Genetic polymorphisms modify bladder cancer recurrence and survival in a USA population-based prognostic study

Abstract

Objective: To identify genetic variants that modify bladder cancer prognosis focusing on genes involved in major biological carcinogenesis processes (apoptosis, proliferation, DNA repair, hormone regulation, immune surveillance, and cellular metabolism), as nearly half of patients with bladder cancer experience recurrences reliable predictors of this recurrent phenotype are needed to guide surveillance and treatment.

Patients and methods: We analysed variant genotypes hypothesised to modify these processes in 563 patients with urothelial-cell carcinoma enrolled in a population-based study of incident bladder cancer conducted in New Hampshire, USA. After diagnosis, patients were followed over time to ascertain recurrence and survival status, making this one of the first population-based studies with detailed prognosis data. Cox proportional hazards regression was used to assess the relationship between single nucleotide polymorphisms (SNPs) and prognosis endpoints.

Results: Patients with aldehyde dehydrogenase 2 (ALDH2) variants had a shorter time to first recurrence (adjusted non-invasive hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.29-2.78). There was longer survival among patients with non-invasive tumours associated with DNA repair X-ray repair cross-complementing protein 4 (XRCC4) heterozygous genotype compared with wild-type (adjusted HR 0.53, 95% CI 0.38-0.74). Time to recurrence was shorter for patients who had a variant allele in vascular cellular adhesion molecule 1 (VCAM1) and were treated with immunotherapy (P interaction < 0.001).

Conclusions: Our analysis suggests candidate prognostic SNPs that could guide personalised bladder cancer surveillance and treatment.

Keywords: bladder cancer; immune; polymorphism; prognosis; recurrence; survival.

Fig. 1

Bladder cancer recurrence by SNP genotype. Kaplan-Meier plots depict the percent of patients by the time to their first bladder cancer recurrence in years. Shaded lines separate patients by genotype for a) ALDH2 rs2238151 among all patients, logrank P=0.0001 b) IGF1 rs5742714 among all patients, log-rank P=0.0018. Vertical hatches represent censoring due to death or end of follow-up period.

Fig. 2

Bladder cancer survival by SNP genotype. Kaplan-Meier plots depict the percent of patients by the time to death in years. Shaded lines separate patients by genotype for a) XRCC4 rs2662238 restricted to patients with non- invasive tumors, logrank P=0.018, b) DRD4 rs4987059, restricted to patients with non- invasive tumors, log-rank P=0.041, and c) RB1CC1 rs35402311 among all patients, log-rank P=0.001. Vertical hatches represent censoring due to end of follow-up period.

Fig. 3

Bladder cancer prognosis by SNP genotype combination. Kaplan-Meier plots depict the percent of patients by the time to recurrence or death in years. Shaded lines separate patients with non-invasive tumors by genotype for a) IL15RA rs2228059/ MBL2 rs2099902 in relation to recurrence, log-rank P=0.05 and b) TNKS rs34206126/ APC rs2229992 in relation to survival, log-rank P=0.016. Vertical hatches represent censoring due to end of follow-up period.