Three-dimensional genomic mapping of human pancreatic tissue reveals striking multifocality and genetic heterogeneity in precancerous lesions

作者：Alicia M. Braxton, Ashley Kiemen, Mia P. Grahn, André Forjaz, Jaanvi Mahesh Babu, Lily Zheng, Liping Jiang, Haixia Cheng, Qianqian Song, Rebecca Reichel, Sarah E. Graham, Alexander Damanakis, Catherine G. Fischer, Stephanie Mou, Cameron Metz, Julie Granger, Xiaoding Liu, Niklas Bachmann, Cristina Almagro-Pérez, Ann Chenyu Jiang, Jeong‐Hyun Yoo, Bridgette Kim, Scott Du, Eli Foster, Jocelyn Y. Hsu, Paula Andreu Rivera, Linda C. Chu, Fengze Liu, Noushin Niknafs, 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 · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2023 · DOI：10.1101/2023.01.27.525553 · 被引用次数：8 · 研究领域：Pancreatic and Hepatic Oncology Research、Cancer Genomics and Diagnostics、Single-cell and spatial transcriptomics

ABSTRACT Pancreatic intraepithelial neoplasia (PanIN) is a precursor to pancreatic cancer and represents a critical opportunity for cancer interception. However, the number, size, shape, and connectivity of PanINs in human pancreatic tissue samples are largely unknown. In this study, we quantitatively assessed human PanINs using CODA, a novel machine-learning pipeline for 3D image analysis that generates quantifiable models of large pieces of human pancreas with single-cell resolution. Using a cohort of 38 large slabs of grossly normal human pancreas from surgical resection specimens, we identified striking multifocality of PanINs, with a mean burden of 13 spatially separate PanINs per cm 3 of sampled tissue. Extrapolating this burden to the entire pancreas suggested a median of approximately 1000 PanINs in an entire pancreas. In order to better understand the clonal relationships within and between PanINs, we developed a pipeline for CODA-guided multi-region genomic analysis of PanINs, including targeted and whole exome sequencing. Multi-region assessment of 37 PanINs from eight additional human pancreatic tissue slabs revealed that almost all PanINs contained hotspot mutations in the oncogene KRAS , but no gene other than KRAS was altered in more than 20% of the analyzed PanINs. PanINs contained a mean of 13 somatic mutations per region when analyzed by whole exome sequencing. The majority of analyzed PanINs originated from independent clonal events, with distinct somatic m...