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3D genomic mapping reveals multifocality of human pancreatic precancers

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

Nature, 2024, vol. 629, issue 8012, 679-687

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07359-3

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