Early onset bladder cancers show distinct clinical, pathological and molecular features
Authors: Arndt Hartmann, Robert Stoehr, Dirk Zaak, Max Burger, Peter Wild, Joke M. Van Oers, Ellen Zwarthoff, Theo Van der Kwast, Ferdinand Hofstaedter
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

1465 

Bladder cancer is regarded as one of the paradigms for an tumor caused by exogenous factors. However, there is convincing evidence from large family and twin studies, that inherited risk factors are also important in bladder carcinogenesis. The aim of this study was to built a large database of early onset bladder cancer patients for cohort studies to detect genetic variants with impact on bladder cancer risk. To get insights in possible genetic risk factors, we conducted a clinico- pathological and molecular study to investigate the natural history and prognosis and the molecular alterations of bladder cancer in young patients. 250 early-onset bladder cancer patients (diagnosis ≤45 years) were collected through database search of cancer registries and 14 pathologies in Germany. The most frequent and earliest genetic alterations found in bladder cancer were investigated in a first cohort of 109 patients (mean age 36 years) and compared with 129 bladder cancer patients (mean age 72 years) from a prospective study of molecular cancer diagnosis in urine. Deletions of chromosome 9p/q and 17p (LOH) and microsatellite instability (MSI) were determined by microsatellite analyses. p53 was directly sequenced and the six known mutations in FGFR3 were detected by SNaPshot analysis. The expression of p53, MIB-1, CK20, mdm2, p21, MSH2, MLH1 and MSH6 was evaluated by immunohistochemistry. The young patient cohort showed significantly more frequent non-invasive (78%-p=0.04) and low-grade (G1/2-89%- p=0.03) tumors than the control group (64% and 78%, respectively), but did not differ in stage- and grade-specific recurrence and survival. There was a higher rate of tumors in relatives and a higher frequency of smokers in the young patients. The young patients showed a lower frequency of chromosome 9 deletions (26%) and FGFR3 mutations (38%) than the control group (58% and 67%, respectively- p<0.01). MSI (evaluated with the Bethesda consensus primer panel) was detected in only 2 of 107 investigated tumors, with no expression loss of the mismatch repair proteins. The rate of p53 positivity by IHCH was significantly higher in the young patients (68%) compared to the control (34%, p<0.0001) and was associated with parallel p21 and mdm2 expression. p53 mutations ware rare in these tumors. In summary, early-onset bladder cancer patients showed distinct clinical and pathological features. The higher tumor rate in the family history and differences in the genetic alterations with lower frequency of chromosome 9 deletions and FGFR3 mutations and a frequent overexpression of wild-type p53 suggest that distinct molecular mechanisms could play a role in early onset bladder cancer. The mutator phenotype and the HNPCC syndrome do not play a role in young patients with bladder cancer. The investigation of genetic variants in this large selected patient cohort could reveal polymorphims with impact on bladder cancer development in the general population.