Abstract

Prostate cancer (CaP) remains the most common male malignancy worldwide. Although some localized cancers can be indolent, others can manifest aggressive biology with abnormal cancer metabolism and genetic instability. These men need intensified treatment to prevent metastatic castrate-resistant disease (mCRPC). We have embarked upon a broad analysis of cancer metabolism (hypoxia), whole-genomes and methylomes in close to 400 men treated with surgery or radiotherapy to derive novel signatures of outcome. Non-indolent tumours treated by surgery or radiotherapy have a paucity of clinically-actionable mutations; in distinct contrast to that reported for mCRPC. A significant proportion of tumours harbour recurrent non-coding aberrations, important genomic rearrangements, and chromothripsis or kataegis. Importantly, this disparity in genomic landscape between otherwise pathologically similar cancers explained heterogeneity in clinical outcome as multiple driver mutations, gene methylation and copy-number alterations are directly with aggressive disease and patient outcome. The presence of hypoxia furthers the effect of genetic instability on adverse outcome. Our data strongly suggest that novel therapeutic approaches should also focus on recurrent non-mutation targets in localized prostate cancer in order to improving cures in aggressive localized disease. It also provides genetically disparate risk groups that can be triaged to treatment intensification to improve cure.