We approached this problem from an epigenomic perspective. Rather than focusing solely on mutations or traditional histopathologic parameters, we asked whether chromatin architecture —the three-dimensional organization of DNA within the nucleus—could capture prostate cancer heterogeneity and reveal biologically and clinically meaningful subtypes.
By analyzing diagnostic needle biopsies, we identified two major chromatin-based subtypes of prostate cancer.
Unexpectedly, the subtype characterized by extensive chromatin remodeling showed reduced activation of invasive and metastatic programs, corresponding to lower aggressiveness and more favorable clinical outcomes.
A direct comparison of these two tumor epigenomic states yielded an 18-gene RNA signature capable of distinguishing the subtypes and stratifying patients into prognostically distinct groups.
Our findings support a simple but powerful concept: the 3D genome represents a clinically relevant layer of information in prostate cancer. Moreover, our study introduces a paradigm shift by demonstrating that, in prostate cancer, chromatin reprogramming within the tumor microenvironment can function as a brake—rather than a driver—of disease progression, restraining oncogenic programs and confining the tumor to the prostate.
From a clinical perspective, the 18-gene signature—currently undergoing patenting—may complement existing diagnostic and prognostic tools. While several steps are needed before this signature can enter routine practice, including prospective multi-center validation and adaptation with standard clinical workflows, this signature may be particularly valuable for patients in the grey zone, where decisions between active surveillance and definitive local treatment are most challenging.
Written by: Valentina Rosti, PhD, and Chiara Lanzuolo, PhD
- ITB-CNR, Institute of Biomedical Technologies, National Research Council, Segrate, Italy; INGM Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy