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Liquid biopsy epigenomic profiling for cancer subtyping.

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.

SUBMITTER: Baca SC

PROVIDER: S-EPMC10695830 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Liquid biopsy epigenomic profiling for cancer subtyping.

Baca Sylvan C SC Seo Ji-Heui JH Davidsohn Matthew P MP Fortunato Brad B Semaan Karl K Sotudian Shahabbedin S Lakshminarayanan Gitanjali G Diossy Miklos M Qiu Xintao X El Zarif Talal T Savignano Hunter H Canniff John J Madueke Ikenna I Saliby Renee Maria RM Zhang Ziwei Z Li Rong R Jiang Yijia Y Taing Len L Awad Mark M Chau Cindy H CH DeCaprio James A JA Figg William D WD Greten Tim F TF Hata Aaron N AN Hodi F Stephen FS Hughes Melissa E ME Ligon Keith L KL Lin Nancy N Ng Kimmie K Oser Matthew G MG Meador Catherine C Parsons Heather A HA Pomerantz Mark M MM Rajan Arun A Ritz Jerome J Thakuria Manisha M Tolaney Sara M SM Wen Patrick Y PY Long Henry H Berchuck Jacob E JE Szallasi Zoltan Z Choueiri Toni K TK Freedman Matthew L ML

Nature medicine 20231021 11

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 meas ...[more]

PMID: 37865722

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Project description:IntroductionMolecular profiling of tumor tissue is the gold standard for treatment decision-making in advanced non-small cell lung cancer (NSCLC). Results may be delayed or unavailable due to insufficient tissue, prolonged wait times for biopsy, pathology assessment and testing. We piloted the use of plasma testing in the initial diagnostic workup for patients with suspected advanced lung cancer.MethodsPatients with ⩽15 pack-year smoking history and suspected advanced lung cancer referred to the lung cancer rapid diagnostic program underwent plasma circulating-tumor DNA testing using a DNA-based mutation panel. Tissue testing was performed per standard of care, including comprehensive next-generation sequencing (NGS). The primary endpoint was time from diagnostic program referral to cancer treatment in stage IV NSCLC patients (Cohort A) compared to a contemporary cohort not enrolled in the study (Cohort B) and an historical pre-COVID cohort referred to the program between 2018 and 2019 (Cohort C).ResultsFrom January to June 2021, 20 patients were enrolled in Cohort A; median age was 70.5 years (range 33-87), 70% were female, 55% Caucasian, 85% never smokers, and 75% were diagnosed with NSCLC. Seven had actionable alterations detected in plasma or tissue (4/7 concordant). Fusions, not tested in plasma, were identified by immunohistochemistry for three patients. Mean result turnaround time was 17.8 days for plasma NGS and 23.6 days for tissue (p = 0.10). Mean time from referral to treatment initiation was significantly shorter in cohort A at 32.6 days (SD 13.1) versus 62.2 days (SD 31.2) in cohort B and 61.5 days (SD 29.1) in cohort C, both p < 0.0001.ConclusionLiquid biopsy in the initial diagnostic workup of patients with suspected advanced NSCLC can lead to faster molecular results and shorten time to treatment even with smaller DNA panels. An expansion study using comprehensive NGS plasma testing with faster turnaround time is ongoing (NCT04862924).

Dataset Information

Liquid biopsy epigenomic profiling for cancer subtyping.

Publications

Liquid biopsy epigenomic profiling for cancer subtyping.

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