Abstract
Tumour progression is an evolutionary process in which different clones evolve over time, leading to intra-tumour heterogeneity. Interactions between clones can affect tumour evolution and hence disease progression and treatment outcome. Intra-tumoural pairs of mutations that are overrepresented in a co-occurring or clonally exclusive fashion over a cohort of patient samples may be suggestive of a synergistic effect between the different clones carrying these mutations. We therefore developed a novel statistical testing framework, called GeneAccord, to identify such gene pairs that are altered in distinct subclones of the same tumour. We analysed our framework for calibration and power. By comparing its performance to baseline methods, we demonstrate that to control type I errors, it is essential to account for the evolutionary dependencies among clones. In applying GeneAccord to the single-cell sequencing of a cohort of 123 acute myeloid leukaemia patients, we find 1 clonally co-occurring and 8 clonally exclusive gene pairs. The clonally exclusive pairs mostly involve genes of the key signalling pathways.
Highlights
Intra-tumour heterogeneity results from an evolutionary process, giving rise to different populations of cancer cells known as clones
We may observe pairs of mutations that co-occur in clones or exclude each other more often than we would expect for a given cohort of patient samples
Exclusive pairs are suggestive that clones carrying one or the other mutation may cooperate in the evolutionary process
Summary
Intra-tumour heterogeneity refers to a diverse set of genetically or phenotypically distinct cell populations that coexist within a tumour [1, 2] It is the result of mutation, selection, and possibly other evolutionary forces during tumour evolution [3,4,5]. For acute myeloid leukeamia (AML), highthroughput single-cell panel sequencing has uncovered the clonal diversity across two cohorts of 123 patients [12, 13]. These studies show that AML samples tend to have a relatively small number of clones, and importantly that multiple different mutations in signalling pathway genes often occur in distinct subclones
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