Abstract
Intratumour heterogeneity (ITH) may foster tumour adaptation and compromise the efficacy of personalized medicine approaches. The scale of heterogeneity within a tumour (intratumour heterogeneity) relative to genetic differences between tumours (intertumour heterogeneity) is unknown. To address this, we obtained 48 biopsies from eight stage III and IV clear cell renal cell carcinomas (ccRCCs) and used DNA copy-number analyses to compare biopsies from the same tumour with 440 single tumour biopsies from the Cancer Genome Atlas (TCGA). Unsupervised hierarchical clustering of TCGA and multi-region ccRCC samples revealed segregation of samples from the same tumour into unrelated clusters; 25% of multi-region samples appeared more similar to unrelated samples than to any other sample originating from the same tumour. We found that the majority of recurrent DNA copy number driver aberrations in single biopsies were not present ubiquitously in late-stage ccRCCs and were likely to represent subclonal events acquired during tumour progression. Such heterogeneous subclonal genetic alterations within individual tumours may impair the identification of robust ccRCC molecular subtypes classified by distinct copy number alterations and clinical outcomes. The co-existence of distinct subclonal copy number events in different regions of individual tumours reflects the diversification of individual ccRCCs through multiple evolutionary routes and may contribute to tumour sampling bias and impact upon tumour progression and clinical outcome.
Highlights
Over the last 5 years, tumour deep sequencing studies have revealed the scale of diversity between tumours, with few somatic alterations shared between tumours of the same histopathological subtype [1,2,3,4,5]
Cytoband-based copy number profiles were derived from Affymetrix SNP 6 array analysis for biopsies from 48 regions of eight individual tumours and 440 the Cancer Genome Atlas (TCGA)
Accumulating evidence suggests that intratumour heterogeneity impacts upon disease outcome [19,21], therapeutic response [23,37] and biomarker analysis [15]
Summary
Over the last 5 years, tumour deep sequencing studies have revealed the scale of diversity between tumours (intertumour heterogeneity), with few somatic alterations shared between tumours of the same histopathological subtype [1,2,3,4,5]. Morphological intratumour heterogeneity has been recognized for several decades and forms the basis of many pathological grading tools, where variation in nuclear size (nuclear pleomorphism), a poor prognostic marker, provides an estimate of diversity between cells of the same tumour [16]. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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