Paradigm Lost

Journal article

Simple Summary: Clinical outcomes can be linked to the fundamental role played by the regulatory 3D architecture of the genome in a living cell and the unique properties offered as a molecular biomarker modality. Here, we describe how this molecular phenomenon acts as an imprint of the cellular genetic, epigenetic and metabolic status which form discriminatory stable conditional structures that inform on the state of the cell and its phenotype. Consequently, 3D architecture, as a biomarker, offers a more comprehensive translation from molecular readouts to clinical outcomes, with examples and evidence provided by the highly accurate diagnostic and prognostic clinical tests already reduced to practice in the US and UK. Moreover, with support from Large Language Models, we can elucidate the complexities and inter-relationships of molecular pathways and regulation using a 3D genomic architecture knowledge base, to gain insights into various molecular modalities and associated clinical conditions. Abstract: Background/Objectives: The 3-dimensional (3D) architecture of the genome in the nucleus of a living cell plays an unexpected yet fundamental regulatory role in cell biology. As an imprint of the cellular genetic, epigenetic and metabolic status, it discriminates pathological conditions through conditional changes to long-range 3D interactions (up to 300 kb) and thus could act as a powerful molecular biomarker linked closely to clinical outcomes. Methods: Here an assessment is made of the latest paradigm shift in molecular biology from a supply chain where information flows from DNA to RNA to protein, to the concept of heritable 3D folding of the genome reflecting the epigenetic and metabolic state of the cell, and which serves as a molecular biomarker for complex clinical outcome. Results: While biomarkers based on individual components of the supply chain fail to accurately reflect clinical outcomes, 3D genomics offers highly informative insights, exemplified for immuno-oncology and prostate cancer diagnosis by clinical tests of superior performance, already in practice in the US and UK. Conclusions: A more complete understanding of human biology will require models that account for the flow of information to and from the 3D genomic architecture in living cells, together with its regulation and logic. Integrating these principles into biomarker discovery and therapeutic design, along with other frontline approaches in precision medicine, including multi-omics and other system-level tools, will be essential for advancing precision medicine beyond its current limitations.

Authors: Mellor, J; Hunter, E; Akoulitchev, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: MDPI
• Journal: Cancers
• Volume: 17
• Issue: 13
• Article number: 2187
• Publication date: 2025-06-28
• Acceptance date: 2025-06-25
• DOI: 10.3390/cancers17132187
• EISSN: 2072-6694
• ISSN: 2072-6694
• Language: English
• Keywords: 3D genome architecture; clinical diagnostics; metabolism; capturing chromosome conformation (3C); phenotype; epigenetics