Department of Surgery & Cancer, Imperial College London
Doi
Abstract
Genetic and Epigenetic mechanisms underlie the natural complexity of phenotypical and morphological aspects of cancer. Extensive phenotypical intra and inter-patient heterogeneity of cancer specimens is a relevant limiting factor in cancer studies. Besides, loss of cell identity and frequent phenotypic switches occurring during cancer progression are elusive and intrinsically challenging to study. Historically, significant efforts have been devoted to identifying the genetic alterations occurring within DNA coding regions of cancer cells. More recently, new studies point the attention on the strong interplay between the epigenetic layout of cells and non-coding regulatory network of DNA. Mutations and alterations of the epigenetic asset among these regions are frequent in cancer; however relevant questions about the different key players involved are still unsolved.
This dissertation aims to provide novel insights into the complex regulatory network of oestrogen receptor-positive breast cancer progression by mining the epigenetic and genetic landscape of patient tissues.
We depict the epigenomic landscape ERα-positive BC focusing on active promoters and enhancers. We describe a novel computational workflow which led to the identification of YY1 and SLC9A3R1 proteins. We show data supporting the concept of a phenotypical evolution of epigenetic traits during cancer progression and experimentally validate the findings.
Also, we introduce a new approach aiming to prioritise the investigation of sites prone to be critical players in breast cancer by coupling the systematic tracking of regulatory regions modulation during cancer progression with single nucleotide variants (SNV) discovery at high depth. This approach resulted with the identification of a recurrent mutation occurring in the core of a CTCF site lying at a border of a silent TAD in q25.1 of the chromosome 17.
Finally, we provide evidence of an epigenetic induced reprogramming occurring in a distinct subpopulation of cancer cell lines exhibiting high plasticity. These cells become quiescent upon oestrogen deprivation and resume proliferation after a deterministic epigenetic modulation of NOTCH target regions.Open Acces