Substantial interindividual and limited intraindividual genomic diversity among tumours from men with metastatic prostate cancer

Multiple tumours from men with disseminated prostate cancer were analysed by whole-exome sequencing, array comparative genomic hybridisation and RNA transcript profiling, and genomic diversity within and between individuals was compared. In contrast to the substantial heterogeneity between men, there was limited diversity among metastases within an individual: the number of somatic mutations, the burden of copy-number alterations and aberrations in known oncogenic drivers were all highly concordant, as were metrics of androgen receptor activity and cell-cycle activity. Androgen receptor activity was inversely associated with cell proliferation, while expression of Fanconi anaemia complex genes correlated with elevated cell-cycle progression, E2F1 expression and RB1 loss. Men with somatic aberrations in Fanconi anaemia complex genes or in ATM had significantly longer responses to carboplatin than men without DNA repair gene defects.