Early- and Elderly-Onset Prostate Cancers Are Mechanistically Distinct

A small subset (approximately 2%) of prostate cancers is diagnosed in men aged 50 years or younger, but it is unknown whether these cancers are genetically or mechanistically distinct from “classical,” elderly-onset prostate cancer, which has a median age of diagnosis of 70 years. To address this question, Weischenfeldt and colleagues performed whole-genome sequencing on 11 early-onset prostate cancer samples and compared their findings to recently published data from 7 elderly-onset prostate cancer samples. Strikingly, although the elderly-onset prostate cancers had a higher overall number of structural rearrangements, the early-onset prostate cancers were significantly enriched for balanced structural rearrangements leading to gene fusions. Given that androgen receptor (AR) activation can facilitate fusions between its target genes, the authors hypothesized that the different spectrum of structural rearrangements in early-onset prostate cancer could be AR driven. Consistent with this hypothesis, genes with androgen-regulated expression and increased AR binding in vitro were more frequently rearranged in early-onset prostate cancer than in elderly-onset prostate cancer. Early-onset prostate cancers were also more likely to harbor androgen-driven oncogenic ETS family gene fusions such as TMPRSS2–ERG than were elderly-onset prostate cancers, as shown by the whole-genome sequencing data as well as tissue microarrays representing thousands of patients. In contrast, unbalanced, non–androgen-regulated structural rearrangements, such as those involving PTEN, CHD1, and chromosome 6q15, were enriched in elderly-onset prostate cancers. Early age of prostate cancer initiation was not related to faster tumor growth kinetics but was significantly correlated with high AR expression and ERG rearrangements. Collectively, these findings suggest that androgen-driven structural rearrangements may distinguish early-onset from elderly-onset prostate cancers, which may have implications for prostate cancer treatment and screening in young men.

Weischenfeldt J, Simon R, Feuerbach L, Schlangen K, Weichenhan D, Minner S, et al. Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer. Cancer Cell 2013;23:159–70.