Frequent mutation of the untranslated region in prostate cancer.

Prostate cancer has a low somatic mutation rate but non-coding regions remain underexplored. We sequenced the untranslated regions (UTRs) of 72 established driver genes in 428 patients with metastatic prostate cancer and identified 3'-UTR mutations in 12% of patients. The mutations were predominantly insertions or deletions, covered the entire UTR without motif enrichment, and were not detected in other cancers. lies in head-on orientation with the androgen-regulated non-coding gene , resulting in strong prostate lineage-specific bidirectional transcription across the 3'-UTR. This suggests transcriptional activity as a cause for the localized hypermutation. The indel-dominant pattern of somatic mutation extends into the coding region, where it is shaped by clonal selection to yield a cluster of non-frameshift indels inside the forkhead domain. Somatic 3'-UTR mutations may prove useful for diagnostic and screening approaches, given their high frequency and lineage specificity.