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      Using Epidemiology and Genomics to Understand Osteosarcoma Etiology

      review-article
      * ,
      Sarcoma
      Hindawi Publishing Corporation

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          Abstract

          Osteosarcoma is a primary bone malignancy that typically occurs during adolescence but also has a second incidence peak in the elderly. It occurs most commonly in the long bones, although there is variability in location between age groups. The etiology of osteosarcoma is not well understood; it occurs at increased rates in individuals with Paget disease of bone, after therapeutic radiation, and in certain cancer predisposition syndromes. It also occurs more commonly in taller individuals, but a strong environmental component to osteosarcoma risk has not been identified. Several studies suggest that osteosarcoma may be associated with single nucleotide polymorphisms in genes important in growth and tumor suppression but the studies are limited by sample size. Herein, we review the epidemiology of osteosarcoma as well as its known and suspected risk factors in an effort to gain insight into its etiology.

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          Most cited references146

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          A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans.

          The tumor suppressor p53 gene is mutated in minimally half of all cancers. It is therefore reasonable to assume that naturally occurring polymorphic genetic variants in the p53 stress response pathway might determine an individual's susceptibility to cancer. A central node in the p53 pathway is the MDM2 protein, a direct negative regulator of p53. In this report, a single nucleotide polymorphism (SNP309) is found in the MDM2 promoter and is shown to increase the affinity of the transcriptional activator Sp1, resulting in higher levels of MDM2 RNA and protein and the subsequent attenuation of the p53 pathway. In humans, SNP309 is shown to associate with accelerated tumor formation in both hereditary and sporadic cancers. A model is proposed whereby SNP309 serves as a rate-limiting event in carcinogenesis.
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            Osteosarcoma, chondrosarcoma, and Ewing's sarcoma: National Cancer Data Base Report.

            We summarize descriptive epidemiologic and survival data from the National Cancer Data Base of the American College of Surgeons for 26,437 cases of osteosarcoma (n = 11,961), chondrosarcoma (n = 9606), and Ewing's sarcoma (n = 4870) from 1985 to 2003. Survival data are reported on cases with a minimum 5-year followup from 1985 to 1998 (8,104 osteosarcomas, 6,476 chondrosarcomas, and 3,225 Ewing's sarcomas). The relative 5-year survival rate was 53.9% for osteosarcoma, 75.2% for chondrosarcoma, and 50.6% for Ewing's sarcoma. Survival rates did not change notably over the collection period. Within osteosarcomas, the relative 5-year survival rates were 52.6% for high grade, 85.9% for parosteal, and 17.8% for Paget's subtypes. For osteosarcoma patients, the relative 5-year survival rate was 60% for those younger than 30 years, 50% for those aged 30 to 49 years, and 30% for those aged 50 years or older. Within chondrosarcomas, the relative 5-year survival rate was 76% for conventional, 71% for myxoid, 87% for juxtacortical, and 52% for mesenchymal. While the National Cancer Data Base has limitations, the survival data and demographics for bone sarcomas are unprecedented in numbers and duration. Our report supports continued efforts to refine data collection and stimulate further data analysis.
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              Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms.

              Familial cancer syndromes have helped to define the role of tumor suppressor genes in the development of cancer. The dominantly inherited Li-Fraumeni syndrome (LFS) is of particular interest because of the diversity of childhood and adult tumors that occur in affected individuals. The rarity and high mortality of LFS precluded formal linkage analysis. The alternative approach was to select the most plausible candidate gene. The tumor suppressor gene, p53, was studied because of previous indications that this gene is inactivated in the sporadic (nonfamilial) forms of most cancers that are associated with LFS. Germ line p53 mutations have been detected in all five LFS families analyzed. These mutations do not produce amounts of mutant p53 protein expected to exert a trans-dominant loss of function effect on wild-type p53 protein. The frequency of germ line p53 mutations can now be examined in additional families with LFS, and in other cancer patients and families with clinical features that might be attributed to the mutation.
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                Author and article information

                Journal
                Sarcoma
                SRCM
                Sarcoma
                Hindawi Publishing Corporation
                1357-714X
                1369-1643
                2011
                8 March 2011
                : 2011
                : 548151
                Affiliations
                Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Boulevard, EPS/7018, Rockville, MD 20892, USA
                Author notes

                Academic Editor: Stephen Lessnick

                Article
                10.1155/2011/548151
                3061299
                21437228
                1284ea70-ef11-4f93-9f1a-b4841c3024ba
                Copyright © 2011 S. A. Savage and L. Mirabello.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 September 2010
                : 9 November 2010
                : 19 December 2010
                Categories
                Review Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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