Early-onset prostate cancer (EO-PCA) represents the earliest clinical manifestation of prostate cancer. To compare the genomic alteration landscapes of EO-PCA with "classical" (elderly-onset) PCA, we performed deep sequencing-based genomics analyses in 11 tumors diagnosed at young age, and pursued comparative assessments with seven elderly-onset PCA genomes. Remarkable age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. Whereas EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG, elderly-onset PCAs displayed primarily non-androgen-associated SRs. Data from a validation cohort of > 10,000 patients showed age-dependent androgen receptor levels and a prevalence of SRs affecting androgen-regulated genes, further substantiating the activity of a characteristic "androgen-type" pathomechanism in EO-PCA.

Regulatory T cells (Treg) perform two distinct functions: they maintain self-tolerance and support organ homeostasis by differentiation into specialized tissue Treg cells. We now report that epigenetic modifications define molecular characteristics of tissue Treg cells. Tagmentation-based whole-genome bisulfite sequencing of tissue and lymphoid T cells revealed more than 11,000 differentially methylated regions. Similarities of the epigenetic landscape led to the identification of a common tissue Treg population, present in many organs and characterized by gain and loss of DNA methylation, including many TH2-associated sites such as the IL-33 receptor ST2, and the production of tissue-regenerative factors. Furthermore, this ST2-expressing population (which we term here tisTregST2) was dependent on the transcriptional regulator BATF and could be expanded by IL-33. Thus, tissue Treg cells integrate different waves of epigenetic reprogramming which define their tissue-restricted specializations.