Implications for personalised medicine
- Date : 03 May 2012
- Topic : Personalised medicine
Intratumour heterogeneity may foster tumour evolution and adaptation and hinder personalised-medicine strategies that depend on results from single tumour-biopsy samples. A team of the UK's most exciting young cancer researchers have performed a careful genetic analysis of tumours and shown that no two samples from the same patient were genetically identical.
To examine intratumour heterogeneity, the researchers led by Charles Swanton performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal cell carcinomas and associated metastatic sites. They characterised the consequences of intratumour heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression.
The results describe in some considerable detail the burden of the genetic differences between cancer cells or between regions of one tumour.
Main findings of a multiregion sequencing study illustrate the complexities of personalised medicine
Phylogenetic reconstruction revealed branched evolutionary tumour growth, with 63 to 69% of all somatic mutations not detectable across every tumour region. This detailed analysis of the biopsies confirmed that no two tumours are the same. Furthermore, no two biopsies of the same tumour are the same. In this study, approximately two-thirds of the mutations present in a single biopsy were not shared in all biopsies across the same tumour.
These intratumour genetic differences occurred in genes that encode proteins that are targets for some of the available anticancer drugs, such as mTOR, a target of everolimus. Targeted anticancer drugs are the core of personalised therapy and if mutations are only detected in some biopsies but not in all, this has obvious implications for the application of personalised medicine.
The assessment revealed that the tumours underwent convergent phenotypic evolution with multiple distinct loss of function mutations occurring in the same tumour-suppressor gene across different regions of the tumour. Intratumour heterogeneity can lead to underestimation of the tumour genomics landscape portrayed from single tumour-biopsy samples and may present major challenges to personalised-medicine and biomarker development. Intratumour heterogeneity, associated with heterogeneous protein function, may foster tumour adaptation and therapeutic failure through Darwinian selection.
The researchers published their findings in March 8 issue of The New England Journal of Medicine. Their work was supported by grants from the UK Medical Research Council, Cancer Research UK, the Royal Marsden Hospital Renal Research Fund, Novartis, EU Framework 7 Personalised RNA Interference to Enhance the Delivery of Individualised Cytotoxic and Targeted Therapeutics (PREDICT), and the Wellcome Trust.
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