Pan-cancer inference of intra-tumor heterogeneity reveals associations with different forms of genomic instability

Franck Raynaud,Daniele Tavernari,Marco Mina,Giovanni Ciriello,Marcel Kool

doi:10.1371/journal.pgen.1007669

Franck Raynaud, Daniele Tavernari + Show 3 more

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https://doi.org/10.1371/journal.pgen.1007669

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Abstract

Genomic instability is a major driver of intra-tumor heterogeneity. However, unstable genomes often exhibit different molecular and clinical phenotypes, which are associated with distinct mutational processes. Here, we algorithmically inferred the clonal phylogenies of ~6,000 human tumors from 32 tumor types to explore how intra-tumor heterogeneity depends on different implementations of genomic instability. We found that extremely unstable tumors associated with DNA repair deficiencies or high chromosomal instability are not the most intrinsically heterogeneous. Conversely, intra-tumor heterogeneity is greatest in tumors exhibiting relatively high numbers of both mutations and copy number alterations, a feature often observed in cancers associated with exogenous mutagens. Independently of the type of instability, tumors with high number of clones invariably evolved through branching phylogenies that could be stratified based on the extent of clonal (early) and subclonal (late) instability. Interestingly, tumors with high number of subclonal mutations frequently exhibited chromosomal instability, TP53 mutations, and APOBEC-related mutational signatures. Vice versa, mutations of chromatin remodeling genes often characterized tumors with few subclonal but multiple clonal mutations. Understanding how intra-tumor heterogeneity depends on genomic instability is critical to identify markers predictive of the tumor complexity and envision therapeutic strategies able to exploit this association.

Highlights

Cancer is a dynamic and ever-changing disease that mutates and evolves during its progression [1]
Cancer cells sometimes exhibit a high number of such alterations, often driven by defects of the DNA repair pathway or by external mutagens, such as tobacco smoking or UV-radiation
We examined how different forms of genomic instability are associated with intra-tumor heterogeneity

Summary

Introduction

Cancer is a dynamic and ever-changing disease that mutates and evolves during its progression [1]. Multiple implementations of genomic instability have been identified and characterized in tumors [5]. These differ by type of genetic lesions being accumulated, e.g. somatic mutations [6] or copy number alterations [7], as well as by the extent of time and space throughout the genome that is affected by these lesions [8], [9]. Genomic instability encompasses diverse molecular phenotypes associated with distinct mutational processes and clinical outcome. Whether these phenotypes are associated with diverse extent and patterns of intra-tumor heterogeneity remains an outstanding question

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