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3D genomic mapping reveals multifocality of human pancreatic precancers.
Braxton, Alicia M; Kiemen, Ashley L; Grahn, Mia P; Forjaz, André; Parksong, Jeeun; Mahesh Babu, Jaanvi; 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-Pérez, 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.
Afiliação
  • Braxton AM; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Kiemen AL; Department of Comparative Medicine, Medical University of South Carolina, Charleston, SC, USA.
  • Grahn MP; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Forjaz A; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Parksong J; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Mahesh Babu J; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Lai J; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Zheng L; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Niknafs N; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Jiang L; Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, USA.
  • Cheng H; Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, USA.
  • Song Q; McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
  • Reichel R; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Graham S; State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • Damanakis AI; State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • Fischer CG; State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • Mou S; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Metz C; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Granger J; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Liu XD; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Bachmann N; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Zhu Y; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Liu Y; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Almagro-Pérez C; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Jiang AC; Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • Yoo J; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Kim B; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Du S; Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, USA.
  • Foster E; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Hsu JY; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Rivera PA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Chu LC; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Liu F; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Fishman EK; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Yuille A; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Roberts NJ; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Thompson ED; Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Scharpf RB; Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Cornish TC; Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Jiao Y; Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA.
  • Karchin R; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Hruban RH; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Wu PH; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Wirtz D; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Wood LD; Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA.
Nature ; 629(8012): 679-687, 2024 May.
Article em En | MEDLINE | ID: mdl-38693266
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Lesões Pré-Cancerosas / Heterogeneidade Genética / Imageamento Tridimensional / Genômica / Análise de Célula Única Limite: Adult / Female / Humans / Male Idioma: En Revista: Nature Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Lesões Pré-Cancerosas / Heterogeneidade Genética / Imageamento Tridimensional / Genômica / Análise de Célula Única Limite: Adult / Female / Humans / Male Idioma: En Revista: Nature Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos