Complete association of loss of heterozygosity of chromosomes 13 and 17 in osteosarcoma

Scheffer, Hans; Kruize, Yvonne C. M.; Osinga, Jan; Kuiken, Greetje; Oosterhuis, J. Wolter; Leeuw, Jan A.; Koops, H. Schraffordt; Buys, Charles H.C.M.

doi:10.1016/0165-4608(91)90113-9

Cited by 36 publications

(21 citation statements)

References 26 publications

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“…Except for ring chromosomes in parosteal osteosarcomas, 1 karyotypic changes in osteosarcomas are often complex and include a variety of structural and numerical abnormalities with frequent losses of chromosomes 13q, 17p, 18q, and 3q. [2][3][4][5][6][7][8][9] Of the known tumor suppressor genes at these loci, the RB gene on chromosome 13q has been most clearly implicated in osteosarcoma tumorigenesis. RB mutations occur in a large number of sporadic osteosarcomas and patients with germline RB mutations have an increased incidence of osteosarcomas.…”

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confidence: 99%

CDKN2A Gene Deletions and Loss of p16 Expression Occur in Osteosarcomas That Lack RB Alterations

Nielsen¹,

Burns²,

Rosenberg³

et al. 1998

The American Journal of Pathology

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Osteosarcomas often suffer mutations of the RB (retinoblastoma) gene , with resultant inactivation of the pRb protein. pRb is one component in a cell-cycle control pathway that includes the p16 (encoded by the CDKN2A gene) and cyclin-dependent kinase 4 (cdk4 , encoded by the CDK4 gene) proteins. We therefore sought to determine whether the CDKN2A and CDK4 genes were altered in those osteosarcomas that lacked RB inactivation. Twenty-one osteosarcomas (2 low-grade and 19 high-grade) were evaluated for homozygous deletion of the CDKN2A gene , CDK4 amplification , and allelic loss of the RB gene , as well as for expression of p16 and pRb proteins. Five highgrade osteosarcomas showed loss of p16 expression; four of these had homozygous CDKN2A deletions, and the fifth had a probable deletion obscured by numerous nonneoplastic , p16-immunopositive multinucleated giant cells. Thus , p16 immunohistochemistry may provide a sensitive means for assessing CDKN2A status. Twelve tumors (including the two low-grade osteosarcomas) were immunopositive for pRb , and nine tumors were immunonegative for pRb. Of the five cases with CDKN2A/p16 alterations , none had allelic loss of the RB gene and all expressed pRb, suggesting that each of these tumors had an intact RB gene. None of the tumors showed CDK4 amplification. No alterations were detected in the two lowgrade osteosarcomas. This study suggests that CDKN2A is a tumor suppressor inactivated in osteosarcomas that lack RB mutations and that the p16-pRb cell-cycle control pathway is deregulated in a large number of high-grade osteosarcomas. (Am J Pathol 1998, 153:159 -163)Genetic changes underlying the initiation and progression of osteosarcomas are poorly understood. Except for ring chromosomes in parosteal osteosarcomas, 1 karyotypic changes in osteosarcomas are often complex and include a variety of structural and numerical abnormalities with frequent losses of chromosomes 13q, 17p, 18q, and 3q.2-9 Of the known tumor suppressor genes at these loci, the RB gene on chromosome 13q has been most clearly implicated in osteosarcoma tumorigenesis. RB mutations occur in a large number of sporadic osteosarcomas and patients with germline RB mutations have an increased incidence of osteosarcomas. -15The pRb protein encoded by the RB gene functions as part of a cell cycle regulatory pathway that also involves the p16 protein (encoded by the CDKN2A gene on chromosome 9p21) and cyclin-dependent kinase 4 (cdk4, encoded by the CDK4 gene on chromosome 12q13). p16 appears to inhibit the function of cdk4-cyclin D1 complexes, which regulate pRb through phosphorylation. Phosphorylation inactivates RB, thereby allowing entry of the cell into S phase with resultant cellular proliferation. Thus, either inactivation of p16 or overexpression of cdk4 could promote tumorigenesis in a manner similar to that of pRb inactivation. Accordingly, the various components of this pathway are deregulated in a large number of human cancers. 16 -23 Although RB mutations are a well-recognized oncogenic event in ost...

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confidence: 99%

CDKN2A Gene Deletions and Loss of p16 Expression Occur in Osteosarcomas That Lack RB Alterations

Nielsen¹,

Burns²,

Rosenberg³

et al. 1998

The American Journal of Pathology

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“…Loss of D98OR chromosome 22 was specifically correlated with the acquisition of tumorigenicity in all the HOH cell lines. Loss of chromosome 22 is a common genetic alteration in osteosarcomas [20,24]. Specific loss of one D98OR chromosome 22 allele, along with maintenance of P16T chromosome 22 alleles, as seen by LOH analysis, was functional evidence of the presence of a tumor suppressor gene on chromosome 22 that is important in osteosarcoma tumorigenicity.…”

Section: Discussionmentioning

confidence: 96%

“…As the karyotypes of the HOH cell lines were complex, specific detailed chromosomal analysis was performed only on the chromosomes reported to be commonly altered in osteosarcoma, which are chromosomes 11, 13, 17, and 22 [5,6,12,20,22,24,27,30]. The P16T cell line contained alterations in chromosomes 11, 13, 17, and 22, including a complete loss of normal chromosome 11, an altered RB1 gene on chromosome 13, a mutated p53 gene on chromosome 17, and complete loss of normal chromosome 22 ( Figure 2B).…”

Section: D) C)mentioning

confidence: 99%

“…Isozyme and cytogenetic evaluations of the parental, non-tumorigenic HOH, and tumorigenic HOH cell lines were performed by the Cell Culture Laboratory of Children's Hospital of Michigan according to previously published techniques [5,6,20,23,24,27,30,32,34,35]. For chromosomal content analysis, chromosome counts were obtained from 30 metaphases, and detailed karyotypes were prepared from each cell line by using five to seven individual cell Giemsa-banded chromosome spreads for the analysis.…”

Section: Chromosome and Isozyme Analysismentioning

confidence: 99%

“…Many genetic alterations have been observed in osteosarcomas and the cell lines derived from them . For example, the oncogene c-myc and the tumor suppressor genes p53 and RB1 have been found altered in spontaneous human, radiation-induced mouse, and chemically induced rat osteosarcomas [1][2][3][12][13][14][15]17,19,21,33,25,26,28,29]; alteration of the c-fos oncogene has been observed to give rise to osteosarcomas in the mouse [8]; autocrine growth factor production has been found in many human osteosarcomas [15]; and chromosomal alterations have been observed in human osteosarcomas, the most common alterations involving chromosomes 11, 13, 17, and 22 [5,6,12,20,23,24,30].…”

Section: Introductionmentioning

confidence: 99%

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Analysis of oncogene, tumor suppressor gene, and chromosomal alterations in HeLa � osteosarcoma somatic cell hybrids

et al. 1999

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Using a series of tumorigenic and non-tumorigenic somatic cell hybrids that resulted from the fusion of the human osteosarcoma cell line OHS50-P16T (P16T) with the HeLa cell line D98OR, we investigated the role that genetic mutations, including alterations of oncogenes, tumor suppressor genes, and chromosomes, play in P16T tumorigenicity. Analysis of a previously identified oncogene mutation, c-myc amplification, in the P16T cell line demonstrated that both the tumorigenic and non-tumorigenic hybrids contained the amplified c-myc gene. Analysis of previously identified P16T tumor suppressor gene alterations, p53 mutation, and loss of RB1 expression demonstrated that the mutated p53 gene was selectively maintained in both the non-tumorigenic and tumorigenic hybrids, whereas loss of RB1 expression was not maintained in either the non-tumorigenic or tumorigenic hybrids. Chromosomes 11, 13, 17, and 22 were analyzed for loss of heterozygosity (LOH) to characterize the status of these previously described chromosomal alterations in the tumorigenic and non-tumorigenic hybrids. Loss of HeLa D98OR chromosome 22, with maintenance of P16T chromosome 22, was observed in the tumorigenic hybrids, a result confirmed by LOH analysis, which demonstrated the specific loss of HeLa chromosome 22 genetic material in the tumorigenic segregants. Together, these results demonstrated that amplified c-myc, mutant p53, and RB1 genes seem to be important in osteosarcoma tumorigenicity and that an additional altered gene or genes on chromosome 22 may play a key role in osteosarcoma tumorigenicity.

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Loss of heterozygosity of chromosome 13 in Merkel cell carcinoma

Leonard

Hayward

1997

Genes Chromosom. Cancer

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We have examined a series of 24 Merkel cell carcinoma (MCC) DNAs for loss of heterozygosity (LOH) at eight loci on chromosome 13. All patients were heterozygous for at least one locus. Overall, 18 of 24 (75%) patients showed LOH, among whom 10 patients demonstrated LOH at all informative loci. A single common region of loss was identified in all cases and included the marker D13S233 (13q14.3), which maps close to the retinoblastoma susceptibility gene RB1. The RB1 protein was not detected by Western blot analysis in any of nine MCC cell lines tested. These data indicate that 13q losses are the most common chromosomal losses observed to date in MCC and the likely target of these deletions is the RB1 locus. Genes Chromosom. Cancer 20:93–97, 1997. © 1997 Wiley‐Liss, Inc.

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Complete association of loss of heterozygosity of chromosomes 13 and 17 in osteosarcoma

Cited by 36 publications

References 26 publications

CDKN2A Gene Deletions and Loss of p16 Expression Occur in Osteosarcomas That Lack RB Alterations

CDKN2A Gene Deletions and Loss of p16 Expression Occur in Osteosarcomas That Lack RB Alterations

Analysis of oncogene, tumor suppressor gene, and chromosomal alterations in HeLa � osteosarcoma somatic cell hybrids

Loss of heterozygosity of chromosome 13 in Merkel cell carcinoma

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