Allelic deletions of cell growth regulators during progression of bladder cancer

Cell growth regulators include proteins of the p53 pathway encoded by the g enes CDKN2A (p16, p14arf), MDM2, TP53, and CDKN1A (p21) as well as proteins encoded by genes like RB1, E2F, and MYCL. In the present study we investig ated allelic deletions of all these genes in each recurrent bladder tumor f rom well-defined clinical material with more than 3 years of follow-up. We followed three groups (22 or 23 patients/group) of patients with: (a) recur rent noninvasive tumors (Ta); (b) primary muscle-invasive tumors (T2-T4); a nd (c) progressing tumors (Ta/T1 double right arrow T2/T4). We found a sign ificant difference in the numbers of gene loci hit by deletions in muscle-i nvasive versus noninvasive tumors (P = 0.0000002), with the genes most ofte n hit by deletions in muscle-invasive tumors being TP53, RB1, and MYCL. A n umber of novel findings were made. Losses of MYCL and RB1 alleles were more pronounced in patients having concomitant field disease because 11 of 14 i nformative cases showed losses compared with 3 of 8 cases without field dis ease. A more pronounced deletion of TP53 (P = 0.002) and RB1 (P = 0.02) was found in the progressing tumor group compared with the recurrent noninvasi ve group, and, finally, the combined loss of TP53 and RB1 was present only in the progressing tumor or muscle-invasive groups. Deletion of two or more loci in TP53, MYCL, RB1, and CDKN2A was found in 10 patients in the progre ssing tumor group and in only 1 patient in the recurrent noninvasive group (P = 0.004). The data demonstrate that a characteristic difference between recurrent noninvasive and recurrent progressing bladder tumors is loss of c ell cycle-regulatory genes in the latter group.