Abstract
BackgroundSlow-growing prostate cancer (PC) can be aggressive in a subset of cases. Therefore, prognostic tools to guide clinical decision-making and avoid overtreatment of indolent PC and undertreatment of aggressive disease are urgently needed. PC has a propensity to be multifocal with several different cancerous foci per gland.ResultsHere, we have taken advantage of the multifocal propensity of PC and categorized aggressiveness of individual PC foci based on DNA methylation patterns in primary PC foci and matched lymph node metastases. In a set of 14 patients, we demonstrate that over half of the cases have multiple epigenetically distinct subclones and determine the primary subclone from which the metastatic lesion(s) originated. Furthermore, we develop an aggressiveness classifier consisting of 25 DNA methylation probes to determine aggressive and non-aggressive subclones. Upon validation of the classifier in an independent cohort, the predicted aggressive tumors are significantly associated with the presence of lymph node metastases and invasive tumor stages.ConclusionsOverall, this study provides molecular-based support for determining PC aggressiveness with the potential to impact clinical decision-making, such as targeted biopsy approaches for early diagnosis and active surveillance, in addition to focal therapy.
Highlights
Slow-growing prostate cancer (PC) can be aggressive in a subset of cases
We have taken advantage of the multifocal propensity of PC and categorized aggressiveness of individual PC foci based on DNA methylation patterns in primary PC foci and matched metastases
DNA methylation patterns of lymph node metastases indicate the potential primary focus/foci of origin In this study, we hypothesize that the aggressive primary cancer focus/foci can be identified from multifocal PC by the degree of correlation of DNA methylation to lymph node metastases, which are representative of an aggressive trait (Fig. 1a)
Summary
Slow-growing prostate cancer (PC) can be aggressive in a subset of cases. prognostic tools to guide clinical decision-making and avoid overtreatment of indolent PC and undertreatment of aggressive disease are urgently needed. One theorizes that an initially transformed cancer spreads to multiple locations within the prostate (monoclonal), while the other model suggests that PC foci arise independently in different areas of the same gland (multiple subclones) [9,10,11,12,13,14,15,16,17,18]. The latter option indicates the possibility that aggressive and non-aggressive cancer foci co-exist in the same prostate gland and is supported by the finding that individual foci of multifocal PC often present with unique GSs [19]. Previous studies that have not accounted for prostate tumor multifocality, or used only the index lesion, are potentially flawed
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
