Longitudinal monitoring of cell-free DNA methylation in ALK-positive non-small cell lung cancer patients

Clinical Epigenetics

Research

Simone Bauer¹  Florian Janke²  Arlou Kristina Angeles²  Holger Sültmann³  Anja Lisa Riediger⁴  Petros Christopoulos⁵  Michael Thomas⁵  Albrecht Stenzinger⁶  Thomas Muley⁷  Marc A. Schneider⁷  Martin Reck⁸ 

[1] Division of Cancer Genome Research, German Cancer Research Center, National Center for Tumor Diseases, Heidelberg, Germany;Division of Cancer Genome Research, German Cancer Research Center, National Center for Tumor Diseases, Heidelberg, Germany;German Center for Lung Research (DZL), TLRC Heidelberg, Heidelberg, Germany;Division of Cancer Genome Research, German Cancer Research Center, National Center for Tumor Diseases, Heidelberg, Germany;German Center for Lung Research (DZL), TLRC Heidelberg, Heidelberg, Germany;German Cancer Consortium (DKTK), Heidelberg, Germany;Division of Cancer Genome Research, German Cancer Research Center, National Center for Tumor Diseases, Heidelberg, Germany;Helmholtz Young Investigator Group, Multiparametric Methods for Early Detection of Prostate Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany;Department of Urology, Heidelberg University Hospital, Heidelberg, Germany;Faculty of Biosciences, Heidelberg University, Heidelberg, Germany;German Center for Lung Research (DZL), TLRC Heidelberg, Heidelberg, Germany;Department of Oncology, Thoraxklinik and National Center for Tumor Disease (NCT) at Heidelberg University Hospital, Heidelberg, Germany;German Center for Lung Research (DZL), TLRC Heidelberg, Heidelberg, Germany;Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany;German Cancer Consortium (DKTK), Heidelberg, Germany;German Center for Lung Research (DZL), TLRC Heidelberg, Heidelberg, Germany;Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany;Lung Clinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany;

关键词: Biomarkers;    Cell-free DNA;    cfMeDIP-seq;    DNA methylation;    Liquid biopsy;    Epigenetics;   

DOI  :  10.1186/s13148-022-01387-4

 received in 2022-09-29, accepted in 2022-11-25,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundDNA methylation (5-mC) signals in cell-free DNA (cfDNA) of cancer patients represent promising biomarkers for minimally invasive tumor detection. The high abundance of cancer-associated 5-mC alterations permits parallel and highly sensitive assessment of multiple 5-mC biomarkers. Here, we performed genome-wide 5-mC profiling in the plasma of metastatic ALK-rearranged non-small cell lung cancer (NSCLC) patients receiving tyrosine kinase inhibitor therapy. We established a strategy to identify ALK-specific 5-mC changes from cfDNA and demonstrated the suitability of the identified markers for cancer detection, prognosis, and therapy monitoring.MethodsLongitudinal plasma samples (n = 79) of 21 ALK-positive NSCLC patients and 13 healthy donors were collected alongside 15 ALK-positive tumor tissue and 10 healthy lung tissue specimens. All plasma and tissue samples were analyzed by cell-free DNA methylation immunoprecipitation sequencing to generate genome-wide 5-mC profiles. Information on genomic alterations (i.e., somatic mutations/fusions and copy number alterations) determined in matched plasma samples was available from previous studies.ResultsWe devised a strategy that identified tumor-specific 5-mC biomarkers by reducing 5-mC background signals derived from hematopoietic cells. This was followed by differential methylation analysis (cases vs. controls) and biomarker validation using 5-mC profiles of ALK-positive tumor tissues. The resulting 245 differentially methylated regions were enriched for lung adenocarcinoma-specific 5-mC patterns in TCGA data and indicated transcriptional repression of several genes described to be silenced in NSCLC (e.g., PCDH10, TBX2, CDO1, and HOXA9). Additionally, 5-mC-based tumor DNA (5-mC score) was highly correlated with other genomic alterations in cell-free DNA (Spearman, ρ > 0.6), while samples with high 5-mC scores showed significantly shorter overall survival (log-rank p = 0.025). Longitudinal 5-mC scores reflected radiologic disease assessments and were significantly elevated at disease progression compared to the therapy start (p = 0.0023). In 7 out of 8 instances, rising 5-mC scores preceded imaging-based evaluation of disease progression.ConclusionWe demonstrated a strategy to identify 5-mC biomarkers from the plasma of cancer patients and integrated them into a quantitative measure of cancer-associated 5-mC alterations. Using longitudinal plasma samples of ALK-positive NSCLC patients, we highlighted the suitability of cfDNA methylation for prognosis and therapy monitoring.

【 授权许可】

CC BY   
© The Author(s) 2022

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