DNA methylation profiling of HPV associated Head and Neck Squamous Cell Cancer (HNSCC)

Epithelial ovarian carcinoma is the leading cause of death amongst gynaecological cancers. Although mortality rates have not improved dramatically during the last 30 years, it has been well demonstrated that prophylactic salpingo-oophorectomy in high risk women with familial predisposition, is a cost-effective procedure to dramatically reduce the risk of ovarian and fallopian tube cancer. However, only 10% of ovarian cancers are attributable to familial predisposition so there is a need for markers of predisposition to ovarian cancer independent of family history to guide preventative strategies in the 90% of ovarian cancers which are sporadic. The ideal markers would be DNA based surrogates for genetic, transgenerational, developmental and environmental events which subsequently lead to cancer. Employing 5-methylcytosine methylation - a covalent modification of cytosine at CpG dinucleotides which is likely to meet these criteria - there is good evidence for an early stem cell origin of cancer. Embryonic stem (ES) cells rely on Polycomb group (PcG) proteins to reversibly repress genes required for differentiation. These PcG targets were shown to be much more likely to reveal cancer-specific promoter DNA hypermethylation in cancer than genes not targeted by Polycomb repressive complexes (PRC) in ES cells. These changes were also identified at a low level in normal adjacent tissue and in haematopoietic stem/progenitor cells. So it seems to be proven that cancer arises from wayward stem cells in which DNA methylation mediated permanent silencing of specific genes has locked the cell into a perpetual state of self-renewal and rendering it susceptible to malignant transformation by further genetic and epigenetic events. To identify changes associated with a risk of ovarian cancer, we will analyze these epigenetic stem cell markers in peripheral white blood cells. Within a training set, 240 different DNA methylation based stem cell markers will be tested. Based on ROC statistics and logistic regression a model consisting of specific markers will be created and tested in an independent set of cases and controls. The samples for these studies will be obtained from unique sample banks at the Institute of Women`s Health (UCL). Results gained within this study may form the basis for a novel, non-invasive strategy for risk assessment (DNA methylation in WBCs) of ovarian cancer.