PIN-like ductal carcinoma of the prostate has frequent activating RAS/RAF mutations.

AIMS Prostatic intraepithelial neoplasia-like (PIN-like) ductal carcinoma is a rare tumor characterized by often cystically dilated glands architecturally resembling high-grade PIN, but lacking basal cells. These tumors are frequently accompanied by Grade Group 1 acinar cancer and behave relatively indolently. In contrast, conventional ductal adenocarcinoma of the prostate is an aggressive variant comparable to Grade Group 4 acinar cancer. Here, we used targeted next generation sequencing to molecularly profile PIN-like ductal carcinoma cases at radical prostatectomy. METHODS AND RESULTS Five PIN-like ductal carcinoma samples at radical prostatectomy with sufficient tumor tissue available were analyzed for genomic alterations by targeted next generation sequencing using the JHU solid tumor panel. DNA was captured using SureSelect for 640 genes and sequenced on the Illumina HiSeq platform. Three of five (60%) of the PIN-like ductal carcinomas showed activating mutations in the RAS/RAF pathways which are extraordinarily rare in conventional primary prostate carcinoma (<3% of cases), including an activating hotspot BRAF mutation (p.K601E), an activating hotspot mutation in HRAS (p.Q61K) and an in-frame activating deletion in BRAF (p.T488_Q493delinsK). An additional two cases lacked BRAF or HRAS mutations but harbored in-frame insertions of uncertain significance in MAP2K4 and MAP3K6. One case had sufficient acinar tumor for sequencing, and showed similar molecular profile as the concurrent PIN-like ductal carcinoma, suggesting a clonal relationship between the two components. CONCLUSIONS PIN-like ductal carcinoma represents a molecularly unique tumor, enriched for potentially targetable oncogenic driver mutations in the RAS/RAF/MAPK pathway. This molecular profile contrasts with that of conventional ductal adenocarcinoma, which is typically enriched for pathogenic mutations in the mismatch repair (MMR) and homologous recombination (HR) DNA repair pathways.