Abstract 101: The mechanism of clonal expansion determines the tempo and mode of neoplastic progression in Barrett's esophagus

Abstract

Abstract Barrett's Esophagus is a pre-malignant condition with a low rate of progression to esophageal adenocarcinoma. Endoscopic surveillance is recommended for early detection of cancer, which allows the study neoplastic progression in vivo over space and time. Since genetic clonal diversity predicts neoplastic progression (Maley Nat. Gen. 38, 468-473 (2006)), we developed an agent-based model to explore the effect of different parameters, such as mutation rate, selective effect of mutations and clonal expansion probability, on the spatio-temporal dynamics of genetic diversity. A typical Barrett's segment contains ∼90,000 crypts and we assume that clonal expansion occurs by crypt bifurcation, since the rate of crypt bifurcation is high in other diseases marked by chronic inflammation (Cheng The Anat. Record 216, 44-48 (1986)). The Barrett's segment is a cylinder that we model as a two-dimensional 300 by 300 hexagonal grid, wrapped around along one dimension. Crypts (agents) divide, die or mutate according to basal division, death and mutation rates as well as the mutation states of loci conferring reproductive and survival advantages. If a crypt needs to divide, and all of its six neighbors are alive, a daughter crypt displaces one of the neighbors at random with probability r, the “mechanism of clonal expansion probability”. We use a Gillespie algorithm for rapid simulation of the evolutionary dynamics of the constant-size crypt population, consistent with the stability of the Barrett's segment length. We ran 1080 simulations, varying selective mutation rate from 1e-5 to 1e-8, neutral mutation rate from 1e-4 to 1e-7, selective effect of mutations conferring reproductive or survival advantage from 0.001 to 2, and mechanism of clonal expansion probability r from 0 to 1. Our results show that when r is high, clones expand rapidly, selective sweeps occur often and a single dominant clone bearing all reproductive advantage mutations is likely to emerge. When r is low, clones expand slowly, clonal interference occurs often and multiple independent competing clones emerge. This model predicts that genetic diversity increases over time, since a clone only expanded when it acquired mutations conferring quicker crypt division rate, which is coupled to higher stem cell division and mutation rates, thereby generating higher diversity within the expanding clone compared to its surroundings. Our results suggest that designing experiments to measure the rate and mechanism of crypt bifurcation will help distinguish between two neoplastic progression modes: clonal evolution with successive selective sweeps versus multiple independent interfering clones. We also show that sampling few cells from many biopsies estimates the underlying genetic diversity better than sampling many cells from few biopsies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 101.