Frequent mutation of the FOXA1 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 FOXA1 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. FOXA1 lies in head-on orientation with the androgen-regulated non-coding gene AL121790.1, resulting in strong prostate lineage-specific bidirectional transcription across the FOXA1 3′-UTR. This suggests transcriptional activity as a cause for the localized hypermutation. The indel-dominant pattern of somatic mutation extends into the FOXA1 coding region, where it is shaped by clonal selection to yield a cluster of non-frameshift indels inside the forkhead domain. Somatic FOXA1 3′-UTR mutations may prove useful for diagnostic and screening approaches, given their high frequency and lineage specificity.Matti Annala et al. report the recurrence of new FOXA1 mutations in prostate cancer. These FOXA1 mutations in 3’ untranslated region may prove useful as diagnostic markers for prostate cancer.

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