Combined tumour suppressor defects characterise clinically defined aggressive variant prostate cancers

Morphologically heterogeneous prostate cancers that behave clinically like small cell prostate cancers share their chemotherapy responsiveness. Fifty-nine prostate cancer samples from 40 clinical trial participants meeting aggressive variant criteria, and 8 patient-derived xenografts from 6 of them, were stained for markers aberrantly expressed in small cell prostate cancer, and DNA from 36 samples and 8 xenografts was analysed for copy-number gains and losses. Irrespective of morphology, Ki67 and Tp53 stained in at least 10% of cells in 80% and 41% of samples; RB1 stained in fewer than 10% of cells in 61% and androgen receptor in 36%. MYC copy gain, a surrogate for 8q, and RB1 copy loss were each present in 54% of 44 samples and PTEN copy loss in 48%. All but 1 of 8 xenografts carried Tp53 missense mutations. RB1 copy loss was the strongest discriminator between unselected castration-resistant prostate cancer and the aggressive variant, and combined alterations in RB1, Tp53 and PTEN were more frequent in aggressive variant disease than in unselected castration-resistant disease or in TCGA samples.