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Cancer genetics

Pan-cancer atlas of intratumour heterogeneity

Nature Reviews Genetics volume 24, page 487 (2023)Cite this article

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Transcriptional differences between tumours have been extensively studied using bulk RNA sequencing. More recently, single-cell RNA-sequencing (scRNA-seq) has led to the discovery of marked transcriptional heterogeneity between malignant cells of the same tumour that has important implications in terms of prognosis and response to therapy. Individual scRNA-seq studies of intratumour heterogeneity (ITH) have so far been limited by sample size; reporting in Nature, Gavish et al. integrate data from 77 scRNA-seq studies to define a comprehensive pan-cancer atlas that characterizes 11 ‘hallmarks’ of transcriptional ITH.

Based on previous scRNA-seq studies showing that sets of genes (ITH programmes) have coordinated variability within a tumour, the authors set out to identify related ITH programmes from different tumours. For each tumour, they used non-negative matrix factorization (NMF) to characterize ITH programmes of malignant cells as defined by their 50 top-scoring genes. ‘Robust’ ITH programmes that were consistently identified in individual tumours using multiple parameter values were grouped across tumours into 41 clusters according to shared genes. 83% of clusters were derived from several cancer types and the clusters covered 66% of all ITH programmes, which indicates that most ITH can be described by recurrent patterns common to different types of tumour. For each cluster, a meta-programme (MP) of ITH was defined as the most commonly shared genes in that cluster. MPs were given a functional annotation based on those genes, and MPs with related functions were grouped into 11 ‘hallmarks’ of transcriptional ITH. Twenty-one of the 41 MPs (mainly those of low frequency) had not been detected previously in smaller scRNA-seq studies, indicating the increased sensitivity of the combined dataset. Using bulk RNA-seq data from The Cancer Genome Atlas (TCGA), the authors identified associations between expression of the 41 MPs and tumour metastasis, therapy resistance and overall survival, some of which were consistent across cancer types, which indicates the functional relevance of the MP classification.

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  1. Nature Reviews Genetics http://www.nature.com/nrg/

    Kirsty Minton

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  1. Kirsty Minton
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Correspondence to Kirsty Minton.

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Minton, K. Pan-cancer atlas of intratumour heterogeneity. Nat Rev Genet 24, 487 (2023). https://doi.org/10.1038/s41576-023-00627-4

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