DNA repair and bladder cancer.
We are investigating the role of DNA repair in bladder cancer aetiology, development of muscle invasive disease, and response to radiation and combined modality treatments.
Two bladder cancer risk factors are cigarette smoking and occupational exposure to chemicals which form bulky adducts with DNA. Bulky adducts are repaired by nucleotide excision repair (NER). In germline DNA from bladder cancer patients, we have identified five rare variants in the NER gene XPC and functional studies are ongoing.
Radiotherapy and surgery are equivalent in Leeds as curative treatment for muscle invasive disease. Radiotherapy produces double strand breaks (DSB), which are lethal to cells if not repaired. We found extracts from muscle invasive tumours repair DSB via an error-prone microhomology-mediated end-joining pathway (Fig 1), which may be exploitable to increase the therapeutic ratio.
In 90 bladder radiotherapy patients, we found those with lower expression of the DNA DSB signalling protein MRE11 had poorer survival post-radiotherapy and this was validated in a further cohort of 93 patients (Figure 2). As DSB repair is not implicated in surgical outcomes, we expect no such effect in our surgical series, so this might be used as a predictive test to direct individual patient treatment in future.
Figure 1: Error prone pathway for DSB repair
Figure 2: MRE11 expression and outcome following radiotherapy in both test and validation cohorts.
Bentley J, Diggle CP, Harnden P, Knowles MA, Kiltie AE (2004) DNA double strand break repair in human bladder cancer is error prone and involves microhomology associated end joining. Nucleic Acids Res 32:5249-5259.
Sak SC, Barrett JH, Paul AB, Bishop DT, Kiltie AE (2006) Comprehensive analysis of 22 XPC polymorphisms and bladder cancer risk. Cancer Epidemiology Biomarkers and Prevention 15:2537-41.
Kotwal S, Choudhury A, Johnston C, Paul AB Whelan P, Kiltie AE (2007) Similar treatment outcomes for radical surgery and radical radiotherapy in invasive bladder cancer treated in a UK specialist treatment centre. Submitted to Int J Radiation Oncol Biol Phys doi:10.1016/j.ijrobp.2007.06.030