Journal Article

3D genomic mapping reveals multifocality of human pancreatic precancers

Grahn, Mia P., Cornish, Toby C., Mahesh Babu, Jaanvi, Metz, Cameron, Roberts, Nicholas J., Hruban, Ralph H., Zhu, Yutong, Jiang, Ann Chenyu, Wirtz, Denis, Reichel, Rebecca, Chu, Linda C., Liu, Fengze, Granger, Julie, Rivera, Paula Andreu, Wood, Laura D., Hsu, Jocelyn Y., Yuille, Alan, Liu, YunZhou, Wu, Pei-Hsun, Almagro-Pérez, Cristina, Cheng, Haixia, Liu, Xiao-Ding, Song, Qianqian, Parksong, Jeeun, Kiemen, Ashley L., Kim, Bridgette, Jiao, Yuchen, Thompson, Elizabeth D., Forjaz, André, Karchin, Rachel, Fischer, Catherine G., Zheng, Lily, Graham, Sarah, Damanakis, Alexander I., Bachmann, Niklas, Fishman, Elliot K., Scharpf, Robert B., Lai, Jiaying, Braxton, Alicia M., Niknafs, Noushin, Foster, Eli, Mou, Stephanie, Yoo, Jeonghyun, Jiang, Liping, Du, Scott

2024

Overview

Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors of pancreatic cancer, but their small size and inaccessibility in humans make them challenging to study 1 . Critically, the number, dimensions and connectivity of human PanINs remain largely unknown, precluding important insights into early cancer development. Here, we provide a microanatomical survey of human PanINs by analysing 46 large samples of grossly normal human pancreas with a machine-learning pipeline for quantitative 3D histological reconstruction at single-cell resolution. To elucidate genetic relationships between and within PanINs, we developed a workflow in which 3D modelling guides multi-region microdissection and targeted and whole-exome sequencing. From these samples, we calculated a mean burden of 13 PanINs per cm 3 and extrapolated that the normal intact adult pancreas harbours hundreds of PanINs, almost all with oncogenic KRAS hotspot mutations. We found that most PanINs originate as independent clones with distinct somatic mutation profiles. Some spatially continuous PanINs were found to contain multiple KRAS mutations; computational and in situ analyses demonstrated that different KRAS mutations localize to distinct cell subpopulations within these neoplasms, indicating their polyclonal origins. The extensive multifocality and genetic heterogeneity of PanINs raises important questions about mechanisms that drive precancer initiation and confer differential progression risk in the human pancreas. This detailed 3D genomic mapping of molecular alterations in human PanINs provides an empirical foundation for early detection and rational interception of pancreatic cancer. Quantitative multimodal 3D reconstruction of human pancreatic tissue at single-cell resolution reveals a high burden of multifocal, genetically heterogeneous pancreatic intraepithelial neoplasias in the normal adult pancreas.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/71 / 45 / 45/23 / 631/67/1504/1713 / 631/67/69 / 639/705/1042 / Adult / Cancer / Clone Cells - metabolism / Clone Cells - pathology / Connectivity / Disease Progression / Early Detection of Cancer / Empirical analysis / Exome Sequencing / Female / Females / Gene mapping / Genetic Heterogeneity / Genetic relationship / Genomics / Heterogeneity / Humanities and Social Sciences / Humans / Imaging, Three-Dimensional / Interception / K-Ras protein / Machine Learning / Male / Mapping / multidisciplinary / Mutation / Mutation hot spots / Neoplasms / Oncogenes - genetics / Pancreas / Pancreas - anatomy & histology / Pancreas - cytology / Pancreas - metabolism / Pancreas - pathology / Pancreatic cancer / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - pathology / Precancerous Conditions - genetics / Precancerous Conditions - pathology / Proto-Oncogene Proteins p21(ras) / Science / Science (multidisciplinary) / Single-Cell Analysis / Subpopulations / Tumors / Workflow