A genome-wide cell-free DNA methylation analysis identifies an episignature associated with metastatic luminal B breast cancer

Author:

Rodriguez-Casanova Aitor,Costa-Fraga Nicolas,Castro-Carballeira Clara,González-Conde Miriam,Abuin Carmen,Bao-Caamano Aida,García-Caballero Tomás,Brozos-Vazquez Elena,Rodriguez-López Carmela,Cebey Victor,Palacios Patricia,Cueva Juan F.,López-López Rafael,Costa Clotilde,Díaz-Lagares Angel

Abstract

Breast cancers of the luminal B subtype are frequent tumors with high proliferation and poor prognosis. Epigenetic alterations have been found in breast tumors and in biological fluids. We aimed to profile the cell-free DNA (cfDNA) methylome of metastatic luminal B breast cancer (LBBC) patients using an epigenomic approach to discover potential noninvasive biomarkers. Plasma cfDNA was analyzed using the Infinium MethylationEpic array in a cohort of 14 women, including metastatic LBBC patients and nontumor controls. The methylation levels of cfDNA and tissue samples were validated with droplet digital PCR. The methylation and gene expression data of 582 primary luminal breast tumors and 79 nontumor tissues were obtained from The Cancer Genome Atlas (TCGA). We found an episignature of 1,467 differentially methylated CpGs that clearly identified patients with LBBC. Among the genes identified, the promoter hypermethylation of WNT1 was validated in cfDNA, showing an area under the ROC curve (AUC) of 0.86 for the noninvasive detection of metastatic LBBC. Both paired cfDNA and primary/metastatic breast tumor samples showed hypermethylation of WNT1. TCGA analysis revealed significant WNT1 hypermethylation in the primary tumors of luminal breast cancer patients, with a negative association between WNT1 methylation and gene expression. In this proof-of-principle study, we discovered an episignature associated with metastatic LBBC using a genome-wide cfDNA methylation approach. We also identified the promoter hypermethylation of WNT1 in cfDNA as a potential noninvasive biomarker for luminal breast cancer. Our results support the use of EPIC arrays to identify new epigenetic noninvasive biomarkers in breast cancer.

Funder

Sociedad Española de Oncología Médica

Axencia Galega de Innovación

Xunta de Galicia

Instituto de Salud Carlos III

Fundación Científica Asociación Española Contra El Cáncer

Publisher

Frontiers Media SA

Subject

Cell Biology,Developmental Biology

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1. Methods in DNA methylation array dataset analysis: A review;Computational and Structural Biotechnology Journal;2024-12

2. Comprehensive Guide of Epigenetics and Transcriptomics Data Quality Control;2024-08-06

3. Omics Technologies Improving Breast Cancer Research and Diagnostics;International Journal of Molecular Sciences;2023-08-11

4. Epigenetic reprogramming in cancer: From diagnosis to treatment;Frontiers in Cell and Developmental Biology;2023-02-14

5. Epigenetics of Thymic Epithelial Tumors;Cancers;2023-01-05

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