MDM2 SNP309 promoter polymorphism and p53 mutations in urinary bladder carcinoma stage T1.
BACKGROUND
Urinary bladder carcinoma stage T1 is an unpredictable disease that in some cases has a good prognosis with only local or no recurrence, but in others can appear as a more aggressive tumor with progression to more advanced stages. The aim here was to investigate stage T1 tumors regarding MDM2 promoter SNP309 polymorphism, mutations in the p53 gene, and expression of p53 and p16 measured by immunohistochemistry, and subsequently relate these changes to tumor recurrence and progression. We examined a cohort of patients with primary stage T1 urothelial carcinoma of the bladder and their tumors.


METHODS
After re-evaluation of the original slides and exclusions, the study population comprised 141 patients, all with primary stage T1 urothelial carcinoma of the bladder. The hospital records were screened for clinical parameters and information concerning presence of histologically proven recurrence and progression. The paraffin-embedded tumor material was evaluated by immunohistochemistry. Any mutations found in the p53 gene were studied by single-strand conformation analysis and Sanger sequencing. The MDM2 SNP309 polymorphism was investigated by pyrosequencing. Multivariate analyses concerning association with prognosis were performed, and Kaplan-Meier analysis was conducted for a combination of changes and time to progression.


RESULTS
Of the 141 patients, 82 had at least one MDM2 SNP309 G allele, and 53 had a mutation in the p53 gene, but neither of those anomalies was associated with a worse prognosis. A mutation in the p53 gene was associated with immunohistochemically visualized p53 protein expression at a cut-off value of 50%. In the group with p53 mutation Kaplan-Meier analysis showed higher rate of progression and shorter time to progression in patients with immunohistochemically abnormal p16 expression compared to them with normal p16 expression (p = 0.038).


CONCLUSIONS
MDM2 SNP309 promoter polymorphism and mutations in p53 were not associated with worse prognosis in this cohort of patients with primary stage T1 urinary bladder carcinoma. However, patients with abnormal p16 expression and a mutated p53 gene had a higher rate of and a shorter time to progression, and p53 gene mutation was associated with an abnormal immunohistochemistry for p53 at a cut-off of 50%.
Molecular and Immunological Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Department of Clinical Pathology and Clinical Genetics, Östergötland County Council, Linköping, Sweden. hansolsson33@telia.com
Hans
H
Olsson
Per
P
Hultman
Johan
J
Rosell
Peter
P
Söderkvist
Staffan
S
Jahnson
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
C493956:CDKN1A protein, human; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009363:Neoplasm Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2