Faculty Collaboration Database

3D genomic mapping reveals multifocality of human pancreatic precancers. Nature 2024 May;629(8012):679-687

Date

05/02/2024

Pubmed ID

38693266

DOI

10.1038/s41586-024-07359-3

Scopus ID

2-s2.0-85191953996 (requires institutional sign-in at Scopus site)   13 Citations

Abstract

Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors of pancreatic cancer, but their small size and inaccessibility in humans make them challenging to study¹. 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 cm³ 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.

Author List

Braxton AM, Kiemen AL, Grahn MP, Forjaz A, Parksong J, Mahesh Babu J, Lai J, Zheng L, Niknafs N, Jiang L, Cheng H, Song Q, Reichel R, Graham S, Damanakis AI, Fischer CG, Mou S, Metz C, Granger J, Liu XD, Bachmann N, Zhu Y, Liu Y, Almagro-Pérez C, Jiang AC, Yoo J, Kim B, Du S, Foster E, Hsu JY, Rivera PA, Chu LC, Liu F, Fishman EK, Yuille A, Roberts NJ, Thompson ED, Scharpf RB, Cornish TC, Jiao Y, Karchin R, Hruban RH, Wu PH, Wirtz D, Wood LD

Author

Toby Charles Cornish MD, PhD Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Clone Cells
Disease Progression
Early Detection of Cancer
Female
Genetic Heterogeneity
Genomics
Humans
Imaging, Three-Dimensional
Machine Learning
Male
Mutation
Oncogenes
Pancreas
Pancreatic Neoplasms
Precancerous Conditions
Single-Cell Analysis
Workflow