PCR Techniques for Clonality Assays

Díaz‐Cano, Salvador; Blanes, Alfredo; Wolfe, Hubert J.

doi:10.1097/00019606-200103000-00005

Cited by 74 publications

(105 citation statements)

References 56 publications

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“…been found at various chromosomal loci in many types of human cancers, 38 including urothelial carcinomas. 20 -26 The chromosomal regions in which LOH has been detected are thought to contain specific genes that when disrupted lead to either neoplastic transformation or progression.…”

Section: Discussionmentioning

confidence: 99%

Molecular Genetic Evidence for a Common Clonal Origin of Urinary Bladder Small Cell Carcinoma and Coexisting Urothelial Carcinoma

Liu

Jones

McCarthy

et al. 2005

The American Journal of Pathology

176

105

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In most cases, small-cell carcinoma of the urinary bladder is admixed with other histological types of bladder carcinoma. To understand the pathogenetic relationship between the two tumor types, we analyzed histologically distinct tumor cell populations from the same patient for loss of heterozygosity (LOH) and X chromosome inactivation (in female patients). We examined five polymorphic microsatellite markers located on chromosome 3p25-26 (D3S3050), chromosome 9p21 (IFNA and D9S171), chromosome 9q32-33 (D9S177), and chromosome 17p13 (TP53) in 20 patients with small-cell carcinoma of the urinary bladder and concurrent urothelial carcinoma. DNA samples were prepared from formalin-fixed, paraffin-embedded tissue sections using laser-assisted microdissection. A nearly identical pattern of allelic loss was observed in the two tumor types in all cases, with an overall frequency of allelic loss of 90% (18 of 20 cases). Three patients showed different allelic loss patterns in the two tumor types at a single locus; however, the LOH patterns at the remaining loci were identical. Similarly, the same pattern of nonrandom X chromosome inactivation was present in both carcinoma components in the four cases analyzed. Concordant genetic alterations and X chromosome inactivation between small-cell carcinoma and coexisting urothelial carcinoma suggest that both tumor compo- Small-cell carcinoma of the urinary bladder histologically resembles that occurring in the lung and has been reported with an increasing frequency in recent years. [1][2][3][4][5][6][7][8][9][10] It has been estimated to represent 0.5% of bladder malignancies and develops more frequently in older men, with hematuria as the most common presenting symptom. 8 Small-cell carcinoma of the urinary bladder behaves aggressively, often with locally advanced or metastatic disease at the time of presentation. 11 Over the years, three principal theories have been proposed to account for the development of small-cell carcinoma in the urinary bladder. The first theory is that small-cell carcinomas originate from multipotential, undifferentiated cells or stem cells in the urothelium. 5,8,12,13 The frequent association of this tumor with coexisting urothelial carcinoma supports this theory. The second theory is that these tumors arise from neuroendocrine cells within normal or metaplastic urothelium. 14 The third theory is that small-cell carcinomas are derived from an undefined population of submucosal neuroendocrine cells. 1 In this study, we investigated the clonal relationships between small-cell carcinoma and coexisting urothelial carcinoma using loss of heterozygosity (LOH) and X chromosome inactivation analysis. Materials and Methods PatientsTwenty patients with small-cell carcinoma of the urinary bladder and concurrent urothelial carcinoma were included in our study. Archival materials from the 20 cases

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Section: Discussionmentioning

confidence: 99%

Molecular Genetic Evidence for a Common Clonal Origin of Urinary Bladder Small Cell Carcinoma and Coexisting Urothelial Carcinoma

Liu

Jones

McCarthy

et al. 2005

The American Journal of Pathology

176

105

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“…[6][7][8] Selective kinetic advantages contribute to dominant growth [9][10][11][12] and are mainly regulated at the restriction point by TP53, pRB, and cyclin-dependent kinase inhibitors (Figure 1), 13 where a maintained G 1 arrest will lead to apoptosis only if pRB is not functional. 1,14 Genetic lesions within all cells imply a common progenitor contributing that mutation, 9,15,16 and it has been found to be associated with loss of heterozygosity of certain loci.…”

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confidence: 99%

“…1,14 Genetic lesions within all cells imply a common progenitor contributing that mutation, 9,15,16 and it has been found to be associated with loss of heterozygosity of certain loci. 7,17 The DNA deletions of a given genetic marker should be linked to the loss of tumor suppressor genes, 15,16 which also contribute to the multistep carcinogenesis process selecting those cells with growth advantages. 9 A monoclonal tumor origin is supported by concordant tumor suppressor gene abnormalities, 7,17,18 which have been found to be associated with the loss of heterozygosity of certain loci.…”

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confidence: 99%

“…7,17 The DNA deletions of a given genetic marker should be linked to the loss of tumor suppressor genes, 15,16 which also contribute to the multistep carcinogenesis process selecting those cells with growth advantages. 9 A monoclonal tumor origin is supported by concordant tumor suppressor gene abnormalities, 7,17,18 which have been found to be associated with the loss of heterozygosity of certain loci. The coexistence of several genetic abnormalities and intratumor heterogeneity would be the expression of either tumor cell selection or a simple passive byproduct of genetic instability.…”

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confidence: 99%

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Heterogeneous topographic profiles of kinetic and cell cycle regulator microsatellites in atypical (dysplastic) melanocytic nevi

et al. 2011

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Atypical (dysplastic) melanocytic nevi are clinically heterogeneous malignant melanoma precursors, for which no topographic analysis of cell kinetic, cell cycle regulators and microsatellite profile is available. We selected low-grade atypical melanocytic nevi (92), high-grade atypical melanocytic nevi (41), melanocytic nevi (18 junctional, 25 compound) and malignant melanomas (16 radial growth phase and 27 vertical growth phase). TP53, CDKN2A, CDKN1A, and CDKN1B microsatellite patterns were topographically studied after microdissection; Ki-67, TP53, CDKN2A, CDKN1A, and CDKN1B expressions and DNA fragmentation by in situ end labeling for apoptosis were topographically scored. Results were statistically analyzed. A decreasing junctional-dermal marker expression gradient was observed, directly correlating with atypical melanocytic nevus grading. High-grade atypical melanocytic nevi revealed coexistent TP53-CDKN2A-CDKN1B microsatellite abnormalities, and significantly higher junctional Ki67-TP53 expression (inversely correlated with CDKN1A-CDKN1B expression and in situ end labeling). Malignant melanomas showed coexistent microsatellite abnormalities (CDKN2A-CDKN1B), no topographic gradient, and significantly decreased expression. Melanocytic nevi and low-grade atypical melanocytic nevi revealed sporadic junctional CDKN2A microsatellite abnormalities and no significant topographic kinetic differences. High-grade atypical melanocytic nevi accumulate junctional TP53-CDKN1A-CDKN1B microsatellite abnormalities, being progression TP53-independent and better assessed in the dermis. Melanocytic nevi and low-grade atypical melanocytic nevi show low incidence of microsatellite abnormalities, and kinetic features that make progression unlikely.

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“…25 The advantage of microsatellite analysis is, in particular, its independence from patient's sex and the presence of specific mutations. Furthermore, microsatellite analysis can be performed on DNA extracted from formalin-fixed, paraffin-embedded tissue.…”

Section: Discussionmentioning

confidence: 99%

Bilateral carcinomas of the breast with local recurrence: analysis of genetic relationship of the tumors

Regitnig¹,

Ploner

Maderbacher³

et al. 2004

Modern Pathology

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Local recurrence of bilateral breast carcinomas is rare, but of biological interest, since it is unclear as to which tumor the local recurrence is related to, the ipsilateral or the contralateral, or whether it is an independent neoplasm. The aim of this study was to investigate the genetic relationship of bilateral breast carcinomas to each other and to their local recurrences. Eight cases of bilateral breast carcinomas, five with and three without local recurrence were analyzed using a microsatellite assay for 13 microsatellite loci. The presence of loss of heterozygosity and microsatellite instability in the various tumors was used for clonal analysis. All eight bilateral breast carcinomas showed divergent alterations in at least two microsatellite loci, which ruled out a genetic relationship. Four of five local recurrences were genetically related to the ipsilateral tumor and unrelated to the contralateral tumor. Only one local recurrence that occurred 11.8 years after the surgery of an infiltrative lobular carcinoma simultaneously with distant metastases was genetically related to the contralateral breast carcinoma. Although the number of cases in our study is limited, there is evidence that local recurrence of bilateral breast carcinoma frequently arises from the ipsilateral tumor. Keywords: bilateral breast carcinoma; local recurrence; microsatellite analysis; loss of heterozygosity; clonality Epidemiologic data on breast carcinomas show that 2-11% of breast carcinoma patients will develop contralateral breast carcinoma in their lifetime. Women with unilateral breast carcinoma are at a 2-6-fold increased risk of developing contralateral breast carcinoma, compared to the risk in the general population. 1 Bilateral breast carcinomas are of particular interest with respect to their relationship, whether they represent independent neoplasms or occur by metastatic tumor spread. This issue becomes more complex in the setting of local tumor recurrence. In this situation, the question arises whether the local recurrence is related to one of the bilateral tumors or is an independent, de novo arising neoplasm, or whether both of the tumors and the recurrence are metastases of the other tumor. The fact that whether bilateral breast carcinomas and its local recurrence have to be considered a local or a metastatic process has important therapeutic and prognostic implications.A second independently arising breast carcinoma is favored, if the histological tumor types are different. However, if the histological tumor types are identical, the distinction between a subsequently occurred novel tumor and a local recurrence of the original tumor is difficult. Conventional parameters such as the histopathological grade and various immunohistochemical analyses such as estrogen, progesterone and HER-2/neu receptor expression are not reliable to prove the relationship of these tumors.During recent years, several studies using different molecular methods have indicated that bilateral breast carcinomas are most likely genetically u...

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PCR Techniques for Clonality Assays

Cited by 74 publications

References 56 publications

Molecular Genetic Evidence for a Common Clonal Origin of Urinary Bladder Small Cell Carcinoma and Coexisting Urothelial Carcinoma

Molecular Genetic Evidence for a Common Clonal Origin of Urinary Bladder Small Cell Carcinoma and Coexisting Urothelial Carcinoma

Heterogeneous topographic profiles of kinetic and cell cycle regulator microsatellites in atypical (dysplastic) melanocytic nevi

Bilateral carcinomas of the breast with local recurrence: analysis of genetic relationship of the tumors

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