Multiple Origin and Tumor Heterogeneity of Prostatic Ductal Adenocarcinoma in the Han Chinese Population.

Abstract

Purpose: Prostatic ductal adenocarcinoma (PDA) is recognized as an advanced stage cancer and is often observed in conjunction with acinar adenocarcinoma, with abundant cytoplasm arranged in a papillary pattern. When compared with acinar adenocarcinoma, it is characterized by an increased biochemical recurrence rate and unusual metastasis sites. The purpose of the present study was to further elucidate the genomic alterations associated with PDA. Methods: Whole-exome sequencing (WES) and linkage analyses were performed on genomic DNA isolated from formalin-fixed, paraffin-embedded (FFPE) samples obtained from eleven PDA tumors and paired benign tissues. The profiles of somatic mutations, indels as well as copy-number alterations were confirmed in PDA patients. The clonal evolution patterns of the eleven PDA cases were compared with the data obtained from the Cancer Genome Atlas (TCGA) for eight primary prostatic acinar adenocarcinoma patients. Results: The same somatic changes were observed in PDA as in advanced and/or metastatic acinar adenocarcinomas. For example, the mutations of a known prostate cancer driver gene CDKN1A, were the most significant events among 17% of tumors. In addition to the known amplification of chromosomes 1q, 4p, 8q, and 14q, the copy number of several large regions also increased significantly. The origin of PDA was heterogeneous: some patients (e.g. P5) were consistent with the monoclonal model, while others (e.g. P7) were polyclonal. Conclusions: PDA and acinar adenocarcinomas of prostate with high Gleason score have similar mutational profiles. The somatic mutations in PDA may be the reason for its invasive biological behavior.