Molecular Characterization of Bone Tumors and Implications for Treatment and Prognosis

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Neoplastic transformation is a consequence of maladaptive alterations in the cellular processes normally involved in cell growth, proliferation, differentiation, and survival. Despite the relative infrequent nature of skeletal neoplasms, current understanding of the pathobiology underlying these conditions is becoming increasingly characterized. This article highlights some of the established molecular abnormalities identified in various benign and malignant skeletal neoplasms and how they pertain to tumor biology, diagnosis, and prognosis. Most of the commonly accepted cellular aberrancies in skeletal neoplasms pertain to mutations, copy number changes, and/or chromosomal rearrangements. However, it is becoming increasingly understood that the complexity of tumorigenic pathways necessary for neoplastic growth are manipulated by numerous overlapping alterations in the genetic code and are further influenced by higher-order molecular programs, such as pretranscriptional and posttranscriptional regulation and chromatin reorganization. Over time, identification and quantification of these increasingly recognized neoplastic processes will gradually translate into valuable clinical applications, enhancing the current diagnostic and prognostic capabilities.

Correspondence: Kevin B. Jones, MD, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Room 4260, Salt Lake City, UT 84016. E-mail: kevin.jones@hci.utah.edu
  • 1.

    Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med 2004;10:789799.

  • 2.

    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646674.

  • 3.

    Jones KB, Piombo V, Searby C. A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes. Proc Natl Acad Sci U S A 2010;107:20542059.

    • Search Google Scholar
    • Export Citation
  • 4.

    de Andrea CE, Wiweger M, Prins F. Primary cilia organization reflects polarity in the growth plate and implies loss of polarity and mosaicism in osteochondroma. Lab Invest 2010;90:10911101.

    • Search Google Scholar
    • Export Citation
  • 5.

    Hameetman L, Szuhai K, Yavas A. The role of EXT1 in nonhereditary osteochondroma: identification of homozygous deletions. J Natl Cancer Inst 2007;99:396406.

    • Search Google Scholar
    • Export Citation
  • 6.

    Jennes I, Pedrini E, Zuntini M. Multiple osteochondromas: mutation update and description of the multiple osteochondromas mutation database (MOdb). Hum Mutat 2009;30:16201627.

    • Search Google Scholar
    • Export Citation
  • 7.

    Schmale GA, Conrad EU 3rd, Raskind WH. The natural history of hereditary multiple exostoses. J Bone Joint Surg Am 1994;76:986992.

  • 8.

    Wicklund CL, Pauli RM, Johnston D, Hecht JT. Natural history study of hereditary multiple exostoses. Am J Med Genet 1995;55:4346.

  • 9.

    Amary MF, Damato S, Halai D. Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2. Nat Genet 2011;43:12621265.

    • Search Google Scholar
    • Export Citation
  • 10.

    Damato S, Alorjani M, Bonar F. IDH1 mutations are not found in cartilaginous tumours other than central and periosteal chondrosarcomas and enchondromas. Histopathology 2012;60:363365.

    • Search Google Scholar
    • Export Citation
  • 11.

    Amary MF, Bacsi K, Maggiani F. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 2011;224:334343.

    • Search Google Scholar
    • Export Citation
  • 12.

    Pansuriya TC, van Eijk R, d’Adamo P. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet 2011;43:12561261.

    • Search Google Scholar
    • Export Citation
  • 13.

    Verdegaal SH, Bovee JV, Pansuriya TC. Incidence, predictive factors, and prognosis of chondrosarcoma in patients with Ollier disease and Maffucci syndrome: an international multicenter study of 161 patients. Oncologist 2011;16:17711779.

    • Search Google Scholar
    • Export Citation
  • 14.

    Schwartz HS, Zimmerman NB, Simon MA. The malignant potential of enchondromatosis. J Bone Joint Surg Am 1987;69:269274.

  • 15.

    Riminucci M, Robey PG, Saggio I, Bianco P. Skeletal progenitors and the GNAS gene: fibrous dysplasia of bone read through stem cells. J Mol Endocrinol 2010;45:355364.

    • Search Google Scholar
    • Export Citation
  • 16.

    Bourne HR, Landis CA, Masters SB. Hydrolysis of GTP by the alpha-chain of Gs and other GTP binding proteins. Proteins 1989;6:222230.

  • 17.

    Bhattacharyya N, Wiench M, Dumitrescu C. Mechanism of FGF23 processing in fibrous dysplasia. J Bone Miner Res 2012;27:11321141.

  • 18.

    Riminucci M, Collins MT, Fedarko NS. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest 2003;112:683692.

    • Search Google Scholar
    • Export Citation
  • 19.

    Oliveira AM, Perez-Atayde AR, Inwards CY. USP6 and CDH11 oncogenes identify the neoplastic cell in primary aneurysmal bone cysts and are absent in so-called secondary aneurysmal bone cysts. Am J Pathol 2004;165:17731780.

    • Search Google Scholar
    • Export Citation
  • 20.

    Ye Y, Pringle LM, Lau AW. TRE17/USP6 oncogene translocated in aneurysmal bone cyst induces matrix metalloproteinase production via activation of NF-kappaB. Oncogene 2010;29:36193629.

    • Search Google Scholar
    • Export Citation
  • 21.

    Selvarajah S, Yoshimoto M, Ludkovski O. Genomic signatures of chromosomal instability and osteosarcoma progression detected by high resolution array CGH and interphase FISH. Cytogenet Genome Res 2008;122:515.

    • Search Google Scholar
    • Export Citation
  • 22.

    Cavenee WK, Bogler O, Hadjistilianou T, Newsham IF. Retinoblastoma syndrome. In: Fletcher CD, Bridge JA, Hogendoorn PC, Mertens F, eds. World Health Organization Classification of Tumours of Soft Tissue and Bone. Lyon: International Agency for Research on Cancer (IARC); 2013:388390.

    • Search Google Scholar
    • Export Citation
  • 23.

    Thomas DM, Carty SA, Piscopo DM. The retinoblastoma protein acts as a transcriptional coactivator required for osteogenic differentiation. Mol Cell 2001;8:303316.

    • Search Google Scholar
    • Export Citation
  • 24.

    Heinsohn S, Evermann U, Zur Stadt U. Determination of the prognostic value of loss of heterozygosity at the retinoblastoma gene in osteosarcoma. Int J Oncol 2007;30:12051214.

    • Search Google Scholar
    • Export Citation
  • 25.

    Malkin D. Li-Fraumeni syndrome. In: Fletcher CD, Bridge JA, Hogendoorn PC, Mertens F, eds. World Health Organization Classification of Tumours of Soft Tissue and Bone. Lyon: International Agency for Research on Cancer (IARC); 2013:379381.

    • Search Google Scholar
    • Export Citation
  • 26.

    Duhamel LA, Ye H, Halai D. Frequency of Mouse Double Minute 2 (MDM2) and Mouse Double Minute 4 (MDM4) amplification in parosteal and conventional osteosarcoma subtypes. Histopathology 2012;60:357359.

    • Search Google Scholar
    • Export Citation
  • 27.

    Pakos EE, Kyzas PA, Ioannidis JP. Prognostic significance of TP53 tumor suppressor gene expression and mutations in human osteosarcoma: a meta-analysis. Clin Cancer Res 2004;10:62086214.

    • Search Google Scholar
    • Export Citation
  • 28.

    Mohseny AB, Szuhai K, Romeo S. Osteosarcoma originates from mesenchymal stem cells in consequence of aneuploidization and genomic loss of Cdkn2. J Pathol 2009;219:294305.

    • Search Google Scholar
    • Export Citation
  • 29.

    Kresse SH, Ohnstad HO, Paulsen EB. LSAMP, a novel candidate tumor suppressor gene in human osteosarcomas, identified by array comparative genomic hybridization. Genes Chromosomes Cancer 2009;48:679693.

    • Search Google Scholar
    • Export Citation
  • 30.

    Yen CC, Chen WM, Chen TH. Identification of chromosomal aberrations associated with disease progression and a novel 3q13.31 deletion involving LSAMP gene in osteosarcoma. Int J Oncol 2009;35:775788.

    • Search Google Scholar
    • Export Citation
  • 31.

    Sadikovic B, Thorner P, Chilton-Macneill S. Expression analysis of genes associated with human osteosarcoma tumors shows correlation of RUNX2 overexpression with poor response to chemotherapy. BMC Cancer 2010;10:202.

    • Search Google Scholar
    • Export Citation
  • 32.

    de Andrea CE, Reijnders CM, Kroon HM. Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT. Oncogene 2012;31:10951104.

    • Search Google Scholar
    • Export Citation
  • 33.

    Tallini G, Dorfman H, Brys P. Correlation between clinicopathological features and karyotype in 100 cartilaginous and chordoid tumours. A report from the Chromosomes and Morphology (CHAMP) Collaborative Study Group. J Pathol 2002;196:194203.

    • Search Google Scholar
    • Export Citation
  • 34.

    Schrage YM, Lam S, Jochemsen AG. Central chondrosarcoma progression is associated with pRb pathway alterations: CDK4 down-regulation and p16 overexpression inhibit cell growth in vitro. J Cell Mol Med 2009;13:28432852.

    • Search Google Scholar
    • Export Citation
  • 35.

    Bovee JV, Cleton-Jansen AM, Rosenberg C. Molecular genetic characterization of both components of a dedifferentiated chondrosarcoma, with implications for its histogenesis. J Pathol 1999;189:454462.

    • Search Google Scholar
    • Export Citation
  • 36.

    Bridge JA, DeBoer J, Travis J. Simultaneous interphase cytogenetic analysis and fluorescence immunophenotyping of dedifferentiated chondrosarcoma. Implications for histopathogenesis. Am J Pathol 1994;144:215220.

    • Search Google Scholar
    • Export Citation
  • 37.

    Sankar S, Lessnick SL. Promiscuous partnerships in Ewing’s sarcoma. Cancer Genet 2011;204:351365.

  • 38.

    Graham C, Chilton-MacNeill S, Zielenska M, Somers GR. The CIC-DUX4 fusion transcript is present in a subgroup of pediatric primitive round cell sarcomas. Hum Pathol 2012;43:180189.

    • Search Google Scholar
    • Export Citation
  • 39.

    Italiano A, Sung YS, Zhang L. High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas. Genes Chromosomes Cancer 2012;51:207218.

    • Search Google Scholar
    • Export Citation
  • 40.

    Smith R, Owen LA, Trem DJ. Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing’s sarcoma. Cancer Cell 2006;9:405416.

    • Search Google Scholar
    • Export Citation
  • 41.

    Yoshida A, Sekine S, Tsuta K. NKX2.2 is a useful immunohistochemical marker for Ewing sarcoma. Am J Surg Pathol 2012;36:993999.

  • 42.

    Huang HY, Illei PB, Zhao Z. 2005. Ewing sarcomas with p53 mutation or p16/p14ARF homozygous deletion: a highly lethal subset associated with poor chemoresponse. J Clin Oncol 2005;23:548558.

    • Search Google Scholar
    • Export Citation
  • 43.

    Le Deley MC, Dealttre O, Schaefer KL. Impact of EWS-ETS fusion type on disease progression in Ewing’s sarcoma/peripheral primitive neuroectodermal tumor: prospective results from the cooperative Euro-E.W.I.N.G. 99 trial. J Clin Oncol 2010;28:19821988.

    • Search Google Scholar
    • Export Citation
  • 44.

    van Doorninck JA, Ji L, Schaub B. Current treatment protocols have eliminated the prognostic advantage of type 1 fusions in Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol 2010;28:19891994.

    • Search Google Scholar
    • Export Citation
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