Single-cell chromatin accessibility reveals malignant regulatory programs in primary human cancers.

Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 0404511 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-9203 (Electronic) Linking ISSN: 00368075 NLM ISO Abbreviation: Science Subsets: MEDLINE

Publication: : Washington, DC : American Association for the Advancement of Science
Original Publication: New York, N.Y. : [s.n.] 1880-

Chromatin*/metabolism ; Chromatin*/genetics ; Single-Cell Analysis* ; Neoplasms*/genetics ; Gene Expression Regulation, Neoplastic*; Humans ; Neural Networks, Computer ; Mutation ; DNA Copy Number Variations ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology

To identify cancer-associated gene regulatory changes, we generated single-cell chromatin accessibility landscapes across eight tumor types as part of The Cancer Genome Atlas. Tumor chromatin accessibility is strongly influenced by copy number alterations that can be used to identify subclones, yet underlying cis-regulatory landscapes retain cancer type-specific features. Using organ-matched healthy tissues, we identified the "nearest healthy" cell types in diverse cancers, demonstrating that the chromatin signature of basal-like-subtype breast cancer is most similar to secretory-type luminal epithelial cells. Neural network models trained to learn regulatory programs in cancer revealed enrichment of model-prioritized somatic noncoding mutations near cancer-associated genes, suggesting that dispersed, nonrecurrent, noncoding mutations in cancer are functional. Overall, these data and interpretable gene regulatory models for cancer and healthy tissue provide a framework for understanding cancer-specific gene regulation.

U24 CA264023 United States CA NCI NIH HHS

0 (Chromatin)

Date Created: 20240905 Date Completed: 20240905 Latest Revision: 20250106

20250114

10.1126/science.adk9217

39236169