Abstract
A complex interaction of environmental factors, stochastic events, and genetic susceptibility can lead to cancer development. The aim of this thesis is to investigate the DNA methylome for cancer, cancer risk, and prediction potential. Studies were performed in peripheral blood to explore systemic changes associated with cancer, and in skin for an in-depth view of total body naevus count, the strongest risk factor for melanoma.Peripheral blood DNA methylomes of 41 cancer-discordant female monozygotic (MZ) twin-pairs were assessed for changes associated with any cancers. The epigenome-wide association study (EWAS) identified one genome-wide significant and several suggestive differential methylated positions (DMPs), three of these showed predictive biomarker potential (near SASH1, COL11A2, and LINC00340).
Early breast cancer specific DNA methylation changes were identified in peripheral blood obtained prior to diagnosis. The DNA methylomes were assessed by two genome-wide DNA methylation techniques in a total of 28 breast cancer discordant MZ twin-pairs. Three novel significant breast-cancer differential methylated regions (DMRs) were identified (in MECOM, PCGF3, and near ELN) that were suggestive of predictive biomarker potential.
Skin DNA methylomes were investigated in association with the number of naevi across the body in 322 female individuals. Three genome-wide significant DMPs were identified in novel genes METRNL, C15orf48, and ARRDC1. Suggestive results included CTC1 and RAF, which are known genes involved in naevi predisposition and melanoma progression. Approximately half of the 48 suggestive DMRs were correlated with gene expression in cis.
Overall, DNA methylation changes related to cancer, pan-cancer and breast cancer specifically, as well as with the melanoma risk factor naevus count were identified. These loci are excellent candidates for further research into their potential as biomarkers or risk factor biological mechanisms in cancer.
| Date of Award | 2017 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Jordana Bell (Supervisor) & Tim Spector (Supervisor) |