Systematic pan-cancer analysis of tumour purity.

Dvir Aran,Marina Sirota,Atul J Butte

doi:10.1038/ncomms9971

Abstract

The tumour microenvironment is the non-cancerous cells present in and around a tumour, including mainly immune cells, but also fibroblasts and cells that comprise supporting blood vessels. These non-cancerous components of the tumour may play an important role in cancer biology. They also have a strong influence on the genomic analysis of tumour samples, and may alter the biological interpretation of results. Here we present a systematic analysis using different measurement modalities of tumour purity in >10,000 samples across 21 cancer types from the Cancer Genome Atlas. Patients are stratified according to clinical features in an attempt to detect clinical differences driven by purity levels. We demonstrate the confounding effect of tumour purity on correlating and clustering tumours with transcriptomics data. Finally, using a differential expression method that accounts for tumour purity, we find an immunotherapy gene signature in several cancer types that is not detected by traditional differential expression analyses.

Highlights

The tumour microenvironment is the non-cancerous cells present in and around a tumour, including mainly immune cells, and fibroblasts and cells that comprise supporting blood vessels
While The Cancer Genome Atlas (TCGA) argues that 60% purity is sufficient to distinguish the tumour’s signal from those of other cells, it remains to be evaluated if this level of purity across tumour samples affects the interpretation of genomic analyses
We assigned purity estimates using four methods: ESTIMATE, which uses gene expression profiles of 141 immune genes and 141 stromal genes[6]; ABSOLUTE, which uses somatic copy-number data[7]; LUMP, which averages 44 non-methylated immune-specific CpG sites (Supplementary Fig. 1 and Methods); and IHC, as estimated by image analysis of haematoxylin and eosin stain slides produced by the Nationwide Children’s Hospital Biospecimen Core Resource

Summary

Introduction

The tumour microenvironment is the non-cancerous cells present in and around a tumour, including mainly immune cells, and fibroblasts and cells that comprise supporting blood vessels. With the advancement of genomic technologies, many new computational methods have arisen to infer tumour purity These methods make estimates using different types of genomic information, such as gene expression[6], somatic copy-number variation[7,8,9] somatic mutations[7,10] and DNA methylation[7,11]. The Cancer Genome Atlas (TCGA) is currently the largest available data set for genomic analysis of tumours It contains over 10,000 pretreatment samples across 30 cancer types and includes measurements such as RNA sequencing (RNA-seq), DNA methylation, copy-number variation and more[12]. These studies used different purity estimation methods and tested only specific parameters, which were mainly in the context of detecting somatic mutations[22]

Methods

Results

Conclusion