Statistical Mechanical theory for spatio-temporal evolution of Intra-tumor heterogeneity in cancers: Analysis of Multiregion sequencing data

TL;DR

This paper introduces a statistical mechanical theory to quantify intra-tumor heterogeneity using genetic mutation data, validated with simulations and patient data, revealing spatial variation and co-existing subclones within tumors.

Contribution

The authors develop an analytic model linking tumor heterogeneity to cell division and mutation probabilities, validated with simulations and applied to real multi-region sequencing data.

Findings

Substantial spatial variation in intra-tumor heterogeneity.

Heterogeneity increases with distance between tumor regions.

The theory accurately captures heterogeneity in melanoma and lung cancer samples.

Abstract

Heterogeneity in characteristics from one region (sub-population) to another, commonly observed in complex systems, such as glasses and a collection of cells, is hard to describe theoretically. In the context of cancer, intra-tumor heterogeneity (ITH), characterized by cells with genetic and phenotypic variability that co-exist within a single tumor, is often the cause of ineffective therapy and recurrence of cancer. Multi-region sequencing (M-Seq), obtained by sampling multiple regions of a single tumor, has vividly demonstrated the pervasive nature of ITH, raising the need for a theory that accounts for evolution of tumor heterogeneity. Here, we develop a statistical mechanical theory to quantify ITH, using the Hamming distance, between genetic mutations in distinct regions within a single tumor. An analytic expression for ITH, expressed in terms of cell division probability ($\alpha$) and mutation probability ($p$), is validated using cellular-automaton type simulations. Application of the theory successfully captures ITH extracted from M-seq data in patients with exogenous cancers (melanoma and lung). The theory, based on punctuated evolution at the early stages of the tumor followed by neutral evolution, is accurate provided the spatial variation in the tumor mutation burden is not large. We show that there are substantial variations in ITH in distinct regions of a single solid tumor, which supports the notion that distinct subclones could co-exist. The simulations show that there are substantial variations in the sub-populations, with the ITH increasing as the distance between the regions increases. The analytical and simulation framework developed here could be used in the quantitative analyses of the experimental (M-Seq) data. More broadly, our theory is likely to be useful in analyzing dynamic heterogeneity in complex systems such as super-cooled liquids.