Short Communication Identification of Chromosome 9 Alterations and p53 Accumulation in Isolated Carcinoma in Situ of the Urinary Bladder versus Carcinoma in Situ Associated with Carcinoma

Carcinoma in situ (CIS) of the urinary bladder is a flat, aggressive lesion and may be the most common precursor of invasive bladder cancer. Although chro- mosome 9 alterations are among the earliest and most prevalent genetic alterations in bladder cancer, dis- crepancy exists about the frequency of chromosome 9 losses in CIS. We analyzed 22 patients with CIS of the bladder (15 patients with isolated CIS, 7 patients com- bined with synchronous pTa or pT1 carcinomas) for gains and losses of chromosome (peri)centromere loci 1q12, 7p11-q11, 9p11-q12, and 9p21 harboring the INK4A/ARF locus (p16INK4A/p14ARF) and INK4B (p15INK4B) by multiple-target fluorescence in situ hy- bridization, and for p53 protein accumulation by im- munohistochemistry. In 15 of 20 (75%) CIS lesions analyzed p53 overexpression was detected, whereas aneusomy for chromosomes 1 and 7 was identified in 20 of 22 (91%) CIS. In 13 of 22 (60%) CIS cases ana- lyzed, 12 of which were not associated with a syn- chronous pTa or pT1 carcinoma, no numerical losses for chromosome 9 (p11-q12 and 9p21) were detected as compared with chromosomes 1 and 7. Further- more 6 of 12 (50%) patients showed a metachronous invasive carcinoma within 2 years. In the remaining nine biopsies CIS lesions (40%) were recognized that showed losses of chromosome 9p11-q12 and 9p21, six of these were associated with a synchronous pTa or pT1 carcinoma. Three of these carcinomas were pTa and exhibited loss of 9q12 as well as a homozy- gous deletion of 9p21. The others were invasive car- cinomas in which CIS lesions were also recognized that showed no numerical loss of chromosome 9, but did show an accumulation of p53. In conclusion our data demonstrate that predominantly isolated CIS le- sions contained cells with no specific loss of chromo- some 9, as opposed to CIS lesions with synchronous carcinomas that showed evidence of chromosome 9 loss. Furthermore our data strengthen the proposi- tion that p53 mutations (p53 overexpression) precede loss of chromosomes 9 and 9p21 in CIS as precursor for invasive bladder cancer, as opposed to noninva- sive carcinomas where chromosome 9 (9p11-q12) losses are early and frequently combined with ho- mozygous deletions of 9p21. (Am J Pathol 2002, 161:1119 -1125)