Clonal Origin of Bladder Cancer

Sidransky, David; Frost, Philip; Eschenbach, Andrew von; Oyasu, Ryoichi; Preisinger, Antonette C.; Vogelstein, Bert

doi:10.1056/nejm199203123261104

Cited by 477 publications

(248 citation statements)

References 25 publications

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“…A wealth of evidence supports the concept that viral induced mammary tumors and hyperplasias in mice are clonal dominant populations and probably represent the progeny of a single cell (Cardi et al, 1983;Cohen et al, 1979a,b;Kordon et al, 1995;Young et al, 1971). Similar conclusions about monoclonality have been reached for human breast cancer, carcinoma of the colon, uterine, cervix and bladder, ovarian teratomas and many hematological neoplasms (Fearon et al, 1987, Sidransky et al, 1992, Wainscoat et al, 1990. This implies that mammary tumors and hyperplasias are developed from tissue-speci®c epithelial stem cells and therefore represent populations of mutated stem cells and their di erentiating progeny.…”

Section: Introductionmentioning

confidence: 74%

MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways

2000

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The study of the mouse mammary tumor virus (MMTV) has provided important insights into the mechanisms of gene transcription regulation by steroid hormones, the mode of action of heritable super antigens and the progressive nature of neoplastic transformation in the mammary gland. Here we describe the current situation with respect to the latter aspect of MMTV biology and the prospects for further advance in our understanding of breast cancer in humans that may be expected from a continued study of MMTV-induced mammary neoplasia. MMTV is a heritable somatic mutagen whose target range is limited. Commonly, the tumorigenic capacity of MMTV is restricted to mammary gland, whereas infection is found in a variety of cell types. In order to replicate, proviral DNA must be inserted into the cell DNA and cell division is required to ®x the mutation. Yet only in the mammary epithelium does this lead to neoplastic transformation. This suggests a unique relationship between MMTV and mammary epithelium. In evaluating this relationship, we and others have discovered genes and potential gene pathways that are pertinent in mammary di erentiation and neoplasia. In addition, the clonal nature of these progressive events from normal to malignant phenotype has become increasingly clear. The weight of these observations compel us to conclude that mammary neoplasms arise from multipotent mammary epithelial cells through a process of acquired mutations that are re¯ected in the increasingly malignant nature of the population of progeny produced by these damaged stem cells.

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Section: Introductionmentioning

confidence: 74%

MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways

2000

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“…In this study, two cases were immunohistochemically positive and SSCP negative (6% of the tumors). If the proportion of cells containing the mutation is low or if mutations occur outside the regions examined (exons 5 to 8), this could explain cases in which immunohistochemistry was positive but no mutation was detected (8,38). Conversely, six cases were immunohistochemically negative and SSCP positive (19%).…”

Section: Discussionmentioning

confidence: 99%

“…In the upper aerodigestive tract (3,4), lung (5), stomach (6), and liver (7), multiple carcinomas have been alleged to be multicentric in origin. Conversely, investigators have claimed that multiple tumors in the bladder (8,9), gynecologic organs (10 -12), and breast (13) have the same clonal origin rather than multicentric. Moreover, some investigators have reported that multiple tumors in the urothelial organs and liver can have either a common or an independent origin (14 -16).…”

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confidence: 99%

Discordance of P53 Mutations of Synchronous Colorectal Carcinomas

et al. 2000

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It is unclear whether synchronous multiple tumors arise from multicentric or monoclonal origins. To verify the multicentric origin of synchronous colorectal carcinomas at a genetic level, immunohistochemical and molecular techniques were used to determine the p53 alterations in individual lesions of synchronous colorectal carcinomas. This study was based on a total of 32 colorectal tumors from 16 patients. Twenty-one of the 32 (66%) advanced tumors examined had positive staining for p53. Single-strand conformation polymorphism and polymerase chain reaction direct sequencing were carried out for exons 5 to 8 of p53. All cases had p53 mutations in one or more tumors of synchronous lesions. In nine patients in this series, individual lesions were found to carry a different mutated codon of the p53 gene. In the other seven patients, a p53 mutation was found in one tumor but not in another. These results indicate discordance of the mutation pattern of p53 in individual lesions of multiple colorectal carcinomas and support the idea that most synchronous colorectal carcinomas are genetically distinguishable and are multicentric in origin. We also confirmed the high frequency of p53 mutations in left-sided (71%) and rectal (91%) carcinomas, rather than right-sided (43%; P ‫؍‬ .04) carcinomas, suggesting that the molecular mechanism of synchronous colorectal carcinomas might differ between right-and left-sided tumors in the same patient.KEY WORDS: P53, Single-strand conformation polymorphism, Synchronous colorectal carcinomas.Mod Pathol 2000;13(2):131-139

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“…Molecular genetic studies support the monoclonality theory and indicate that tumour cells spread to multiple sites by intraepithelial or intraluminal seeding (Sidransky et al, 1992;Habuchi et al, 1993;Takahashi et al, 1998;Dalbagni et al, 2001), while other studies have shown that field effect underlies some multifocal urothelial tumours (Paiss et al, 2002;Jones et al, 2005). An understanding of the mechanism leading to accumulation of genetic alterations during multifocal tumour development may provide new prospects for both the early detection and prevention of the recurrence of urothelial cancer.…”

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confidence: 96%

Genetic analysis of multifocal superficial urothelial cancers by array-based comparative genomic hybridisation

et al. 2007

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The purpose of this study was to investigate the accumulation of genetic alterations during metachronous and/or synchronous development of multifocal low-grade superficial urothelial tumours in the same patient, by using array-based comparative genomic hybridisation (array-CGH) and FGFR mutation analysis. We analysed 24 tumours (pTa-1 G1-2) from five patients. We had previously identified a clonal relationship among the tumours of each patient by microsatellite analysis. This time, unsupervised hierarchical cluster analysis revealed that the tumours from each patient were clustered together independently of the tumours from the other patients. All of the tumours from a single patient showed a set of 2 -7 identical regional or whole-arm chromosomal changes. In addition, several individual alterations were also found. Cladistic diagrams revealed that the accumulation of genetic alterations could not be explained by a linear model, and the existence of a hypothetical precursor cell was assumed in four patients. In some cases, FGFR mutation seemed to occur later during multifocal tumour development. Taken together, these findings suggest that low-grade superficial urothelial tumours accumulate minor genetic alterations during multifocal development, although these tumours are genetically stable.

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Clonal Origin of Bladder Cancer

Abstract: A number of bladder tumors can arise from the uncontrolled spread of a single transformed cell. These tumors can then grow independently with variable subsequent genetic alterations.

Cited by 477 publications

References 25 publications

MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways

MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways

Discordance of P53 Mutations of Synchronous Colorectal Carcinomas

Genetic analysis of multifocal superficial urothelial cancers by array-based comparative genomic hybridisation

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