Gleason Score 7 Prostate Cancers Emerge through Branched Evolution of Clonal Gleason Pattern 3 and 4

Abstract

Purpose The molecular features that account for the distinct histology and aggressive biological behavior of Gleason pattern 4 (Gp4) versus Gp3 prostate cancer (PCa), and whether Gp3 tumors progress directly to Gp4, remain to be established. Experimental Design Whole exome sequencing and transcriptome profiling of laser-capture microdissected adjacent Gp3 and cribiform Gp4 were used to determine the relationship between these entities. Results Sequencing confirmed that adjacent Gp3 and Gp4 were clonal based on multiple shared genomic alterations. However, large numbers of unique mutations in the Gp3 and Gp4 tumors showed that the Gp4 were not derived directly from the Gp3. Remarkably, the Gp3 tumors retain their indolent appearing morphology despite acquisition of multiple genomic alterations including tumor suppressor losses. Although there were no consistent genomic alterations that distinguished Gp3 from Gp4, pairwise transcriptome analyses identified increased c-Myc and decreased p53 activity in Gp4 versus adjacent clonal Gp3 foci. Conclusions These findings establish that at least a subset of Gp3 and aggressive Gp4 tumors have a common origin, and support a branched evolution model wherein the Gp3 and Gp4 tumors emerge early from a common precursor and subsequently undergo substantial divergence. Genomic alterations detectable in the Gp3 may distinguish these tumors from truly indolent Gp3. Screening for a panel of these genomic alterations in men who have prostate biopsies showing only Gp3 (Gleason score 6, Gs6) may allow for more precise selection of men who can be safely managed by active surveillance versus those who may benefit from further intervention.

Grading of prostate cancer: a work in progress

“…Further, interobserver variation for individual Gleason grade (sub)patterns was studied in greater detail . Employing molecular–genetic analysis of microdissected samples as a tool to gain insight into prostate cancer evolution shed some light on the clonal evolution of prostate cancer …”

“…[9][10][11] Employing molecular-genetic analysis of microdissected samples as a tool to gain insight into prostate cancer evolution shed some light on the clonal evolution of prostate cancer. 12 After a description of historical aspects of prostate cancer grading, this review will provide an extensive overview of the various subpatterns constituting the individual Gleason grades. The main objectives are: (i) to summarise the current evidence for prognostic impact of each of these Gleason grade subpatterns, (ii) to point out areas where such data are lacking and (iii) discuss potential implications of recent insights in prostate cancer grading for future improvement.…”

MEIS1 down-regulation by MYC mediates prostate cancer development through elevated HOXB13 expression and AR activity

“…DISCUSSION In many cancer types, the role of amplified MYC in mediating tumorigenesis has been linked to genes involved in ribosomal biogenesis, universally upregulated transcription, proliferation, and reprogramming cells to a pluripotent state [47]. A subset of advanced prostate cancers also harbor amplified MYC, but it is distinct from the upregulated MYC that is a hallmark of many localized prostate cancers [3,[14][15][16]]. In the current study, we used transcriptome profiling to assess subpopulations of prostate tumors based on differential MYC protein expression and MYC activity, and we similarly compared differentially expressed genes and pathways within the larger prostate TCGA cohort based on MYC activity.…”

“…Locally advanced prostate cancers harbor a limited number of recurrently altered genes whose expression change at the earliest stages of tumor development. These include down-regulation of the tumor suppressors NKX3-1 and PTEN (often due to genomic deletion), up-regulation of ERG (due to fusion with TMPRSS2), and up-regulation of MYC, which often co-occurs with a single-copy gain of chromosome 8q24 [1][2][3][4][5]. Interestingly, up-regulation of MYC in most neoplastic tissues is a very early event that contributes to self-renewal and proliferation, but localized prostate cancer (PCa) is not hyperproliferative and focal amplification of MYC is rare [6,7].…”

“…Recently, increased awareness that the vast majority of prostate cancers are indolent has led to increased molecular profiling of tumor biopsies prior to definitive treatment. Although MYC expression has been observed in the cancer precursor high-grade prostatic intraepithelial neoplasia, MYC expression in indolent-appearing tumor cells predicts the presence of higher-grade disease and is associated with poor differentiation [3][4][5]. In localized prostate cancers, up-regulated MYC has been further associated with alterations in nucleoli structure, concomitant with increased biogenesis of ribosomal RNA, increased purine metabolism and expression of the telomere RNA subunit TERC [12][13][14].…”