Gene-Morphology Alignment via Graph-Constrained Latent Modeling for Molecular Subtype Prediction from Histopathology...

Molecular subtyping of cancer is traditionally defined in transcriptomic space, yet routine clinical deployment is limited by the availability and cost of sequencing. Meanwhile, histopathology captures rich morphological information that is known to correlate with molecular state but lacks a principled, mechanistic bridge to gene-level representations. We propose a graph-constrained learning framework that aligns morphology-derived signals with a fixed, data-driven gene network discovered via hierarchical Monte Carlo screening. We can derive new gene sets for classification using random sampling, and use the coexpression network of that graph to enforce the learning of a pure morphology model without using gene expression. The resulting model performs subtype prediction using morphology alone, while being explicitly forced to operate through a gene-structured latent space. Structural alignment is enforced during training. For Moffitt classification in pancreatic cancer using PANCAN and TCGA datasets, the model has a reported 85% AUC using an alternative gene set's network structure, while the alternate gene set itself has an 84% AUC in all patients that were classified with subtyping with pancreatic cancer in the dataset. This framework demonstrates that virtual transcriptomics can provide biologically grounded molecular insights using only routine histopathology slides, potentially expanding access to precision oncology in resource-limited settings.