Advertisement

Array Comparative Genomic Hybridization in Osteosarcoma

  • Bekim Sadikovic
  • Paul C. Park
  • Shamini Selvarajah
  • Maria Zielenska
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 973)

Abstract

Osteosarcoma, the most frequent primary bone tumor, is a malignant mesenchymal sarcoma with a peak incidence in young children and adolescents. Left untreated, it progresses relentlessly to local and systemic disease, ultimately leading to death within months. Genomically, osteosarcomas are aneuploid with chaotic karyotypes, lacking the pathognomonic genetic rearrangements characteristic of most sarcomas. The familial genetics of osteosarcoma helped in elucidating some of the etiological molecular disruptions, such as the tumor suppressor genes RB1 in retinoblastoma and TP53 in Li–Fraumeni, and RECQL4 involved in DNA repair/replication in Rothmund–Thomson syndrome. Genomic profiling approaches such as array comparative genomic hybridization (aCGH) have provided additional insights concerning the mechanisms responsible for generating complex osteosarcoma genomes. This chapter provides a brief introduction to the clinical features of conventional osteosarcoma, the predominant subtypes, and a general overview of materials and analytical methods of osteosarcoma aCGH, followed by a more detailed literature overview of aCGH studies and a discussion of emerging genes, molecular mechanisms, and their clinical implications, as well as more recent application of integrative genomics in osteosarcoma. aCHG is helping elucidate genomic events leading to tumor development and evolution as well as identification of prognostic markers and therapeutic targets in osteosarcoma.

Key words

Osteosarcoma aCGH Array comparative genomic hybridization Copy number RUNX2 Genomic instability Genomic integration Integrative analysis 

Notes

Acknowledgments

B.S. was a past recipient of the National Cancer Institute of Canada (currently Canadian Cancer Society) and the Terry Fox Foundation Fellowship in osteosarcoma research. S.S. was a past recipient of the Canadian Institute of Health Research Fellowship for Graduate Training in Molecular Medicine. M.Z is funded by the Canadian Cancer Society grant CCRI-020247.

References

  1. 1.
    Skubitz KM, D’adamo DR (2007) Sarcoma. Mayo Clin Proc 82(11):1409–1432PubMedCrossRefGoogle Scholar
  2. 2.
    Horvai A, Unni KK (2006) Premalignant conditions of bone. J Orthop Sci 11(4):412–423. doi: 10.1007/s00776-006-1037-6 PubMedCrossRefGoogle Scholar
  3. 3.
    Kansara M, Thomas DM (2007) Molecular pathogenesis of osteosarcoma. DNA Cell Biol 26(1):1–18. doi: 10.1089/dna.2006.0505 PubMedCrossRefGoogle Scholar
  4. 4.
    Rozeman LB, Cleton-Jansen AM, Hogendoorn PC (2006) Pathology of primary malignant bone and cartilage tumours. Int Orthop 30(6):437–444. doi: 10.1007/s00264-006-0212-x PubMedCrossRefGoogle Scholar
  5. 5.
    Dick DC, Morley WN, Watson JT (1982) Rothmund-thomson syndrome and osteogenic sarcoma. Clin Exp Dermatol 7(1):119–123PubMedCrossRefGoogle Scholar
  6. 6.
    White LM, Kandel R (2000) Osteoid-producing tumors of bone. Semin Musculoskelet Radiol 4(1):25–43. doi:smr00105[pii]PubMedCrossRefGoogle Scholar
  7. 7.
    Klein MJ, Siegal GP (2006) Osteosarcoma: anatomic and histologic variants. Am J Clin Pathol 125(4):555–581. doi:UC6KQHLD9LV2KENN[pii]10.1309/UC6K-QHLD-9LV2-KENN PubMedGoogle Scholar
  8. 8.
    Hauben EI, Weeden S, Pringle J et al (2002) Does the histological subtype of high-grade central osteosarcoma influence the response to treatment with chemotherapy and does it affect overall survival? A study on 570 patients of two consecutive trials of the european osteosarcoma intergroup. Eur J Cancer 38(9):1218–1225. doi:S0959804902000370[pii] PubMedCrossRefGoogle Scholar
  9. 9.
    Bielack SS, Kempf-Bielack B, Delling G et al (2002) Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 20(3):776–790PubMedCrossRefGoogle Scholar
  10. 10.
    Posthumadeboer J, Witlox MA, Kaspers GJ et al (2011) Molecular alterations as target for therapy in metastatic osteosarcoma: a review of literature. Clin Exp Metastasis 28(5):493–503. doi: 10.1007/s10585-011-9384-x PubMedCrossRefGoogle Scholar
  11. 11.
    Fabbro D, Ruetz S, Buchdunger E et al (2002) Protein kinases as targets for anticancer agents: from inhibitors to useful drugs. Pharmacol Ther 93(2–3):79–98. doi:S0163725802001791[pii] PubMedCrossRefGoogle Scholar
  12. 12.
    Mcgary EC, Weber K, Mills L et al (2002) Inhibition of platelet-derived growth factor-mediated proliferation of osteosarcoma cells by the novel tyrosine kinase inhibitor sti571. Clin Cancer Res 8(11):3584–3591PubMedGoogle Scholar
  13. 13.
    Khanna C, Wan X, Bose S et al (2004) The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med 10(2):182–186. doi:10.1038/nm982nm982[pii] PubMedCrossRefGoogle Scholar
  14. 14.
    Al-Romaih K, Somers GR, Bayani J et al (2007) Modulation by decitabine of gene expression and growth of osteosarcoma u2os cells in vitro and in xenografts: Identification of apoptotic genes as targets for demethylation. Cancer cell Int 7:14PubMedCrossRefGoogle Scholar
  15. 15.
    Selvarajah S, Yoshimoto M, Ludkovski O et al (2008) Genomic signatures of chromosomal instability and osteosarcoma progression detected by high resolution array cgh and interphase fish. Cytogenet Genome Res 122(1):5–15. doi:000151310[pii]10.1159/000151310 PubMedCrossRefGoogle Scholar
  16. 16.
    Nowak NJ, Miecznikowski J, Moore SR et al (2007) Challenges in array comparative genomic hybridization for the analysis of cancer samples. Genet Med 9(9):585–595. doi:10.1097/GIM.0b013e3181461c4a 00125817-200709000-00005[pii] PubMedCrossRefGoogle Scholar
  17. 17.
    Pugh TJ, Delaney AD, Farnoud N et al (2008) Impact of whole genome amplification on analysis of copy number variants. Nucleic Acids Res 36(13):e80. doi:gkn378[pii]10.1093/nar/gkn378 PubMedCrossRefGoogle Scholar
  18. 18.
    Picard F, Lebarbier E, Hoebeke M et al (2011) Joint segmentation, calling, and normalization of multiple cgh profiles. Biostatistics (Oxford, England) 12(3):413–428. doi:kxq076[pii]10.1093/biostatistics/kxq076 CrossRefGoogle Scholar
  19. 19.
    Ragland BD, Bell WC, Lopez RR et al (2002) Cytogenetics and molecular biology of osteosarcoma. Lab Invest 82(4):365–373PubMedCrossRefGoogle Scholar
  20. 20.
    Sandberg AA, Bridge JA (2003) Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: Osteosarcoma and related tumors. Cancer Genet Cytogenet 145(1):1–30PubMedCrossRefGoogle Scholar
  21. 21.
    Bridge JA, Nelson M, Mccomb E et al (1997) Cytogenetic findings in 73 osteosarcoma specimens and a review of the literature. Cancer Genet Cytogenet 95(1):74–87. doi:S0165460896003068[pii] PubMedCrossRefGoogle Scholar
  22. 22.
    Batanian JR, Cavalli LR, Aldosari NM et al (2002) Evaluation of paediatric osteosarcomas by classic cytogenetic and cgh analyses. Mol Pathol 55(6):389–393PubMedCrossRefGoogle Scholar
  23. 23.
    Forus A, Weghuis DO, Smeets D et al (1995) Comparative genomic hybridization analysis of human sarcomas: II. Identification of novel amplicons at 6p and 17p in osteosarcomas. Genes Chromosomes Cancer 14(1):15–21PubMedCrossRefGoogle Scholar
  24. 24.
    Ozaki T, Schaefer KL, Wai D et al (2002) Genetic imbalances revealed by comparative genomic hybridization in osteosarcomas. Int J Cancer 102(4):355–365. doi: 10.1002/ijc.10709 PubMedCrossRefGoogle Scholar
  25. 25.
    Stock C, Kager L, Fink FM et al (2000) Chromosomal regions involved in the pathogenesis of osteosarcomas. Genes Chromosomes Cancer 28(3):329–336PubMedCrossRefGoogle Scholar
  26. 26.
    Tarkkanen M, Karhu R, Kallioniemi A et al (1995) Gains and losses of DNA sequences in osteosarcomas by comparative genomic hybridization. Cancer Res 55(6):1334–1338PubMedGoogle Scholar
  27. 27.
    Tarkkanen M, Kiuru-Kuhlefelt S, Blomqvist C et al (1999) Clinical correlations of genetic changes by comparative genomic hybridization in ewing sarcoma and related tumors. Cancer Genet Cytogenet 114(1):35–41. doi:S016546089900031X[pii] PubMedCrossRefGoogle Scholar
  28. 28.
    Zielenska M, Bayani J, Pandita A et al (2001) Comparative genomic hybridization analysis identifies gains of 1p35 approximately p36 and chromosome 19 in osteosarcoma. Cancer Genet Cytogenet 130(1):14–21PubMedCrossRefGoogle Scholar
  29. 29.
    Hulsebos TJ, Bijleveld EH, Oskam NT et al (1997) Malignant astrocytoma-derived region of common amplification in chromosomal band 17p12 is frequently amplified in high-grade osteosarcomas. Genes Chromosomes Cancer 18(4):279–285. doi:10.1002/(SICI)1098-2264(199704)18:4<279::AID-GCC5>3.0.CO;2-Y[pii]PubMedCrossRefGoogle Scholar
  30. 30.
    Atiye J, Wolf M, Kaur S et al (2005) Gene amplifications in osteosarcoma-cgh microarray analysis. Genes Chromosomes Cancer 42(2):158–163. doi: 10.1002/gcc.20120 PubMedCrossRefGoogle Scholar
  31. 31.
    Man TK, Lu XY, Jaeweon K et al (2004) Genome-wide array comparative genomic hybridization analysis reveals distinct amplifications in osteosarcoma. BMC Cancer 4:45. doi:10.1186/1471-2407-4-45 1471-2407-4-45[pii] PubMedCrossRefGoogle Scholar
  32. 32.
    Squire JA, Pei J, Marrano P et al (2003) High-resolution mapping of amplifications and deletions in pediatric osteosarcoma by use of cgh analysis of cdna microarrays. Genes Chromosomes Cancer 38(3):215–225PubMedCrossRefGoogle Scholar
  33. 33.
    Zielenska M, Marrano P, Thorner P et al (2004) High-resolution cdna microarray cgh mapping of genomic imbalances in osteosarcoma using formalin-fixed paraffin-embedded tissue. Cytogenet Genome Res 107(1–2):77–82PubMedCrossRefGoogle Scholar
  34. 34.
    Lau CC, Harris CP, Lu XY et al (2004) Frequent amplification and rearrangement of chromosomal bands 6p12-p21 and 17p11.2 in osteosarcoma. Genes Chromosomes Cancer 39(1):11–21. doi: 10.1002/gcc.10291 PubMedCrossRefGoogle Scholar
  35. 35.
    Bayani J, Zielenska M, Pandita A et al (2003) Spectral karyotyping identifies recurrent complex rearrangements of chromosomes 8, 17, and 20 in osteosarcomas. Genes Chromosomes Cancer 36(1):7–16PubMedCrossRefGoogle Scholar
  36. 36.
    Lengauer C, Kinzler KW, Vogelstein B (1997) Genetic instability in colorectal cancers. Nature 386(6625):623–627PubMedCrossRefGoogle Scholar
  37. 37.
    Loeb LA (2001) A mutator phenotype in cancer. Cancer Res 61(8):3230–3239PubMedGoogle Scholar
  38. 38.
    Gisselsson D, Bjork J, Hoglund M et al (2001) Abnormal nuclear shape in solid tumors reflects mitotic instability. Am J Pathol 158(1):199–206. doi:S0002-9440(10)63958-2[pii]10.1016/S0002-9440(10)63958-2 PubMedCrossRefGoogle Scholar
  39. 39.
    Lim G, Karaskova J, Beheshti B et al (2005) An integrated mband and submegabase resolution tiling set (smrt) cgh array analysis of focal amplification, microdeletions, and ladder structures consistent with breakage-fusion-bridge cycle events in osteosarcoma. Genes Chromosomes Cancer 42(4):392–403PubMedCrossRefGoogle Scholar
  40. 40.
    Lim G, Karaskova J, Vukovic B et al (2004) Combined spectral karyotyping, multicolor banding, and microarray comparative genomic hybridization analysis provides a detailed characterization of complex structural chromosomal rearrangements associated with gene amplification in the osteosarcoma cell line mg-63. Cancer Genet Cytogenet 153(2):158–164PubMedCrossRefGoogle Scholar
  41. 41.
    Selvarajah S, Yoshimoto M, Park PC et al (2006) The breakage-fusion-bridge (bfb) cycle as a mechanism for generating genetic heterogeneity in osteosarcoma. Chromosoma 115(6):459–467. doi: 10.1007/s00412-006-0074-4 PubMedCrossRefGoogle Scholar
  42. 42.
    Selvarajah S, Yoshimoto M, Maire G et al (2007) Identification of cryptic microaberrations in osteosarcoma by high-definition oligonucleotide array comparative genomic hybridization. Cancer Genet Cytogenet 179(1):52–61. doi:S0165-4608(07)00492-X[pii]10.1016/j.cancergencyto.2007.08.003 PubMedCrossRefGoogle Scholar
  43. 43.
    Tarkkanen M, Bohling T, Gamberi G et al (1998) Comparative genomic hybridization of low-grade central osteosarcoma. Mod Pathol 11(5):421–426PubMedGoogle Scholar
  44. 44.
    Tarkkanen M, Elomaa I, Blomqvist C et al (1999) DNA sequence copy number increase at 8q: a potential new prognostic marker in high-grade osteosarcoma. Int J Cancer 84(2):114–121PubMedCrossRefGoogle Scholar
  45. 45.
    Angstadt AY, Motsinger-Reif A, Thomas R et al (2011) Characterization of canine osteosarcoma by array comparative genomic hybridization and rt-qpcr: signatures of genomic imbalance in canine osteosarcoma parallel the human counterpart. Genes Chromosomes Cancer 50(11):859–874. doi: 10.1002/gcc.20908 PubMedCrossRefGoogle Scholar
  46. 46.
    Dujardin F, Binh MB, Bouvier C et al (2011) Mdm2 and cdk4 immunohistochemistry is a valuable tool in the differential diagnosis of low-grade osteosarcomas and other primary fibro-osseous lesions of the bone. Mod Pathol 24(5):624–637. doi:modpathol2010229[pii]10.1038/modpathol.2010.229 PubMedCrossRefGoogle Scholar
  47. 47.
    Hattinger CM, Reverter-Branchat G, Remondini D et al (2003) Genomic imbalances associated with methotrexate resistance in human osteosarcoma cell lines detected by comparative genomic hybridization-based techniques. Eur J Cell Biol 82(9):483–493PubMedCrossRefGoogle Scholar
  48. 48.
    Hattinger CM, Stoico G, Michelacci F et al (2009) Mechanisms of gene amplification and evidence of coamplification in drug-resistant human osteosarcoma cell lines. Genes Chromosomes Cancer 48(4):289–309. doi: 10.1002/gcc.20640 PubMedCrossRefGoogle Scholar
  49. 49.
    Kresse SH, Ohnstad HO, Paulsen EB et al (2009) Lsamp, a novel candidate tumor suppressor gene in human osteosarcomas, identified by array comparative genomic hybridization. Genes Chromosomes Cancer 48(8):679–693. doi: 10.1002/gcc.20675 PubMedCrossRefGoogle Scholar
  50. 50.
    Lockwood WW, Stack D, Morris T et al (2011) Cyclin e1 is amplified and overexpressed in osteosarcoma. J Mol Diagn 13(3):289–296. doi:S1525-1578(11)00026-2[pii]10.1016/j.jmoldx.2010.11.020 PubMedCrossRefGoogle Scholar
  51. 51.
    Lu XY, Lu Y, Zhao YJ et al (2008) Cell cycle regulator gene cdc5l, a potential target for 6p12-p21 amplicon in osteosarcoma. Mol Cancer Res 6(6):937–946. doi:6/6/937[pii]10.1158/1541-7786.MCR-07-2115 PubMedCrossRefGoogle Scholar
  52. 52.
    Ma O, Cai WW, Zender L et al (2009) Mmp13, birc2 (ciap1), and birc3 (ciap2), amplified on chromosome 9, collaborate with p53 deficiency in mouse osteosarcoma progression. Cancer Res 69(6):2559–2567. doi:0008-5472.CAN-08-2929[pii]10.1158/0008-5472.CAN-08-2929 PubMedCrossRefGoogle Scholar
  53. 53.
    Pasic I, Shlien A, Durbin AD et al (2010) Recurrent focal copy-number changes and loss of heterozygosity implicate two noncoding rnas and one tumor suppressor gene at chromosome 3q13.31 in osteosarcoma. Cancer Res 70(1):160–171. doi:0008-5472.CAN-09-1902[pii]10.1158/0008-5472.CAN-09-1902 PubMedCrossRefGoogle Scholar
  54. 54.
    Sadikovic B, Yoshimoto M, Al-Romaih K et al (2008) In vitro analysis of integrated global high-resolution DNA methylation profiling with genomic imbalance and gene expression in osteosarcoma. PLoS One 3(7):e2834. doi: 10.1371/journal.pone.0002834 PubMedCrossRefGoogle Scholar
  55. 55.
    Sadikovic B, Yoshimoto M, Chilton-Macneill S et al (2009) Identification of interactive networks of gene expression associated with osteosarcoma oncogenesis by integrated molecular profiling. Hum Mol Genet 18(11):1962–1975. doi:ddp117[pii]10.1093/hmg/ddp117 PubMedCrossRefGoogle Scholar
  56. 56.
    Thomas R, Wang HJ, Tsai PC et al (2009) Influence of genetic background on tumor karyotypes: Evidence for breed-associated cytogenetic aberrations in canine appendicular osteosarcoma. Chromosome Res 17(3):365–377. doi: 10.1007/s10577-009-9028-z PubMedCrossRefGoogle Scholar
  57. 57.
    Yang J, Cogdell D, Yang D et al (2010) Deletion of the wwox gene and frequent loss of its protein expression in human osteosarcoma. Cancer Lett 291(1):31–38. doi:S0304-3835(09)00617-X[pii]10.1016/j.canlet.2009.09.018 PubMedCrossRefGoogle Scholar
  58. 58.
    Yasuda T, Kanamori M, Nogami S et al (2009) Establishment of a new human osteosarcoma cell line, utos-1: cytogenetic characterization by array comparative genomic hybridization. J Exp Clin Cancer Res 28:26. doi:1756-9966-28-26[pii]10.1186/1756-9966-28-26 PubMedCrossRefGoogle Scholar
  59. 59.
    Benassi MS, Molendini L, Gamberi G et al (2001) Involvement of ink4a gene products in the pathogenesis and development of human osteosarcoma. Cancer 92(12):3062–3067PubMedCrossRefGoogle Scholar
  60. 60.
    Radig K, Schneider-Stock R, Oda Y et al (1996) Mutation spectrum of p53 gene in highly malignant human osteosarcomas. Gen Diagn Pathol 142(1):25–32PubMedGoogle Scholar
  61. 61.
    Molendini L, Benassi MS, Magagnoli G et al (1998) Prognostic significance of cyclin expression in human osteosarcoma. Int J Oncol 12(5):1007–1011PubMedGoogle Scholar
  62. 62.
    Radig K, Schneider-Stock R, Mittler U et al (1998) Genetic instability in osteoblastic tumors of the skeletal system. Pathol Res Pract 194(10):669–677PubMedCrossRefGoogle Scholar
  63. 63.
    Hansen MF (2002) Genetic and molecular aspects of osteosarcoma. J Musculoskelet Neuronal Interact 2(6):554–560PubMedGoogle Scholar
  64. 64.
    Feugeas O, Guriec N, Babin-Boilletot A et al (1996) Loss of heterozygosity of the rb gene is a poor prognostic factor in patients with osteosarcoma. J Clin Oncol 14(2):467–472PubMedGoogle Scholar
  65. 65.
    Nielsen GP, Burns KL, Rosenberg AE et al (1998) Cdkn2a gene deletions and loss of p16 expression occur in osteosarcomas that lack rb alterations. Am J Pathol 153(1):159–163. doi:S0002-9440(10)65556-3[pii]10.1016/S0002-9440(10)65556-3 PubMedCrossRefGoogle Scholar
  66. 66.
    Levine AJ (1997) P53, the cellular gatekeeper for growth and division. Cell 88(3):323–331. doi:S0092-8674(00)81871-1[pii] PubMedCrossRefGoogle Scholar
  67. 67.
    Ladanyi M, Cha C, Lewis R et al (1993) Mdm2 gene amplification in metastatic osteosarcoma. Cancer Res 53(1):16–18PubMedGoogle Scholar
  68. 68.
    Maitra A, Roberts H, Weinberg AG et al (2001) Loss of p16(ink4a) expression correlates with decreased survival in pediatric osteosarcomas. Int J Cancer 95(1):34–38. doi:10.1002/1097-0215(20010120)95:1<34::AID-IJC1006>3.0.CO;2-V[pii]PubMedCrossRefGoogle Scholar
  69. 69.
    Kruzelock RP, Murphy EC, Strong LC et al (1997) Localization of a novel tumor suppressor locus on human chromosome 3q important in osteosarcoma tumorigenesis. Cancer Res 57(1):106–109PubMedGoogle Scholar
  70. 70.
    Gorlick R, Huvos AG, Heller G et al (1999) Expression of her2/erbb-2 correlates with survival in osteosarcoma. J Clin Oncol 17(9):2781–2788PubMedGoogle Scholar
  71. 71.
    Onda M, Matsuda S, Higaki S et al (1996) Erbb-2 expression is correlated with poor prognosis for patients with osteosarcoma. Cancer 77(1):71–78. doi:10.1002/(SICI)1097-0142(19960101)77:1<71::AID-CNCR13>3.0.CO;2-5[pii]10.1002/(SICI)1097-0142(19960101)77:1<71::AID-CNCR13>3.0.CO;2-5PubMedCrossRefGoogle Scholar
  72. 72.
    Guo W, Gorlick R, Ladanyi M et al (1999) Expression of bone morphogenetic proteins and receptors in sarcomas. Clin Orthop Relat Res 365:175–183PubMedCrossRefGoogle Scholar
  73. 73.
    Mohaghegh P, Hickson ID (2001) DNA helicase deficiencies associated with cancer predisposition and premature ageing disorders. Hum Mol Genet 10(7):741–746PubMedCrossRefGoogle Scholar
  74. 74.
    Wang LL, Gannavarapu A, Kozinetz CA et al (2003) Association between osteosarcoma and deleterious mutations in the recql4 gene in rothmund-thomson syndrome. J Natl Cancer Inst 95(9):669–674PubMedCrossRefGoogle Scholar
  75. 75.
    Tiet TD, Alman BA (2003) Developmental pathways in musculoskeletal neoplasia: Involvement of the indian hedgehog-parathyroid hormone-related protein pathway. Pediatr Res 53(4):539–543. doi:10.1203/01.PDR.0000054688.93486.18 01.PDR.0000054688.93486.18[pii] PubMedCrossRefGoogle Scholar
  76. 76.
    Wu JX, Carpenter PM, Gresens C et al (1990) The proto-oncogene c-fos is over-expressed in the majority of human osteosarcomas. Oncogene 5(7):989–1000PubMedGoogle Scholar
  77. 77.
    Franchi A, Arganini L, Baroni G et al (1998) Expression of transforming growth factor beta isoforms in osteosarcoma variants: Association of tgf beta 1 with high-grade osteosarcomas. J Pathol 185(3):284–289. doi:10.1002/(SICI)1096-9896(199807)185:3<284::AID-PATH94>3.0.CO;2-Z[pii]10.1002/(SICI)1096-9896(199807)185:3<284::AID-PATH94>3.0.CO;2-ZPubMedCrossRefGoogle Scholar
  78. 78.
    Chan HS, Grogan TM, Haddad G et al (1997) P-glycoprotein expression: Critical determinant in the response to osteosarcoma chemotherapy. J Natl Cancer Inst 89(22):1706–1715PubMedCrossRefGoogle Scholar
  79. 79.
    Baldini N, Scotlandi K, Serra M et al (1999) P-glycoprotein expression in osteosarcoma: a basis for risk-adapted adjuvant chemotherapy. J Orthop Res 17(5):629–632. doi: 10.1002/jor.1100170502 PubMedCrossRefGoogle Scholar
  80. 80.
    Dalla-Torre CA, Yoshimoto M, Lee CH et al (2006) Effects of thbs3, sparc and spp 1 expression on biological behavior and survival in patients with osteosarcoma. BMC Cancer 6:237. doi:1471-2407-6-237[pii]10.1186/1471-2407-6-237 PubMedCrossRefGoogle Scholar
  81. 81.
    Dalla-Torre CA, De Toledo SR, Yoshimoto M et al (2007) Expression of major vault protein gene in osteosarcoma patients. J Orthop Res 25(7):958–963. doi: 10.1002/jor.20371 PubMedCrossRefGoogle Scholar
  82. 82.
    Sadikovic B, Al-Romaih K, Squire JA et al (2008) Cause and consequences of genetic and epigenetic alterations in human cancer. Curr Genomics 9(6):394–408. doi: 10.2174/138920208785699580 PubMedCrossRefGoogle Scholar
  83. 83.
    Sadikovic B, Thorner P, Chilton-Macneill S et al (2010) Expression analysis of genes associated with human osteosarcoma tumors shows correlation of runx2 overexpression with poor response to chemotherapy. BMC Cancer 10:202. doi:1471-2407-10-202[pii]10.1186/1471-2407-10-202 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  • Bekim Sadikovic
    • 1
  • Paul C. Park
    • 2
  • Shamini Selvarajah
    • 3
  • Maria Zielenska
    • 4
  1. 1.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA
  2. 2.Department of Pathology and Molecular MedicineQueens UniversityKingstonCanada
  3. 3.Department of Medical OncologyDana-Farber Cancer Institute, Harvard Medical SchoolBostonUSA
  4. 4.Department of Laboratory Medicine and PathobiologyThe Hospital for Sick ChildrenTorontoCanada

Personalised recommendations