Significance of loss of heterozygosity of the <i>RB1</i> gene during tumour progression in well‐differentiated liposarcomas

Schneider‐Stock, Regine; Boltze, Carsten; Jaeger, Viola; Stumm, Marcus; Seiler, Christiane; Ryś, Janusz; Schütze, Karin; Roessner, Albert

doi:10.1002/path.1145

Cited by 24 publications

(21 citation statements)

References 18 publications

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“…5,6 Schneider-Stock et al investigated RB1-LOH in two microdissected components of 11 dedifferentiated liposarcoma patients, and RB1-LOH was detected in all the dedifferentiated components, using four intragenic RB1 markers and restriction fragments analysis. 7 In our present study, LOH for one or more markers out of five microsatellite markers at 13q12-14 was found in 15 out of 25 (60%) cases with dedifferentiated component and in three out of 24 (12.5%) cases with well-differentiated component. We detected LOH at D13S153, one of the five microsatellite markers located within intron 2 of the RB1 gene, in 13 out of 24 (54%) dedifferentiated components and in two out of 23 (8.7%) well-differentiated components.…”

Section: Discussionsupporting

confidence: 55%

“…32 Using immunohistochemical methods, the present study demonstrated the expression of pRb to be abnormal in 18 dedifferentiated components and in nine welldifferentiated components, results which are similar to those observed in a previous study. 7 These results suggest that pRB plays a role in dedifferentiation from well-differentiated liposarcoma to dedifferentiated liposarcoma, through the alteration of the coding gene RB1, or through the interaction of CDK4 or MDM2, which are considered to be expressed at a higher level in dedifferentiated component than in well-differentiated component, as described above. pRB has been shown to promote adipocyte differentiation by enhancing the DNA-binding and transactivation activity of C/EBPb, and/or by inhibiting Ras signaling to suppress the activation of the ERK1/2 MAPKs.…”

Section: Discussionmentioning

confidence: 52%

“…Dedifferentiation is mostly considered a time-dependent phenomenon, and several reports have suggested an association between dedifferentiation and the altered expression of specific proteins, such as MDM2, P53, H-ras, b-catenin, and retinoblastoma protein (pRB). [3][4][5][6][7] pRB negatively regulates the cellular G1/S transition of the proliferative cell cycle and is required for proper differentiation of certain cell types, including skeletal muscle and adipocytes. 8 Decreased expression of pRB in malignant mesenchymal tumors has been reported by some authors based on immunohistochemistry or Western blotting.…”

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confidence: 99%

“…Biallelic inactivation of RB1 is a hallmark not only of retinoblastoma, but has also been described in a variety of other tumors, including osteosarcoma and malignant fibrous histiocytoma. 13,14 SchneiderStock et al analyzed RB1-loss of heterozygosity (LOH) in 11 dedifferentiated liposarcoma patients and concluded that RB1-LOH plays an important role in the tumor progression of well-differentiated liposarcoma to dedifferentiated liposarcoma; 7 however, whether or not there are alterations to the other allele in this tumor has not been previously ascertained. In the present study, we first performed LOH analysis using five microsatellite markers at 13q12-q14 in 27 cases of dedifferentiated liposarcoma.…”

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confidence: 99%

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Alterations of the RB1 gene in dedifferentiated liposarcoma

et al. 2005

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Dedifferentiated liposarcoma is a malignant adipocytic neoplasm containing a nonlipogenic sarcoma of variable histological grade that arises against the background of a pre-existing well-differentiated liposarcoma. The phenomenon of dedifferentiation is considered to be time-dependent, but the mechanism is not well known. The retinoblastoma protein, encoded by the RB1 gene located at 13q14, is a key regulator of proliferation, development, and differentiation of certain cell types, including adipocytes. In the current study, we investigated the genetic alterations of the RB1 gene, such as mutation (the essential promoter region and the protein-binding pocket domain; exons 20-24) and methylation of the promoter region, in addition to pRB expression and loss of heterozygosity (LOH) status, in two morphologically distinct areas (nonlipogenic dedifferentiated and well-differentiated components) in 27 patients. As a control, 11 undifferentiated high-grade pleomorphic sarcoma/pleomorphic malignant fibrous histiocytoma samples and 11 well-differentiated liposarcoma samples were also evaluated. Dedifferentiated components showed LOH (15/25; 60%) and abnormal retinoblastoma protein expression (18/27; 66.7%) more frequently than noted in the well-differentiated components (3/24; 12.5% and 9/27; 33.3%, respectively). Five and four out of the 27 dedifferentiated components harbored mutations and promoter methylation, respectively, whereas none of these alterations were seen in the well-differentiated components. These results suggest that retinoblastoma protein has a major role to play in dedifferentiation and that a 'two-hit' mechanism is involved in the altered retinoblastoma protein expression in dedifferentiated liposarcoma.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 52%

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confidence: 99%

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confidence: 99%

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Alterations of the RB1 gene in dedifferentiated liposarcoma

et al. 2005

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“…Each row represents a single chromosomal subregion, each column shows the chromosomal status for a single tumour sample. Selected, cluster-associated chromosomal subregions are indicated on the right gested an association between dedifferentiation and the altered expression of specific proteins such as MDM2, p53, H-ras, β-catenin, and retinoblastoma protein [12,[26][27][28][29]. Also, chromosomal imbalances additionally to overrepresent 12q13-q15 were more frequent in DDLS than in WDLS [19].…”

Section: Discussionmentioning

confidence: 99%

Genomic profiling reveals subsets of dedifferentiated liposarcoma to follow separate molecular pathways

et al. 2009

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With the aim to provide more insight into their biology, a series of 79 liposarcomas (LS) representative of all main subtypes was analysed for chromosomal imbalances using comparative genomic hybridization. Based on the genetic data, unsupervised hierarchical clustering unveiled two main LS clusters, each with two subclusters, one comprising three subsets. The first main cluster consisted of one larger subcluster, being characterised by gains/high-level amplifications of chromosomal subregions 12q13-q15, and exclusively included well-differentiated and dedifferentiated LS. A smaller subcluster was set apart on the basis of recurrent gains of 20q13 and 8q24, and mainly comprised pleomorphic and myxoid/round cell LS. The larger subcluster was subdivided into three subsets, one with nearly exclusive overrepresentations of 12q13-q15, the second with additional frequent gains of 1q21-q24, and the third with further recurrent overrepresentations of 6q22-q24, 20q13, and 12q24 and frequent losses of 13q14-q21 and 11q22-q23. While the first subset comprised both well-differentiated and dedifferentiated LS, the second and third subsets entirely included dedifferentiated LS. The second main cluster was characterised by recurrent overrepresentations of 5p13-p15, 1q21-q24, 1p12-p21, and 17p11.2-p12 and essentially comprised pleomorphic and myxoid/round cell LS. A separation of this second main cluster into two subclusters was based on additional gains on 22q13 and losses on 1q42-q43. Genomic profiling reveals genetically distinct subsets of dedifferentiated LS, which are clearly different from pleomorphic, myxoid/round cell, and, for some subsets, from well-differentiated LS. These data indicate that dedifferentiated LS follow separate tumourigenic pathways and that genetic analysis is important to unravel these differences.

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Complementary Techniques

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Advances in Experimental Medicine and Biology

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Recent developments in sensitive genome characterization and quantitative gene expression analyses that permit precise molecular genetic fingerprinting of tumoral tissue are having a huge impact on cancer diagnostics. However, the significance of the data obtained with these techniques strictly depends on the composition of the biological sample to be analyzed and is greatly enhanced by including a preprocessing step that allows the researcher to distinguish and isolate selected cell populations from surrounding undesired material. This may represent a remarkable problem: indeed, genomic and proteomic analysis in the context of cancer investigation is susceptible to contamination by nonneoplastic cells, which can mask some tumor-specific alterations. Moreover, the heterogeneity of the tissues of a histological section, in which the cell population of interest may constitute only a small fraction, can represent an insurmountable difficulty for the use of quantitative techniques that absolutely depend on genomic material strictly derived from the cells that require analysis. This is obviously not possible if DNA or RNA is extracted from entire biopsies. In the past, this obstacle was partially overcome by manual dissection from slides with a needle or scalpel; however, this method is feasible only if there is a clear demarcation between the tissue under consideration and its surroundings and moreover, allows only an approximate separation of tissues. The recent development of microdissection systems based on laser technology has largely solved this important problem. Laser microdissection is a powerful tool for the isolation of specific cell populations (or single cells) from stained sections of both formalin-fixed, paraffin-embedded and frozen tissues, from cell cultures and even of a single chromosome within a metaphase cell. Resulting material is suitable for a wide range of downstream assays such LOH (loss of heterozygosity) studies, gene expression analysis at the mRNA level and a variety of proteomic approaches such as 2D gel analysis, reverse phase protein array and SELDI protein profiling. This chapter describes the characteristics of the most widely utilized laser microdissection systems and their current applications.

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Significance of loss of heterozygosity of the RB1 gene during tumour progression in well‐differentiated liposarcomas

Cited by 24 publications

References 18 publications

Alterations of the RB1 gene in dedifferentiated liposarcoma

Alterations of the RB1 gene in dedifferentiated liposarcoma

Genomic profiling reveals subsets of dedifferentiated liposarcoma to follow separate molecular pathways

Complementary Techniques

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