DNA repair in bladder cancer predisposition and radiotherapy treatment response

The genetic contribution to bladder cancer risk remains undetermined, while the role of radiotherapy versus surgery in muscle-invasive bladder cancer (MIBC) treatment is hotly debated with the need for predictive biomarkers of treatment response. DNA repair pathways are involved in repairing DNA damage from carcinogens thus preventing carcinogenesis, but also form one of the 5 R’s of radiobiology for determining cancer response to radiotherapy. The aims of this project were: 1) To study the contribution of germline DNA repair gene variants, specifically rare variants (RV) and 3’-untranslated region (3’UTR) single nucleotide polymorphisms (SNP), on bladder cancer risk. 2) To investigate the predictive value of germline DNA repair gene variants and tumour DNA repair protein expression on radiotherapy outcomes in MIBC. RVs can only be identified by sequencing so a developmental multiplexed next-generation sequencing (NGS) project was undertaken, identifying two approaches, with the choice of method based on balancing costs and labour versus accuracy and data needed. Using these methods, candidate RVs were identified in the DNA repair genes, MUTYH and XPC, with XPC RVs being associated with an increased bladder cancer risk (P=0.008) independent of previously identified GWAS SNPs. Putatively functional DNA repair gene 3’UTR SNPs, PARP1 rs8679 and RAD51 rs7180135, were found to increase bladder cancer risk (P=0.05) and predict improved survival following radiotherapy (P=0.01) respectively. Multiplexed NGS of MRE11A identified rs1805363 to be predictive of survival following radiotherapy (P=0.001) but not surgery (P=0.89), and to affect MRE11A isoform expression. Tumour DNA repair protein expression of CtIP, MUTYH and XPC were not found to predict survival following radiotherapy. This study demonstrated the contribution of DNA repair gene variants in bladder cancer risk and predicting radiotherapy response. These findings could contribute to the goal of personalised medicine for targeted primary prevention, early diagnosis and treatment individualisation.