Ductal and acinar components of mixed prostatic adenocarcinoma frequently have a common clonal origin

Abstract

Background: Ductal adenocarcinoma (DA) is an aggressive subtype of prostate cancer. It is most commonly seen in mixed tumors together with conventional acinar adenocarcinoma (AA). The genetic profile of DA and its clonal origin is not fully characterized.

Objective: To investigate whether DA represents a distinct genetic subtype and to investigate the somatic relationship between the ductal and acinar components of mixed cancers.

Design, setting, and participants: In 17 radical prostatectomy specimens ductal and acinar tumor components from the same tumor foci were dissected. DNA was extracted and genomic sequencing performed. After exclusion of two cases with low cell yield, 15 paired samples remained for analysis.

Results: In 12 of 15 cases a common somatic denominator was identified, while three cases had clonally separate components. In DA, TMPRSS2-ERG gene fusions were detected in 47% (7/15), clonal FOXA1 alterations in 33% (5/15) and SPOP alterations in 27% (4/15) of cases. In one case KIAA1549-BRAF fusion was identified. Genome doubling events, resulting in an increased ploidy, were identified in the DA in 53% (8/15) of cases, but not seen in any AA. PTEN and CTNNB1 alterations were enriched in DA (6/15) but not seen in any AA. No cancers showed microsatellite instability or high tumor mutation burden.

Conclusions: Ductal and acinar prostate adenocarcinoma components of mixed tumors most often share the same origin and are clonally related. DA components in mixed tumor often exhibit genome doubling events resulting in aneuploidy, consistent with the aggressive nature of high grade prostate cancer.

Keywords: clonality; ductal adenocarcinoma; genetics; prostate cancer.

Figure 1

Microscopic slides were reviewed and cancer and sampling areas of its ductal adenocarcinoma (DA) and acinar adenocarcinoma (AA) components were outlined with Indian ink (Case 11, clonal). Cases were included only if spatially separated and morphologically distinct areas of DA and AA were found within the same tumor focus. Black: cancer; blue: DA; red: AA. Hematoxylin and eosin (HE) [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Broad genomic profiling of paired samples of tissues from ductal and acinar adenocarcinoma. The top heatmap displays the somatic alterations detected from tumor tissue profiling. The type of alteration is coded according to the top legend. Subclonal mutations and structural variants are defined as having an allele frequency <1/4 of the cancer DNA fraction. Synonymous point mutations are not displayed here. Variants of unknown significance are non‐synonymous single nucleotide variants outside hotspots and not annotated as pathogenic. The single‐row middle heatmaps provide information on clonal origin, shared variants by variant type, tumor mutation burden and ploidy. The bottom panel displays the estimated fraction of cancer DNA in each sequenced tissue sample. The dashed lines at 0.01, 0.10, and 0.20 denote the cutoffs for reliable detection of point mutations, loss of heterozygosity, and homozygous deletions, respectively [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Mixed cancers showed strikingly similar morphology of both the ductal adenocarcinoma (DA) and acinar adenocarcinoma (AA) components regardless to whether they were clonally related or not. (A,B) Mixed DA and AA with clonal relationship (Case 11). (A) DA component showing papillary architecture and tall, columnar epithelium with stratified high‐grade nuclei. (B) AA component showing conventional glandular architecture and less pronounced nuclear atypia. (C and D) Mixed DA and AA without clonal relationship (Case 5). (C) DA component showing papillary architecture and tall, columnar epithelium with stratified high‐grade nuclei. (D) AA component showing conventional glandular architecture and less pronounced nuclear atypia. All images hematoxylin and eosin (HE), 20x lens magnification [Color figure can be viewed at wileyonlinelibrary.com]