3D genomic mapping reveals multifocality of human pancreatic precancers

Date:	May 2024
PMID:	38693266
Category:	N/A
Authors:	Alicia M Braxton, Ashley L Kiemen, Mia P Grahn, André Forjaz, Jeeun Parksong, Jaanvi Mahesh Babu, Jiaying Lai, Lily Zheng, Noushin Niknafs, Liping Jiang, Haixia Cheng, Qianqian Song, Rebecca Reichel, Sarah Graham, Alexander I Damanakis, Catherine G Fischer, Stephanie Mou, Cameron Metz, Julie Granger, Xiao-Ding Liu, Niklas Bachmann, Yutong Zhu, YunZhou Liu, Cristina Almagro-Pérez, Ann Chenyu Jiang, Jeonghyun Yoo, Bridgette Kim, Scott Du, Eli Foster, Jocelyn Y Hsu, Paula Andreu Rivera, Linda C Chu, Fengze Liu, Elliot K Fishman, Alan Yuille, Nicholas J Roberts, Elizabeth D Thompson, Robert B Scharpf , Toby C Cornish, Yuchen Jiao, Rachel Karchin, Ralph H Hruban, Pei-Hsun Wu, Denis Wirtz, Laura D Wood
Abstract:

1. 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.

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Acknowledgements:

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, or the National Institute of Health.

The Translational and Basic Science Research in Early Lesions (TBEL) Research Consortia is supported and funded by grants from the National Cancer Institute and the National Institutes of Health under the following award numbers:

Project Number:	Awardee Organization
U54CA274374	Fred Hutchinson Cancer Center
U54CA274375	Houston Methodist Research Institute
U54CA274370	Johns Hopkins University
U54CA274371	UT MD Anderson Cancer Center
U54CA274367	Vanderbilt University Medical Center