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Fifty men who died of prostate cancer had their tumours sequenced within hours of death. Even after years of treatment the cancers carried few mutations, and the recurring ones were in genes that control how DNA is packaged and read rather than in classic cancer genes.
Catherine Grasso, Arul Chinnaiyan and colleagues sequenced the exomes of 50 lethal, heavily pre-treated metastatic castration-resistant prostate cancers obtained at rapid autopsy, including three separate deposits from one patient, alongside 11 treatment-naive high-grade localised cancers.
The low mutation rate, 2.00 per megabase even after years of therapy, is the number to remember: prostate cancer is a structurally rearranged genome rather than a heavily mutated one, which is why tumour mutational burden rarely qualifies it for immunotherapy. The recurrent mutations that were found sit in chromatin and histone-modifying genes and in the androgen receptor's collaborators, and the paper showed physical interaction between the MLL complex and the receptor. CHD1 disruption defined a subtype of ETS fusion-negative disease, and FOXA1 mutations were found in 5 of 147 tumours.
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.
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.
The origin of the idea that a prostate tumour's copy-number pattern carries prognostic information the pathologist's grade does not. That idea became Decipher and the other genomic classifiers, which are now used in some systems to decide whether a man needs radiotherapy after surgery.
Shares Arul M. Chinnaiyan, TMPRSS2, University of Michigan Rogel Cancer Center, ERG and the tag prostate-evidence.
Shares FOXA1, TMPRSS2, Somatic mutations from exome and genome sequencing (WXS, WGS), ERG and the tag prostate-evidence.
Shares TMPRSS2, Chromoplexy, ERG, SU2C-PCF: integrative clinical genomics of advanced prostate cancer and the tag prostate-evidence.
Shares Punctuated evolution of prostate cancer genomes, Chromoplexy, Nature, Tumour heterogeneity and clonal evolution and the tag prostate-evidence.
Shares Prostate cancer (KEGG map), Androgen receptor signalling, Tumour heterogeneity and clonal evolution, Castration-resistant prostate cancer (CRPC) and the tag prostate-evidence.
Shares Epigenetic reprogramming, Androgen receptor signalling, Tumour heterogeneity and clonal evolution, Castration-resistant prostate cancer (CRPC) and the tag prostate-evidence.
Shares Castration-resistant prostate cancer (CRPC), 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, Androgen receptor and the tag prostate-evidence.
Shares Next-generation sequencing (NGS), Tumour heterogeneity and clonal evolution, Castration-resistant prostate cancer (CRPC), The undruggable drivers and the tag prostate-evidence.