Unveiling the Multifocal Nature of Pancreatic Precancers Through 3D Genomic Mapping

A groundbreaking study has revealed the extensive multifocality and genetic diversity of pancreatic intraepithelial neoplasias (PanINs), precursors to pancreatic cancer. Using a novel machine-learning pipeline for 3D histological reconstruction and targeted sequencing, researchers analyzed 46 samples of normal pancreas tissue at single-cell resolution. They identified an average of 13 PanINs per cubic centimeter, with hundreds likely present in a typical pancreas, nearly all harboring oncogenic KRAS mutations. Surprisingly, many PanINs arose as independent clones with distinct mutation profiles, and even within continuous PanINs, multiple KRAS mutations localized to different cell subpopulations, confirming their polyclonal origins. These insights into the genetic and spatial heterogeneity of PanINs provide a vital foundation for advancing early detection strategies and targeted interventions in pancreatic cancer.