Factor XIIIA Genotypes to Outcome in Epithelial Ovarian Cancer

Epithelial ovarian cancer (EOC) is often diagnosed at the more aggressive stages of disease and its heterogeneity makes treatment challenging. Factor XIIIA (FXIIIA) is a transglutaminase which crosslinks fibrin to form stable blood clots, as well as having other roles in inflammation and angiogenesis. FXIIIA plasma levels, activity and protein expression have been linked to cancer, including a brief study in ovarian cancer (OC). The gene for FXIIIA, F13A1, is highly polymorphic with several single nucleotide polymorphisms (SNPs) linked to thrombotic disease and cancers. In this PhD project, F13A1 SNPs 1951G>A and 1954G>C were associated with OC overall survival detriment and benefit, respectively. This was maintained in long-term survival (>20 year, n=252). F13A1 SNPs were further investigated for associations with range of survival intervals in a cohort of newly diagnosed patients (ICON7 translational cohort, n=448). The SNP 103G>T (Val34Leu), which has been linked to faster activation of the transglutaminase, and has been linked to cancer risk and thrombotic disease, was associated with survival in EOC. Heterozygotes for this SNP in particular benefited for survival post-progression and overall survival. Expression of FXIIIA protein was explored for the first time in OC tissues and was present in OC stroma, with evidence of poor prognosis with positive stroma staining. However, 34Leu carriers survived longer than wildtype patients when stroma staining was present. As FXIIIA is involved in angiogenesis, when 34Leu protein variants were used in angiogenesis assays, the presence of active Leu variants produced smaller angiogenic networks at a slower rate than wildtype protein, and evidence of a reduction in migratory signalling was seen. The benefit to survival for 34Leu carrying patients is hypothesised to be due to less successful blood vessel recruitment which results in smaller tumours which are easier to treat, posing a potentially exciting future for this protein in EOC.