3D genomic mapping reveals multifocality of human pancreatic precancers

• 成果类型: Article
• 署名作者: Braxton, Alicia M.; Kiemen, Ashley L.; Grahn, Mia P.; Forjaz, Andre; Parksong, Jeeun; Babu, Jaanvi Mahesh; Lai, Jiaying; Zheng, Lily; Niknafs, Noushin; Jiang, Liping; Cheng, Haixia; Song, Qianqian; Reichel, Rebecca; Graham, Sarah; Damanakis, Alexander I.; Fischer, Catherine G.; Mou, Stephanie; Metz, Cameron; Granger, Julie; Liu, Xiao-Ding; Bachmann, Niklas; Zhu, Yutong; Liu, YunZhou; Almagro-Perez, Cristina; Jiang, Ann Chenyu; Yoo, Jeonghyun; Kim, Bridgette; Du, Scott; Foster, Eli; Hsu, Jocelyn Y.; Rivera, Paula Andreu; Chu, Linda C.; Liu, Fengze; Fishman, Elliot K.; Yuille, Alan; Roberts, Nicholas J.; Thompson, Elizabeth D.; Scharpf, Robert B.; Cornish, Toby C.; Jiao, Yuchen; Karchin, Rachel; Hruban, Ralph H.; Wu, Pei-Hsun; Wirtz, Denis; Wood, Laura D.
• 署名单位: Johns Hopkins University; Medical University of South Carolina; Johns Hopkins University; Johns Hopkins University; Johns Hopkins Medicine; Johns Hopkins University; Johns Hopkins University; Chinese Academy of Medical Sciences - Peking Union Medical College; Cancer Institute & Hospital - CAMS; Peking Union Medical College; Chinese Academy of Medical Sciences - Peking Union Medical College; Cancer Institute & Hospital - CAMS; Peking Union Medical College; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Peking Union Medical College Hospital; Johns Hopkins University; Johns Hopkins University; University of Colorado System; University of Colorado Anschutz Medical Campus; Henan Academy of Innovations in Medical Science; Johns Hopkins University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6045
• DOI: 10.1038/s41586-024-07359-3
• 发表日期: 2024-05-16
• 页码: 679-+
• 关键词: intraepithelial neoplasia; braf mutations; high-frequency; cancer; number; individuals; signatures; FRAMEWORK; events; polyps

摘要

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.