Insertion/deletion polymorphism in the promoter of NFKB1 as a potential molecular marker for the risk of recurrence in superficial bladder cancer.
OBJECTIVE
Bladder cancer is a leading cause of morbidity and mortality. Despite intensive research efforts, histopathological diagnosis of grade and stage, the most important markers for predicting the outcome of the disease, is still necessary. Therefore, a new candidate gene was investigated with regard to its potential utility as a prognostic marker for the course of disease in bladder cancer. A functional insertion/deletion polymorphism has recently been identified in the promoter region of NFKB1 which regulates transcription of the transcription factor NF-kappaB. Several genes involved in oncogenic processes are controlled by NF-kappaB and might be influenced by alterations in its expression.


METHODS
Genotype distributions in patients with bladder cancer (n = 242), in a subgroup consisting only of patients with superficial bladder cancer (n = 101, stage pTa and pT1) and in a group of healthy control subjects (n = 307) were determined using pyrosequencing. The results were compared and the relationship between genotype and survival, and genotype and first recurrence were determined. NFKB1 expression was assessed using native tumor tissue and quantitative real-time PCR.


RESULTS
No statistically significant differences in genotype frequency between healthy controls and patients were detected. Survival was not dependent on the genotype of the polymorphism. Nevertheless, time to first recurrence differed significantly between genotypes (p = 0.037) and this difference could be ascribed to the patients with superficial tumors (p = 0.013). Moreover, multivariate analysis showed that this promoter variant was an independent risk factor. The risk of recurrence in patients with superficial tumors and the homozygous deletion was higher (HR 2.86, p = 0.005) than in those with the homozygous insertion. NFKB1 mRNA expression was highest in tumors from patients carrying the homozygous insertion genotype (p = 0.038).


CONCLUSIONS
These results suggest that the NFKB1 promoter polymorphism is a useful marker for the identification of patients with superficial bladder cancer where the risk of recurrence is high.
Riemann
K
K
Institute of Pharmacogenetics, University Hospital Essen, Essen, Germany. kathrin.riemann@uk-essen.de
Becker
L
L
Struwe
H
H
Rübben
H
H
Eisenhardt
A
A
Siffert
W
W
D000483:Alleles; D015415:Biomarkers; D004251:DNA Transposable Elements / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology; D052002:NF-kappa B p50 Subunit / Q000235:genetics* / Q000502:physiology*; D009364:Neoplasm Recurrence, Local; D011110:Polymorphism, Genetic / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D001749:Urinary Bladder Neoplasms / Q000235:genetics*
D015415:Biomarkers; D004251:DNA Transposable Elements; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human