Three-dimensional nanoscale nuclear architecture mapping for improved cancer risk stratification

One of the greatest challenges for early cancer detection is how to effectively manage patients who are at risk for developing invasive cancer. As most at-risk patients will not develop cancer, frequent and invasive surveillance of atrisk patients carries financial, physical, and emotional burdens. But clinicians lack tools to accurately predict which patients will likely progress into malignancy. With our increased understanding of molecular changes in cancer development, it is now established that disrupted epigenome that can alter nuclear architecture occurs in all stages of cancer development including in normal precursor cells. Therefore, assessment of nanoscale nuclear architecture represents a promising strategy for identifying pre-cancerous changes. Here we present the development of threedimensional nuclear architecture mapping (3D-nanoNAM) to assess the depth-resolved properties of phase objects with slowly varying refractive index without a strong interface, based on a variant form of Fourier-domain optical coherence tomography (FD-OCT). By computing the Fourier phase of the FD-OCT signal resulting from the light back-scattered by cell nuclei, 3D-nanoNAM quantifies, with nanoscale sensitivity, the depth-resolved alterations in mean nuclear optical density, and localized heterogeneity in optical density of the cell nuclei. We demonstrate that 3D-nanoNAM distinguishes high-risk patients with inflammatory bowel disease (IBD) colitis from those at low-risk via/through imaging tissue sections that appear histologically normal according to pathologists. As 3D-nanoNAM uses clinically prepared formalin-fixed, paraffin-embedded tissue sections, it can be integrated into the clinical workflow.