Abstract
Breast cancer in very young women (≤35 years; BCVY) presents more aggressive and complex biological features than their older counterparts (BCO). Our aim was to evaluate methylation differences between BCVY and BCO and their DNA epigenetic age. EPIC and 450k Illumina methylation arrays were used in 67 breast cancer tumours, including 32 from BCVY, for methylation study and additionally we analysed their epigenetic age. We identified 2 219 CpG sites differently-methylated in BCVY vs. BCO (FDR < 0.05; β-value difference ± 0.1). The signature showed a general hypomethylation profile with a selective small hypermethylation profile located in open-sea regions in BCVY against BCO and normal tissue. Strikingly, BCVY presented a significant increased epigenetic age-acceleration compared with older women. The affected genes were enriched for pathways in neuronal-system pathways, cell communication, and matrix organisation. Validation in an independent sample highlighted consistent higher expression of HOXD9, and PCDH10 genes in BCVY. Regions implicated in the hypermethylation profile were involved in Notch signalling pathways, the immune system or DNA repair. We further validated HDAC5 expression in BCVY. We have identified a DNA methylation signature that is specific to BCVY and have shown that epigenetic age-acceleration is increased in BCVY.
Highlights
Breast cancer (BC) is the most common malignancy in women worldwide[1]
CpG sites differently-methylated between biological features than their older counterparts (BCO) vs normal tissue samples and 36 628 CpG for BC in very young women (BCVY) vs. normal tissues
After removing 18 150 different methylated CpGs that were common to both the control and experimental groups, we analysed the differences in methylation between BCVY and BCO; we identified 2219 CpG sites significantly differentially methylated in BC depending on patient age (Supplementary Fig. S1)
Summary
Breast cancer (BC) is the most common malignancy in women worldwide[1]. Approximately 6.6% of BCs are diagnosed in women aged 40 or younger, and of all cancers diagnosed in this age group, 40% are BCs; the average risk of developing BC by age 40 is one in 1732 and they are not included in mammography screening programmes. Genomic factors, including mutations in tumour suppressor and oncogenes, copy number variation, and epigenetics, are likely implicated in cancer initiation and progression in young women. Previous studies from our group[5] suggest that miRNA expression is different in BCVY and that this may be involved in the increased aggressiveness of tumours in this age group. These alterations do not fully explain carcinogenesis and subsequent progression in these young women. Understanding the role of the epigenome in younger women may lead to the development of novel epigenetic-based diagnostic strategies, taking the young age of these patients into account
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