Single-cell chromatin accessibility reveals malignant regulatory programs in primary human cancers-Reference-Cited by-同舟云学术

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

Published:2024-09-06 Issue:6713 Volume:385 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Sundaram Laksshman¹²³⁴^ORCID,Kumar Arvind³^ORCID,Zatzman Matthew⁵^ORCID,Salcedo Adriana³,Ravindra Neal³^ORCID,Shams Shadi¹⁶⁷^ORCID,Louie Brian H.⁶⁷,Bagdatli S. Tansu¹⁶⁷,Myers Matthew A.⁵^ORCID,Sarmashghi Shahab⁸^ORCID,Choi Hyo Young⁹¹⁰^ORCID,Choi Won-Young¹¹,Yost Kathryn E.⁶⁷^ORCID,Zhao Yanding¹⁶⁷,Granja Jeffrey M.¹,Hinoue Toshinori¹²^ORCID,Hayes D. Neil⁹¹⁰¹¹^ORCID,Cherniack Andrew⁸^ORCID,Felau Ina¹³^ORCID,Choudhry Hani¹⁴,Zenklusen Jean C.¹³^ORCID,Farh Kyle Kai-How³^ORCID,McPherson Andrew⁵^ORCID,Curtis Christina¹⁷¹⁵¹⁶¹⁷^ORCID,Laird Peter W.¹²^ORCID, ,Corces M. Ryan⁶¹⁸¹⁹²⁰^ORCID,Chang Howard Y.¹⁶⁷²¹^ORCID,Greenleaf William J.¹⁷²²^ORCID,Demchok John A.²³,Yang Liming²³,Tarnuzzer Roy²³,Caesar-Johnson Samantha J.²³,Wang Zhining²⁴,Doane Ashley S.²⁵,Khurana Ekta²⁵²⁶²⁷²⁸,Castro Mauro A. A.²⁹,Lazar Alexander J.³⁰,Broom Bradley M.³¹,Weinstein John N.³¹³²,Akbani Rehan³¹,Kumar Shwetha V.³¹,Raphael Benjamin J.³³,Wong Christopher K.³⁴,Stuart Joshua M.³⁴,Safavi Rojin³⁴,Benz Christopher C.³⁵,Johnson Benjamin K.¹²,Kyi Cindy²³,Shen Hui¹²

Affiliation:

1. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.

2. Department of Computer Science, Stanford University, Stanford, CA, USA.

3. Illumina AI laboratory, Illumina Inc, Foster City, CA, USA.

4. NVIDIA Bio Research, NVIDIA, Santa Clara, CA, USA.

5. Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

6. Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.

7. Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA.

8. Broad Institute of MIT and Harvard, Cambridge, MA, USA.

9. Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.

10. Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.

11. UTHSC Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.

12. Center for Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA.

13. National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

14. Department of Biochemistry, Faculty of Science, Cancer and Mutagenesis Unit, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah, Saudi Arabia.

15. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.

16. Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.

17. Chan Zuckerberg Biohub, San Francisco, CA, USA.

18. Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.

19. Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA, USA.

20. Department of Neurology, University of California San Francisco, San Francisco, CA, USA.

21. Howard Hughes Medical Institute, Stanford University, School of Medicine, Stanford, CA, USA.

22. Department of Applied Physics, Stanford University, Stanford, CA, USA.

23. Center for Cancer Genomics, National Cancer Institute, Bethesda, MD 20892, USA.

24. Center for Biomedical Informatics and Information Technology, National Cancer Institute, NIH, 9609 Medical Center Drive, Rockville, MD 20850, USA.

25. Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA.

26. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.

27. Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, USA.

28. Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA.

29. Bioinformatics and Systems Biology Laboratory, Federal University of Paraná, Curitiba 81520-260, Brazil.

30. Departments of Pathology & Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

31. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

32. Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.

33. Department of Computer Science, Princeton University, 35 Olden Street, Princeton, NJ 08540.

34. Biomolecular Engineering Department, School of Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.

35. Buck Institute for Research on Aging, Novato, CA 94945, USA.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/science.adk9217

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