Tumour-based DNA methylation markers of breast cancer survival: a pooled analysis of 2157 cases

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BACKGROUND: Tumour DNA methylation is a potentially valuable marker of breast cancer survival, but previous studies have been limited by relatively small sample sizes. This study aimed to use a large sample size to identify survival-associated DNA methylation markers and develop a methylation-based signature predictive of breast cancer survival. METHODS: We used DNA methylation data from 2,157 breast tumours collected in the Melbourne Collaborative Cohort Study (MCCS) and nine publicly available datasets. An epigenome-wide association study (EWAS) was conducted for five-year overall survival (N = 1,992 cases). Subgroup analyses were carried out by estrogen receptor status. Pathway enrichment analyses were conducted to identify related biological pathways. Elastic net Cox regression was used to develop a signature of survival from DNA methylation data and clinical characteristics, trained on publicly available datasets and tested in the MCCS (N = 425) in addition to the main clinical characteristics. A set of triple-negative tumours (N = 165) with disease-free survival as the outcome was used for additional replication. RESULTS: ) with survival in age-adjusted models, including 281 after adjustment for estrogen receptor (ER) status. In ER-positive tumours, there were 389 associations, of which 315 were absent from the primary EWAS. A 228-CpG signature showed a strong association with survival in the MCCS after adjustment for clinical characteristics: per SD, HR = 1.7, 95%CI: 1.2-2.3, P = 0.001, with a C-index of 0.79, compared with a C-index of 0.75 without methylation information (C-index increase: 0.04, 95%CI: 0.01-0.10). The signature was also predictive of disease-free survival beyond clinical characteristics in triple-negative tumours (HR per SD = 1.4, 95% CI: 1.1-1.8). CONCLUSION: Our findings revealed numerous CpG sites where tumour DNA methylation was associated with breast cancer survival. A substantial improvement in the accuracy of five-year overall survival prediction was achieved by adding a 228-CpG epigenetic score to the main clinicopathological variables. These results suggest that DNA methylation markers may provide additional prognostic information beyond established clinicopathological factors.

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