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Cancer is usually described as accumulating damage one change at a time. Sequencing 57 whole prostate cancer genomes showed something else: chains of translocations and deletions that happen together in one burst, disrupting several cancer genes at once.
Sylvan Baca, Levi Garraway, Mark Rubin and colleagues sequenced the genomes of 57 prostate tumours and matched normal tissue, then modelled how the rearrangements they found could have arisen. Translocations and deletions were abundant and highly interdependent, arriving in coordinated chains the authors named chromoplexy.
The consequence is a model of punctuated rather than gradual evolution: a small number of events can derange a large amount of genome at once, and the classical picture of stepwise mutation accumulation does not describe how this cancer is built. By ordering the clonal hierarchy of lesions the authors also charted a path of oncogenic events, which is the beginning of the timing work that Gundem extended to metastasis.
A different picture of how a cancer genome is built, and one that explains why prostate cancer has few point mutations and a great deal of structural damage. It is also why whole-genome rather than exome sequencing is the right assay for this disease.
Metastatic prostate cancer is a communicating population, not a set of independent colonies, which is an argument for treating the whole body rather than chasing individual deposits, and an argument that resistance to androgen receptor drugs will emerge in several places at once because it emerges convergently.
The explanation for why prostate cancer has so few targeted drugs outside the hormone axis and the DNA-repair genes: it is a quiet genome with structural rather than point-mutational damage, and the recurrent changes sit in the machinery that reads DNA rather than in kinases.
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Shares ERG, The mutational landscape of lethal castration-resistant prostate cancer, Cell, Next-generation sequencing (NGS) and the tag prostate-evidence.
Shares Next-generation sequencing (NGS), Tumour heterogeneity and clonal evolution, The undruggable drivers, Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch and the tag prostate-evidence.
Shares Localised prostate cancer, high and very high risk, Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch, Prostate cancer and the tag prostate-evidence.
Shares The undruggable drivers, Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch, Prostate cancer and the tag prostate-evidence.