Szabo and Yokovlev (42) showed that there are technical limitations in inferring the ordering of genetic events from frequency and correlation data, regardless if the cross-sectional order obtained was a path or a tree. In particular, small sample sizes, inherent undercounting of mutations associated with early tumor grades, and current methods that assume that the mutations are independent are problematic.…”