P53 mutations as an identification marker for the clonal origin of bladder tumors and its recurrences

The clonality of synchronous and metachronous bladder tumors has been studied for years with controversial results. Some recent studies support the ‘polyclonal origin’ hypothesis, i.e. that independently transformed different tumor cell clones exist in the same bladder cancer patient and arise from the field cancerogenisation affecting the entire bladder urothelium by environmental mutagens. Others could demonstrate a monoclonal origin of primary bladder tumors and its recurrences due to a single genetically transformed cell clone spread through the urinary system. With increasing understanding of the clonal origin of bladder tumors and recurrences, clonality markers might contribute to an early and accurate prediction of tumor recurrence and progression. We used p53 mutations as an identification marker permitting the prediction of clonality in bladder tumors and its recurrences. Primary tumors (n=33) and recurrences (n=63) were screened by direct genomic sequencing the p53 mutation hot spot region, exons 5-8. P53 mutations occurred in 12% in our cohort, predominantly in higher malignant (≥G2), invasive (≥T1) tumor samples. We were able to demonstrate intratumoral heterogeneity regarding the p53 status and that recurrences may occur from genetically unrelated primary tumor sites. Some of our results argue for a polyclonal origin of synchronous and metachronous bladder tumors possibly due to the field effect in bladder carcinogenesis. Evidence for a monoclonal origin was found in two cases: one case with a high malignant primary tumor and 3 metachronous recurrences, all of them harbouring the same exon 8 mutation found in the primary tumor; one case with identical mutations of exon 8 in the primary and one recurrent tumor. For further implications concerning clonality of recurrent bladder tumors, p53 status should be combined with a broader range of markers such as CGH and LOH pattern.