Pediatric Hematology and Oncology
ISSN: 0888-0018 (Print) 1521-0669 (Online) Journal homepage: http://www.tandfonline.com/loi/ipho20
Tumor Suppressor Gene (Rb and p53) Mutations in Osteosarcoma Rhona R. Schreck To cite this article: Rhona R. Schreck (1992) Tumor Suppressor Gene (Rb and p53) Mutations in Osteosarcoma, Pediatric Hematology and Oncology, 9:2, ix-x, DOI: 10.3109/08880019209018322 To link to this article: http://dx.doi.org/10.3109/08880019209018322
Published online: 09 Jul 2009.
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Date: 15 March 2016, At: 14:06
Annotation
TUMOR SUPPRESSOR GENE (Rb and p53) MUTATIONS IN OSTEOSARCOMA
Downloaded by [RMIT University Library] at 14:06 15 March 2016
Rhona R. Schrexk, PhD 0 Medical Genetics-Birth Defects Center, Cedars-Sinai Medical Center, P.O. Box 48750, Los Angeles, California 90048-0750, USA
In 1971, Jensen and Miller’ reported an excess of secondary neoplasms outside of the field of irradiation in survivors of retinoblastoma. Of these secondary cancers, 27 % were osteosarcomas. This initial observation of an association between retinoblastoma and osteosarcoma has been supported by many additional studies.*” However, the relationship between the development of these two distinct tumors did not become clear until molecular genetic studies became available. In 1985, Hansen et a15demonstrated loss of heterozygosity at chromosome 13 loci (the site of the putative retinoblastoma susceptibility gene) in osteosarcomas from both patients with prior bilateral retinoblastoma, as well as in osteosarcomas from patients with no history of retinoblastoma, suggesting an involvement of the gene responsible for retinoblastoma in the pathogenesis of osteosarcoma. A similar conclusion was reached by Dryja et Indeed, isolation of the retinoblastoma gene itself by Friend et al’ relied upon the absence of transcripts complementary to a putative cDNA segment from both retinoblastomas and osteosarcomas for confirmation. Subsequent to the cloning of the retinoblastoma gene, its involvement in a majority of osteosarcomas has been Yet not all surviving patients with constitutional retinoblastoma gene mutations develop osteosarcoma; indeed, their risk of developing this as a secondary tumor is only 12%,” which suggests that other factors (genes) are also required for the development of osteosarcoma. In a survey of human tumor types, Masuda et al” detected alterations of the p53 gene in 50% of osteosarcomas. Shortly thereafter, Toguchida et a18 found 7 7 % of osteosarcomas show loss of heterozygosity for chromosome 17, and later” narrowed the region of common loss to 1 7 ~ 1 3the , chromosomal location of p53. Mulligan et a l l 3 detected a variety of p53 lesions in 44% of osteosarcomas examined. Thus, a viable hypothesis suggests that, as is becoming evident for many other solid tumors, multiple genetic lesions
Pedktric Hmatologv and Oncolou, 9:ix-x, 1992 Copyniht @ 1992 by Hemisphere Publishing Corporation
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Downloaded by [RMIT University Library] at 14:06 15 March 2016
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are necessary before a cancer develops, and in the case of osteosarcoma, two of the necessary lesions are loss of function of two tumor suppressor genes, retinoblastoma and osteosarcoma. The paper presented in this issue, “Studies of the R b l Gene and the p53 Gene in Human Osteosarcoma” by Scholz et al.“ attempts to test this hypothesis. The authors examined osteosarcomas, looking for both Rb and p53 alterations. Better than 60 % of the tumors showed abnormalities of the Rb gene or lack of gene expression. Of these, 30% also showed abnormalities of p53 or lack of expression. The authors point out that subtle aberrations of either gene capable of producing nonfunctional protein products would have been missed by their analysis, so that the rate of coincident mutation of Rb and p53 could be even higher, although an alternate hypothesis is that not all osteosarcomas have the same second mutation. Only with further studies of this nature will the minimal criteria for the development of osteosarcoma be defined.
References 1. Jensen RD, Miller RW. Retinoblastoma: epidemiologic characteristics. New Engl J Med. 1971;285:307-311. 2. Draper GJ, Sanders BM, Kingston JE. Secondary primary neoplasms in patients with retinoblastoma. BrJ Cancer. 1986;53:661-671. 3. Kitchin FD, Ellsworth RM. Pleiotropic effects of the gene for retinoblastoma. J Med &el. 1974;11:244-246. 4. Abramson DH, Ellsworth RM, Kitchin FD, Tung G . Second non-ocular tumors in retinoblastoma survivors. Ophfhalmology. 1984;91:1352-1355. 5. Hansen MF, Koufos A, Gallie BL, et al. Osteosarcoma and retinoblastoma: a shared chromosomal mechanism revealing recessive predisposition. Roc Natl Acad Sci USA. 1985;82:6216-6220. 6. Dryja TP, Rapaport JM, Epstein J, et al. Chromosome 13 homozygosity in osteosarcoma without retinoblastoma. Am J Hum Genet. 1986;38:59-66. 7. Friend SH, Bernards R, Rogelj S, et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986;323:643-646. 8. Toguchida J , Ishizaki K, Sasaki M , et al. Chromosomal reorganization for the expression of recessive mutations of retinoblastoma susceptibility gene in the development of osteosarcoma. Cancer Res. 1988;48:3939-3943. 9. Reissman PT, Simon MA, Lee W-H, Slamon DJ. Studies of the retinoblastoma gene in human sarcomas. Oncogmc. 1989;4:839-843. 10. Hansen MF. Molecular genetic considerations in osteosarcoma. Clinical Orthopaedits and Relafed Restarch. 1991;270:237-246. 11. Masuda H, Miller C, Koefler HP, Battilora H, Cline MJ. Rearrangement of the p53 gene in human osteogenic sarcoma. R o c Natl Acod Sci USA. 1987;84:7716-7719. 12. Toguchida J , Ishizaki K, Nakamura Y,et al. Assignment of common allele loss in osteosarcoma to the Research. 1989; 49:6247-6251. subregion 1 7 ~ 1 3Cancer . 13. Mulligan LM, Matlashewski GJ, Scrable HJ, Cavenee WK. Mechanisms of p53 loss in human sarcomas. Roc Natl Acad Sci USA. 1990;87:5863-5867. 14. Scholz RB, Kabisch H , Weber B, et d. Studies of the Rbl gene and the p53 gene in human osteosarcoma. Pediatr H d o l Oncol. 1992;9:125-137.
Address concspondmce to R. Schreck.
ISSN: 0888-0018 (Print) 1521-0669 (Online) Journal homepage: http://www.tandfonline.com/loi/ipho20
Tumor Suppressor Gene (Rb and p53) Mutations in Osteosarcoma Rhona R. Schreck To cite this article: Rhona R. Schreck (1992) Tumor Suppressor Gene (Rb and p53) Mutations in Osteosarcoma, Pediatric Hematology and Oncology, 9:2, ix-x, DOI: 10.3109/08880019209018322 To link to this article: http://dx.doi.org/10.3109/08880019209018322
Published online: 09 Jul 2009.
Submit your article to this journal
Article views: 5
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipho20 Download by: [RMIT University Library]
Date: 15 March 2016, At: 14:06
Annotation
TUMOR SUPPRESSOR GENE (Rb and p53) MUTATIONS IN OSTEOSARCOMA
Downloaded by [RMIT University Library] at 14:06 15 March 2016
Rhona R. Schrexk, PhD 0 Medical Genetics-Birth Defects Center, Cedars-Sinai Medical Center, P.O. Box 48750, Los Angeles, California 90048-0750, USA
In 1971, Jensen and Miller’ reported an excess of secondary neoplasms outside of the field of irradiation in survivors of retinoblastoma. Of these secondary cancers, 27 % were osteosarcomas. This initial observation of an association between retinoblastoma and osteosarcoma has been supported by many additional studies.*” However, the relationship between the development of these two distinct tumors did not become clear until molecular genetic studies became available. In 1985, Hansen et a15demonstrated loss of heterozygosity at chromosome 13 loci (the site of the putative retinoblastoma susceptibility gene) in osteosarcomas from both patients with prior bilateral retinoblastoma, as well as in osteosarcomas from patients with no history of retinoblastoma, suggesting an involvement of the gene responsible for retinoblastoma in the pathogenesis of osteosarcoma. A similar conclusion was reached by Dryja et Indeed, isolation of the retinoblastoma gene itself by Friend et al’ relied upon the absence of transcripts complementary to a putative cDNA segment from both retinoblastomas and osteosarcomas for confirmation. Subsequent to the cloning of the retinoblastoma gene, its involvement in a majority of osteosarcomas has been Yet not all surviving patients with constitutional retinoblastoma gene mutations develop osteosarcoma; indeed, their risk of developing this as a secondary tumor is only 12%,” which suggests that other factors (genes) are also required for the development of osteosarcoma. In a survey of human tumor types, Masuda et al” detected alterations of the p53 gene in 50% of osteosarcomas. Shortly thereafter, Toguchida et a18 found 7 7 % of osteosarcomas show loss of heterozygosity for chromosome 17, and later” narrowed the region of common loss to 1 7 ~ 1 3the , chromosomal location of p53. Mulligan et a l l 3 detected a variety of p53 lesions in 44% of osteosarcomas examined. Thus, a viable hypothesis suggests that, as is becoming evident for many other solid tumors, multiple genetic lesions
Pedktric Hmatologv and Oncolou, 9:ix-x, 1992 Copyniht @ 1992 by Hemisphere Publishing Corporation
ix
Downloaded by [RMIT University Library] at 14:06 15 March 2016
x
R.SCHRECK
are necessary before a cancer develops, and in the case of osteosarcoma, two of the necessary lesions are loss of function of two tumor suppressor genes, retinoblastoma and osteosarcoma. The paper presented in this issue, “Studies of the R b l Gene and the p53 Gene in Human Osteosarcoma” by Scholz et al.“ attempts to test this hypothesis. The authors examined osteosarcomas, looking for both Rb and p53 alterations. Better than 60 % of the tumors showed abnormalities of the Rb gene or lack of gene expression. Of these, 30% also showed abnormalities of p53 or lack of expression. The authors point out that subtle aberrations of either gene capable of producing nonfunctional protein products would have been missed by their analysis, so that the rate of coincident mutation of Rb and p53 could be even higher, although an alternate hypothesis is that not all osteosarcomas have the same second mutation. Only with further studies of this nature will the minimal criteria for the development of osteosarcoma be defined.
References 1. Jensen RD, Miller RW. Retinoblastoma: epidemiologic characteristics. New Engl J Med. 1971;285:307-311. 2. Draper GJ, Sanders BM, Kingston JE. Secondary primary neoplasms in patients with retinoblastoma. BrJ Cancer. 1986;53:661-671. 3. Kitchin FD, Ellsworth RM. Pleiotropic effects of the gene for retinoblastoma. J Med &el. 1974;11:244-246. 4. Abramson DH, Ellsworth RM, Kitchin FD, Tung G . Second non-ocular tumors in retinoblastoma survivors. Ophfhalmology. 1984;91:1352-1355. 5. Hansen MF, Koufos A, Gallie BL, et al. Osteosarcoma and retinoblastoma: a shared chromosomal mechanism revealing recessive predisposition. Roc Natl Acad Sci USA. 1985;82:6216-6220. 6. Dryja TP, Rapaport JM, Epstein J, et al. Chromosome 13 homozygosity in osteosarcoma without retinoblastoma. Am J Hum Genet. 1986;38:59-66. 7. Friend SH, Bernards R, Rogelj S, et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986;323:643-646. 8. Toguchida J , Ishizaki K, Sasaki M , et al. Chromosomal reorganization for the expression of recessive mutations of retinoblastoma susceptibility gene in the development of osteosarcoma. Cancer Res. 1988;48:3939-3943. 9. Reissman PT, Simon MA, Lee W-H, Slamon DJ. Studies of the retinoblastoma gene in human sarcomas. Oncogmc. 1989;4:839-843. 10. Hansen MF. Molecular genetic considerations in osteosarcoma. Clinical Orthopaedits and Relafed Restarch. 1991;270:237-246. 11. Masuda H, Miller C, Koefler HP, Battilora H, Cline MJ. Rearrangement of the p53 gene in human osteogenic sarcoma. R o c Natl Acod Sci USA. 1987;84:7716-7719. 12. Toguchida J , Ishizaki K, Nakamura Y,et al. Assignment of common allele loss in osteosarcoma to the Research. 1989; 49:6247-6251. subregion 1 7 ~ 1 3Cancer . 13. Mulligan LM, Matlashewski GJ, Scrable HJ, Cavenee WK. Mechanisms of p53 loss in human sarcomas. Roc Natl Acad Sci USA. 1990;87:5863-5867. 14. Scholz RB, Kabisch H , Weber B, et d. Studies of the Rbl gene and the p53 gene in human osteosarcoma. Pediatr H d o l Oncol. 1992;9:125-137.
Address concspondmce to R. Schreck.
