DNA methylation differences in noncoding regions in ER negative breast tumors between Black and White women

Jianhong Chen; Michael J Higgins; Qiang Hu; Thaer Khoury; Song Liu; Christine B Ambrosone; Zhihong Gong

doi:10.3389/fonc.2023.1167815

DNA methylation differences in noncoding regions in ER negative breast tumors between Black and White women

Front Oncol. 2023 May 24:13:1167815. doi: 10.3389/fonc.2023.1167815. eCollection 2023.

Authors

Jianhong Chen¹, Michael J Higgins², Qiang Hu³, Thaer Khoury⁴, Song Liu³, Christine B Ambrosone¹, Zhihong Gong¹

Affiliations

¹ Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.
² Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.
³ Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.
⁴ Department of Pathology & Laboratory Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.

Abstract

Introduction: Incidence of estrogen receptor (ER)-negative breast cancer, an aggressive tumor subtype associated with worse prognosis, is higher among African American/Black women than other US racial and ethnic groups. The reasons for this disparity remain poorly understood but may be partially explained by differences in the epigenetic landscape.

Methods: We previously conducted genome-wide DNA methylation profiling of ER- breast tumors from Black and White women and identified a large number of differentially methylated loci (DML) by race. Our initial analysis focused on DML mapping to protein-coding genes. In this study, motivated by increasing appreciation for the biological importance of the non-protein coding genome, we focused on 96 DMLs mapping to intergenic and noncoding RNA regions, using paired Illumina Infinium Human Methylation 450K array and RNA-seq data to assess the relationship between CpG methylation and RNA expression of genes located up to 1Mb away from the CpG site.

Results: Twenty-three (23) DMLs were significantly correlated with the expression of 36 genes (FDR<0.05), with some DMLs associated with the expression of single gene and others associated with more than one gene. One DML (cg20401567), hypermethylated in ER- tumors from Black versus White women, mapped to a putative enhancer/super-enhancer element located 1.3 Kb downstream of HOXB2. Increased methylation at this CpG correlated with decreased expression of HOXB2 (Rho=-0.74, FDR<0.001) and other HOXB/HOXB-AS genes. Analysis of an independent set of 207 ER- breast cancers from TCGA similarly confirmed hypermethylation at cg20401567 and reduced HOXB2 expression in tumors from Black versus White women (Rho=-0.75, FDR<0.001).

Discussion: Our findings indicate that epigenetic differences in ER- tumors between Black and White women are linked to altered gene expression and may hold functional significance in breast cancer pathogenesis.

Keywords: Black and White women; DNA methylation; ER negative tumor; breast cancer; noncoding regions.

Grants and funding

This work was supported by the Breast Cancer Research Foundation, the National Cancer Institute (R01 CA133264; R01 CA246688; P01 CA151135), and used Roswell Park Comprehensive Cancer Center’s Data Bank and BioRepository, Genomics Shared Resource, and Bioinformatics Shared Resource (P30 CA016056).