Concurrent mutations of coding and regulatory sequences of the Ha-ras gene in urinary bladder carcinomas

Czerniak, Bogdan; Cohen, Gary; Etkind, Polly R.; Deitch, Daniel; Simmons, Harry; Herz, Fritz; Koss, Leopold G.

doi:10.1016/0046-8177(92)90285-b

Cited by 96 publications

(50 citation statements)

References 25 publications

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“…Moreover, since multiple genetic alterations are simultaneously present in human bladder cancer, the role of a single genetic defect in inducing urothelial tumorigenesis has been di cult to ascertain. Even less is known about the role of other genetic abnormalities that are also prevalent in human bladder cancer, such as the activation of ras, and the overexpression of genes encoding erbB-2, c-myc, and epidermal growth factor receptor (Czerniak et al, 1992;Messing, 1992;Cordon-Cardo et al, 1994;Rezniko et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

“…First, the frequency of Ha-ras mutations in bladder cancer ranged anywhere from 6 to 70% in di erent reports (Visvanathan et al, 1988;Burchill et al, 1991Burchill et al, , 1994Czerniak et al, 1992;Saito, 1992;Knowles and Williamson, 1993;Levesque et al, 1993;Fitzgerald et al, 1995). Second, the stage in which ras mutation occurs varies from early to late or to no stage-correlation (Theodorescu et al, 1990;Czerniak et al, 1992;Knowles and Williamson, 1993;Burchill et al, 1994;Fitzgerald et al, 1995). Third, transfection of an activated ras into primary cultured ®broblasts provoked premature senescence which could be overcome by the inactivation of tumor suppressor genes p53 and p16; this suggests that the activated ras requires the cooperative activity of another oncogenic event to fully transform primary cultured ®broblasts (Serrano et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2001

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“…Mutations of the coding sequence of the H-ras gene, especially at codon 12, are relatively frequent, appearing in approximately 30-40% of urothelial malignancies. 30 Although concurrent mutations within the splicing mechanism and the coding sequence resulting in the overexpression of the transforming gene product were found exclusively in high-grade and high-stage tumors, they could be documented in less than 10% of urothelial tumors. Since the activation of H-ras in bladder carcinogenesis is primarily by point mutations, which do not alter significantly its expression, we could not detect the direct involvement of this gene by the technology used in our study.…”

Section: Expression Profile Of Genes In Bladder Cancer J-h Kim Et Almentioning

confidence: 99%

Alterations in transcription clusters underlie development of bladder cancer along papillary and nonpapillary pathways

Kim

Tuziak

et al. 2005

Laboratory Investigation

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Bladder cancer develops in the urothelial lining from intraurothelial preneoplasia via two pathways, papillary and nonpapillary, which correspond to nonaggressive and aggressive forms of the disease. Because these two forms of cancer may develop via distinct molecular events, we examined the gene expression patterns in the development of bladder cancer from preneoplasia along papillary and nonpapillary pathways. The expression profiles of 19 pairs of RNA samples from adjacent urothelium and tumors were analyzed using cDNA microarrays. For selected genes their expressions were verified on a cohort of 251 bladder cancer patients using tissue microarray and immunohistochemistry and were related to clinicopathological parameters including follow-up data. We identified alterations in seven gene clusters controlling proliferation, differentiation, and programmed cell death that were common for papillary and nonpapillary cancer. In contrast, genes controlling cellular and stromal interactions were altered in the nonpapillary cancer. The expression levels of only two genes from this group could be used to define an aggressive form of the disease. Tumors characterized by the low expression of e-cadherin and the high expression of DNA a-topoisomerase II had a high propensity for distant metastasis and were associated with poor survival. Laboratory Investigation (2005) 85, 532-549. doi:10.1038/labinvest.3700250Keywords: cDNA microarray; bladder cancer; gene expression profile; tissue microarray; preneoplasia Many common human epithelial malignancies develop by progression of microscopically identifiable precursor conditions ranging from mild dysplasia to carcinoma in situ. 1 These conditions progress to clinically aggressive invasive cancer by multiple cumulative molecular events. 2 In fact, the earliest incipient changes occur in normal tissue even before preneoplastic lesions can be microscopically identified. The identification of abnormally expressed genes in such occult preneoplastic lesions may provide important clues as to the molecular pathways involved in the development of human cancer and facilitate early cancer detection and prevention.Carcinoma of the bladder is an exceptionally good candidate for such studies representing a model epithelial malignancy, which develops from microscopically recognizable intraurothelial preneoplastic lesions. [2][3][4] The fifth most frequent human cancer, it primarily affects people over the age of 50 years, and accounts for approximately 3% of all cancerrelated deaths. 5 The common bladder carcinomas arise via two distinct, but sometimes overlapping pathways, papillary and nonpapillary. 6-9 Approximately 80% of bladder tumors are superficially growing lesions that originate from urothelial hyperplasia. They frequently recur after excision but usually do not aggressively invade the bladder wall or metastasize. Most aggressive bladder cancers are of the solid, nonpapillary type and originate from intraurothelial precursor conditions such as dysplasia and carcinoma in situ. They a...

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“…Overall, the frequency of H-rus mutations have been reported to be ranging from 3% to 76% in primary bladder cancer. [37][38][39][40][41][42] Discrepancies in regard to the incidence of the H-ras mutation and its relationship to tumor grade and stage have been reported. These differences are in part due to sample size, population, assay sensitivities, and methodologies.…”

Section: H-ras Oncogene In Bladder Cancermentioning

confidence: 99%

Ribozyme‐Mediated Cancer Gene Therapy

Irie¹,

Bouffard²,

Scanlon³

1997

Int J of Urology

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Concurrent mutations of coding and regulatory sequences of the Ha-ras gene in urinary bladder carcinomas

Cited by 96 publications

References 25 publications

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

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

Alterations in transcription clusters underlie development of bladder cancer along papillary and nonpapillary pathways

Ribozyme‐Mediated Cancer Gene Therapy

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