DNA methylation age in paired tumor and adjacent normal breast tissue in Chinese women with breast cancer.
Level 4 - case-series / case-control
Cross-sectional observational study of paired human tumor and normal tissue samples
PubMed 36991516 · doi:10.1186/s13148-023-01465-1
What was done
Genome-wide DNA methylation profiling was conducted on 196 tumor and 188 paired adjacent normal breast tissue samples from Chinese breast cancer patients in Hong Kong using Illumina MethylationEPIC arrays. DNA methylation (DNAm) age was calculated via Horvath's pan-tissue clock model. Somatic genomic profiles were generated via RNA sequencing, whole-exome sequencing, and whole-genome sequencing. Associations between DNAm age acceleration (AA) and somatic features, tumor subtypes, and breast cancer risk factors were evaluated using Pearson correlation, Kruskal-Wallis tests, and regression models.
What was found
DNAm age correlated strongly with chronological age in adjacent normal tissue (Pearson r = 0.78, P < 2.2e-16) but showed a weaker correlation in tumor tissue (Pearson r = 0.31, P = 7.8e-06). Luminal A tumors showed increased DNAm AA (P = 0.004), whereas HER2-enriched/basal-like tumors showed lower DNAm AA (P < 0.0001) compared with paired normal tissue. Tumor DNAm AA positively correlated with ESR1 expression (r = 0.39, P = 6.3e-06), PGR expression (r = 0.36, P = 2.4e-05), higher body mass index (P = 0.039), and earlier age at menarche (P = 0.035). Conversely, indicators of genomic instability—including TP53 somatic mutations, high tumor mutation/copy number alteration burden, and homologous repair deficiency—were associated with lower DNAm AA.
Why it matters
This study shows that epigenetic age acceleration in breast tissue is tied to estrogen exposure and tumor subtype rather than reflecting a universal aging process across all tumors. It also adds genomic and epigenetic aging data from an understudied East Asian population.
Limits
The cross-sectional design cannot establish causality between genomic alterations and DNAm aging. Adjacent normal tissue may contain field cancerization effects rather than representing healthy breast tissue. All patients were recruited from a single medical center in Hong Kong, and clinical outcomes or survival endpoints were not evaluated.
Cited by
- supports Malignant breast tissue in luminal breast cancer exhibits 10 to 15 years of epigenetic age acceleration.