Unravelling the evolution of prostate cancer through whole genome sequence data

Abstract
As part of the CRUK-ICGC Prostate UK project we have been gath- ering whole genome sequencing data from tissue from prostate cancer patients and applying sophisticated data analysis tech- niques to unravel how prostate cancer evolves. In this talk we will describe two projects:
Project 1 – Whole genome DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer reflecting clonal expansions, and the underlying mutational processes at work in morphologi- cally normal tissue were also at work in cancer. Our observations demonstrate the existence of on-going abnormal mutational pro- cesses, consistent with field-effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing as exemplified by the coexistence of multi- ple cancer lineages harbouring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by mor- phologically normal and malignant tissue or between different ERG-lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.
Project 2 – Cancers emerge from an on-going Darwinian evo- lutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culmi- nates in the formation of metastases, which is the cause of 90% of cancer-related deaths. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported, recent studies using mouse models of cancer demon- strated the existence of polyclonal seeding from and inter-clonal cooperation between multiple subclones. Using whole genome sequencing, we characterised multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprece- dented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daugh- ter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas muta- tions in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen deprivation therapy in prostate cancer.
http://dx.doi.org/10.1016/j.bdq.2017.02.032