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Title: Epigenetic mechanisms of breast cancer risk exposures
Author: Johansson, Annelie Ewa
ISNI:       0000 0004 8499 454X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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The breast cancer incidence rate is increasing and risk prediction needs to be improved. Higher lifetime oestrogen exposure is associated with increased risk, however, the mechanisms between oestrogen exposure and breast cancer development are not clear. It was hypothesised that a woman's lifetime oestrogen exposure accumulates DNA methylation changes, detectable in blood, which can be used for risk assessment for breast cancer. An epigenome-wide association study (EWAS) of an estimated lifetime oestrogen exposure (ELEE)-model was conducted in Illumina HumanMethylation450K (HM450K) data in EPIC-Italy (n=216). A breast cancer-associated Methylation Index (MI) of ELEE, including 31 CpG-sites, was developed using HM450K data from EPIC-Italy (n=237) and the Generations Study (n=65). The MI was validated using targeted bisulphite sequencing in the Generations Study (n=440 case-control pairs), and replicated in a meta-analysis including four study cohorts. In the EWAS, 694 CpG sites were associated (Q < 0.05) with ELEE. The association between the MI and breast cancer risk was validated in the Generations Study targeted sequencing data (ORQ4_vs_Q1=1.77, 95%CI 1.07-2.93, P=0.027) and replicated in the meta-analysis (ORQ4_vs_Q1=1.45, 95%CI: 1.05-2.00, P=0.024). However, the correlation between the MI and ELEE was not replicated across study cohorts. Furthermore, two mechanisms for oestrogen-induced blood DNA methylation changes were explored in lymphocyte cell-lines (LCLs): transcriptional response via the oestrogen receptors (ERs), and DNA repair response following DNA damage. No expression of the ERs was identified in the LCLs, but indications of increasing DNA damage following oestrogen-treatment. In this project, a blood DNA methylation signature for breast cancer risk was identified, however, the signature for lifetime oestrogen exposure was not validated. Further replication of the EWAS and improvements to the MI are needed to assess if an epigenetic signature in blood can be incorporated in population risk screening. Targeted prevention for high-risk women has the potential to reduce the breast cancer incidences.
Supervisor: Flanagan, James ; Vineis, Paolo Sponsor: Breast Cancer Now
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral