Genome-wide Association Study for Tumour Stage, Grade, Size, and Age at Diagnosis of Non-muscle-invasive Bladder Cancer

Abstract

Background: Non-muscle-invasive bladder cancer (NMIBC) causes a considerable health burden due to the high recurrence and progression rates. Past studies have identified multiple candidate loci associated with NMIBC prognosis, albeit lacking validation. Moreover, scarce reports exist on genetic susceptibility to independent prognostic predictors of NMIBC, such as stage or grade.

Objective: To investigate genetic associations with NMIBC tumour and patient characteristics at the time of diagnosis.

Design, setting, and participants: A sample of 653 NMIBC cases comes from the Bladder Cancer Prognosis Programme. Replication of the significant findings was conducted in the Nijmegen Bladder Cancer Study cohort (N=1470).

Outcome measurements and statistical analysis: A genome-wide association study (GWAS) was carried out for outcomes of tumour size (as a continuous variable in centimetres), stage (Tis and T1 vs Ta), grade (G3 vs G2 and G1), and age (as continuous [years] and dichotomous [70.2 yr as a cut-off] variables).

Results and limitations: Significant (p<5E-08) associations (N=61) with tumour size, stage, grade, and age were identified in the GWAS discovery stage. None of the variants were independently significantly associated in the replication cohort. A meta-analysis of both cohorts suggests that rs180940944 (13q13.3 locus, NBEA) was associated with tumour size as a continuous variable (ß=0.9cm, p=2.92E-09). However, other single nucleotide polymorphisms in this region did not show evidence of association in the meta-analysis.

Conclusions: Our study suggests that rs180940944 (NBEA) is associated with an increased NMIBC tumour size at the time of diagnosis. Given study limitations, further replication is essential to validate the finding.

Patient summary: The current study reports on a genome-wide association study on non-muscle-invasive bladder cancer tumour and patient characteristics. We suggest that NBEA gene might be associated with increased tumour size at the time of diagnosis. The result must be replicated to establish validity.

Keywords: Age; Genome-wide association study; Grade; Non–muscle-invasive bladder cancer; Size; Stage.