Liquid biopsy epigenomic profiling for cancer subtyping

Sylvan C Baca; Ji-Heui Seo; Matthew P Davidsohn; Brad Fortunato; Karl Semaan; Shahabbedin Sotudian; Gitanjali Lakshminarayanan; Miklos Diossy; Xintao Qiu; Talal El Zarif; Hunter Savignano; John Canniff; Ikenna Madueke; Renee Maria Saliby; Ziwei Zhang; Rong Li; Yijia Jiang; Len Taing; Mark Awad; Cindy H Chau; James A DeCaprio; William D Figg; Tim F Greten; Aaron N Hata; F Stephen Hodi; Melissa E Hughes; Keith L Ligon; Nancy Lin; Kimmie Ng; Matthew G Oser; Catherine Meador; Heather A Parsons; Mark M Pomerantz; Arun Rajan; Jerome Ritz; Manisha Thakuria; Sara M Tolaney; Patrick Y Wen; Henry Long; Jacob E Berchuck; Zoltan Szallasi; Toni K Choueiri; Matthew L Freedman

doi:10.1038/s41591-023-02605-z

Liquid biopsy epigenomic profiling for cancer subtyping

Nat Med. 2023 Nov;29(11):2737-2741. doi: 10.1038/s41591-023-02605-z. Epub 2023 Oct 21.

Authors

Sylvan C Baca^{1

2

3}, Ji-Heui Seo^{1

2}, Matthew P Davidsohn^{1

2}, Brad Fortunato^{1

2

3}, Karl Semaan^{1

3}, Shahabbedin Sotudian^{1

2

3}, Gitanjali Lakshminarayanan^{1

2}, Miklos Diossy⁴, Xintao Qiu^{1

2}, Talal El Zarif^{1

2}, Hunter Savignano^{1

2}, John Canniff^{1

2}, Ikenna Madueke^{1

2}, Renee Maria Saliby^{1

2}, Ziwei Zhang^{1

2

3}, Rong Li^{1

2}, Yijia Jiang^{1

2}, Len Taing^{1

2}, Mark Awad⁵, Cindy H Chau⁶, James A DeCaprio^{1

7}, William D Figg⁶, Tim F Greten⁸, Aaron N Hata^{9

10}, F Stephen Hodi¹, Melissa E Hughes¹, Keith L Ligon^{1

11}, Nancy Lin¹, Kimmie Ng¹, Matthew G Oser¹, Catherine Meador^{9

10}, Heather A Parsons¹, Mark M Pomerantz^{1

2}, Arun Rajan¹², Jerome Ritz¹, Manisha Thakuria^{13

14}, Sara M Tolaney¹, Patrick Y Wen^{15

16}, Henry Long^{1

2}, Jacob E Berchuck^{1

2}, Zoltan Szallasi^{4

17

18}, Toni K Choueiri¹, Matthew L Freedman^{19

20

21}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
³ Eli and Edythe L. Broad Institute, Cambridge, MA, USA.
⁴ Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA.
⁵ Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁶ Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁷ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁹ Massachusetts General Hospital Cancer Center, Boston, MA, USA.
¹⁰ Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹¹ Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹² Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD, USA.
¹³ Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁴ Center for Cutaneous Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA.
¹⁵ Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁶ Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁷ Danish Cancer Institute, Copenhagen, Denmark.
¹⁸ Department of Bioinformatics and Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Budapest, Hungary.
¹⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. matthew_freedman@dfci.harvard.edu.
²⁰ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA. matthew_freedman@dfci.harvard.edu.
²¹ Eli and Edythe L. Broad Institute, Cambridge, MA, USA. matthew_freedman@dfci.harvard.edu.

Abstract

Although circulating tumor DNA (ctDNA) assays are increasingly used to inform clinical decisions in cancer care, they have limited ability to identify the transcriptional programs that govern cancer phenotypes and their dynamic changes during the course of disease. To address these limitations, we developed a method for comprehensive epigenomic profiling of cancer from 1 ml of patient plasma. Using an immunoprecipitation-based approach targeting histone modifications and DNA methylation, we measured 1,268 epigenomic profiles in plasma from 433 individuals with one of 15 cancers. Our assay provided a robust proxy for transcriptional activity, allowing us to infer the expression levels of diagnostic markers and drug targets, measure the activity of therapeutically targetable transcription factors and detect epigenetic mechanisms of resistance. This proof-of-concept study in advanced cancers shows how plasma epigenomic profiling has the potential to unlock clinically actionable information that is currently accessible only via direct tissue sampling.

MeSH terms

Biomarkers, Tumor / genetics
Circulating Tumor DNA* / genetics
Epigenomics
Humans
Liquid Biopsy / methods
Mutation
Neoplasms* / genetics

Substances

Biomarkers, Tumor
Circulating Tumor DNA

Abstract

MeSH terms

Substances

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