The Evolutionary History of Lethal Metastatic Prostate Cancer

By G. Gundem, P. Loo, B. Kremeyer, Ludmil B. Alexandrov, J. Tubío, E. Papaemmanuil, D. Brewer, H. Kallio, Gunilla Högnäs, Matti Annala and 20 more. Nature, 2015

1,348 citations recorded by the source corpus.

Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culminates 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 demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple subclones. Here we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole-genome sequencing, we characterized multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter 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 mutations 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.

Subfields: Cancer Research, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/714b7e3e64b7039bfc94f68ed16a81fcfbdec5b3

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Citations in the corpus

The molecular taxonomy of primary prostate cancer (2015, result): “This is consistent with prior exome and genome-scale sequencing results for localized prostate cancers (Barbieri et al., 2012, Baca et al., 2013), and is lower than the mutational burden of metastatic prostate cancers (Gundem et al., 2015, Grasso et al., 2012, Robinson et al., 2015).”
EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, neutral): “…by the fact that metastases have been reported to result from polyclonal populations ostensibly derived from clustered CTCs (Cheung et al., 2016), and by the observation that metastatic clones may be transferred between different metastatic lesions in the same patient (Gundem et al., 2015).”
Integrative clinical genomics of advanced prostate cancer (2015, neutral): “Although certain primary prostate cancer alterations or signatures have prognostic clinical significance (Hieronymus et al., 2014; Lalonde et al., 2014), the therapeutic impact of primary prostate cancer genomic events has not yet been realized.”
Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. (2017, neutral): “…(Murugaesu et al., 2015), SMO mutations in medulloblastoma (Morrissy et al., 2016), distinct AR amplification events in prostate cancer (Gundem et al., 2015), KMTD2D and CREBBP mutations in follicular lymphoma (Okosun et al., 2014) and PTEN and TP53 mutations, FGFR2 amplifications and…”
Genetics and biology of prostate cancer (2018, background): “To characterize the subclonal architecture of mCRPC, Gundem et al. (2015) performed whole-genome sequencing of 51 multifocal primary and metastatic tumors from 10 patients and discovered that metastasis derived from multiple clones that transfer between different metastatic sites or a single…”
Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer. (2018, neutral): “However, the exome represents <2% of the genome, and outside of small case series (Gundem et al., 2015; Wedge et al., 2018), the complete genomic landscape of mCRPC remains largely unexplored.”