Patterns of p53, erbB-2, and EGF-r expression in premalignant lesions of the urinary bladder*1

Wagner, Urs; Sauter, Guido; Moch, Holger; Novotna, Hedvika; Epper, Rita; Mihatsch, Michael J.; Waldman, Frederic M.

doi:10.1016/0046-8177(95)90086-1

Cited by 75 publications

(43 citation statements)

References 17 publications

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“…A characteristic specific to p53 was that it was the sole biomarker associated with features of cellular dedifferentiation (ie, tumor grade) and concomitant carcinoma in situ, which is an aggressive precursor lesion of invasive tumors. 16,19,[21][22][23] These differences in the proportion of alterations along the progression model may reflect the role of each cell-cycle regulator and their cumulative effect in carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Cooperative effect of cell-cycle regulators expression on bladder cancer development and biologic aggressiveness

et al. 2007

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The aim of this study was to evaluate the association between p53, p21, p27 and Rb expression, alone or in combination, with pathological features and clinical outcomes of urothelial carcinoma of the bladder. Immunohistochemical staining for p53, p21, p27 and pRB was performed on tissue microarrays comprising normal urothelium from nine controls, transurethral resection specimens from 74 patients with Ta, Tis and/or T1 bladder urothelial carcinoma, radical cystectomy specimens from 226 consecutive urothelial carcinoma patients, and lymph nodes with tumor invasion from 50 of the 226 cystectomy patients. All nine controls had normal status of biomarkers. The proportion of biomarkers alterations was highest in lymph node metastases. p53, pRB and p27 were associated with pathologic stage, lymphovascular invasion and lymph node metastases (P-valuesr0.050). Each biomarker alone, each combination of two biomarkers and the number of altered biomarkers were all independently associated with disease recurrence and bladder cancer-specific death (Pvaluesr0.046). In patients with organ-confined disease, p53, p21 and p27 were independently associated with disease recurrence and bladder cancer-specific death (P-valuesr0.046). There was a good but not perfect concordance in the expression of biomarkers between matched transurethral resection and cystectomy specimens (n ¼ 22; concordance rates: 77-86%) and between matched lymph node and cystectomy specimens (n ¼ 50, 70-92%). In conclusion, p53, p21, p27 and pRB have a cooperative/synergistic role in the biologic behavior of bladder urothelial carcinoma. In contrast to the use of single biological markers, evaluation of their combined status may improve prognostic models and help identify patients who might benefit from adjuvant therapies and in decision-making. Modern Pathology (2007) 20, 445-459.

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Section: Discussionmentioning

confidence: 99%

Cooperative effect of cell-cycle regulators expression on bladder cancer development and biologic aggressiveness

et al. 2007

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“…Notably, deletions involving chromosomes 9p and 9q are frequently found in super®cial papillary tumors, whereas dysfunction of p53 and pRb is primarily associated with CIS and invasive tumors (Dalbagni et al, 1993;Spruck et al, 1994;Rosin et al, 1995;Wagner et al, 1995). However, with the exception of several chemical carcinogenesis models (Oyasu, 1995;Ogawa et al, 1998), most of the clinical data are correlative in nature.…”

Section: Introductionmentioning

confidence: 99%

Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation

et al. 2001

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Urothelial tumors develop along two distinctive phenotypic pathways (super®cial papillary non-invasive tumors versus¯at carcinoma in situ lesions), with markedly di erent biological behavior and prognosis. Although multiple genetic alterations have been identi®ed in human bladder cancer, their cause ± e ect relationship with the two pathways has not been ®rmly established. Using a urothelium-speci®c promoter of the uroplakin II gene, we showed earlier in transgenic mice that the urothelial expression of SV40T antigen, which inactivates p53 and pRb, induced carcinoma in situ and invasive and metastatic bladder cancer. In striking contrast, we demonstrate here that the urothelial expression of an activated Ha-ras in transgenic mice caused urothelial hyperplasia and super®cial papillary non-invasive bladder tumors. These results provide strong, direct experimental evidence that the two phenotypical pathways of bladder tumorigenesis are caused by distinctive genetic defects. Our results indicate that Ha-ras activation can induce urothelial proliferation in vivo; and that urothelial hyperplasia is a precursor of low-grade, super®cial papillary bladder tumors. Our transgenic models provide unique opportunities to study the detailed molecular events underlying di erent types of bladder neoplasms, and can serve as useful preclinical models for evaluating the in vivo e cacy of preventive and therapeutic agents that act on various signaling pathways in bladder cancer.

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“…11,12 CIS lesions often harbor p53 alterations (ie, accumulation of p53 protein because of mutations) and predominantly have an aneuploid DNA content. 5,13,14 Controversy exists on the involvement of chromosome 9 in CIS. Rosin and colleagues 15 found loss of heterozygosity for 9p and q in the majority of CIS cases, including a high frequency of homozygous deletions of the p16 locus.…”

mentioning

confidence: 99%

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

Hopman

Kamps

Speel

et al. 2002

The American Journal of Pathology

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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 chromosome 9 alterations are among the earliest and most prevalent genetic alterations in bladder cancer, discrepancy 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 combined 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 (p16 INK4A /p14 ARF ) and INK4B (p15 INK4B ) by multiple-target fluorescence in situ hybridization, and for p53 protein accumulation by immunohistochemistry. 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 analyzed, 12 of which were not associated with a synchronous pTa or pT1 carcinoma, no numerical losses for chromosome 9 (p11-q12 and 9p21) were detected as compared with chromosomes 1 and 7. Furthermore 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 homozygous deletion of 9p21. The others were invasive carcinomas 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 lesions contained cells with no specific loss of chromosome 9, as opposed to CIS lesions with synchronous carcinomas that showed evidence of chromosome 9 loss. Furthermore our data strengthen the proposition that p53 mutations (p53 overexpression) precede loss of chromosomes 9 and 9p21 in CIS as precursor for invasive bladder cancer, as opposed to noninvasive carcinomas where chromosome 9 (9p11-q12) losses are early and frequently combined with homozygous deletions of 9p21. Carcinoma of the urinary bladder is a common malignancy worldwide. On the basis of histological and clinical observations two types of potential precursor lesions for invasive cancer are recognized, ie, the low-grade, well differentiated, usually papillary neoplasms (pTa), and the high-grade, poorly differentiated, flat lesions, the carcinoma in situ (CIS). 1-3 pTa tumors demonstrate a high recurrence rate whereas CIS show a high progression rate to invasive carcinomas (pT1-4). 4 -6 In pTa lesions chromosome 9 alterations appear to be a frequent and early event, including deletions of 9p21 (harboring three negative cell-cycle regulators: p16 INK4a , p14 ARF , and p15 INK4b ), 7-12 next to deletions of at least three regions on 9q. 6,10 In up to 70% of pTa cases deletions of 9 and/or 9p21 have been reported in hyperplasia or normal appearing epithe...

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Patterns of p53, erbB-2, and EGF-r expression in premalignant lesions of the urinary bladder*1

Cited by 75 publications

References 17 publications

Cooperative effect of cell-cycle regulators expression on bladder cancer development and biologic aggressiveness

Cooperative effect of cell-cycle regulators expression on bladder cancer development and biologic aggressiveness

Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation

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

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