Abstract

Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. To better understand the genetic etiology of osteosarcoma, we performed a multistage genome-wide association study consisting of 941 individuals with osteosarcoma (cases) and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 × 10−9) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 × 10−8 and 2.9 × 10−7, respectively). These two loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma.

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Acknowledgements

We thank G. Maganoli for tissue banking, M. Fanelli for DNA isolation and C. Ferrari for updating clinicopathological data at the Orthopaedic Rizzoli Institute. We thank A. Griffin and D. Marsilio for data collection and T. Selander and the Biospecimen Repository staff at Mount Sinai Hospital. We acknowledge the advice of F. Real at the Spanish National Cancer Research Centre (CNIO). We thank F. Tesser Gamba at the Pediatric Oncology Institute at GRAACC-UNIFESP, and we also thank the International Sarcoma Kindred Study.

This study was funded by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health and the Bone Cancer Research Trust UK. Research is supported by the Chair's Grant U10 CA98543 and Human Specimen Banking Grant U24 CA114766 to the Children's Oncology Group from the National Cancer Institute, US National Institutes of Health. Additional support for research is provided by a grant from the WWWW (QuadW) Foundation to the Children's Oncology Group. This work was supported by grants to I.L.A. and J.S.W. from the Ontario Research Fund and Canadian Foundation for Innovation. This study was also supported by biobank grants from the Regione Emilia-Romagna and by the infrastructure and personnel of the Royal National Orthopaedic Hospital Musculoskeletal Research Programme and Biobank. Support was also provided to A.M.F. by the National Institute for Health Research UCL Hospitals (UCLH) Biomedical Research Centre and the UCL Experimental Cancer Centre. Funding was also provided by PI10/01580, the Fondo de Investigación Sanitaria (FIS), the Instituto de Salud Carlos III (ISCIII) and the Caja de Ahorros de Navarra (CAN) Programme 'Tú eliges, tú decides' to A.P.-G. and L.S. and by an Asociación Española Contra el Cáncer (AECC) project to F.L.

Author information

Affiliations

  1. Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Sharon A Savage
    • , Lisa Mirabello
    • , Sonja I Berndt
    • , Mark P Purdue
    • , Neil E Caporaso
    • , Margaret Tucker
    • , Nathaniel Rothman
    • , Maria Teresa Landi
    • , Debra T Silverman
    • , Sholom Wacholder
    • , Rebecca Troisi
    • , Joseph F Fraumeni Jr
    • , Robert N Hoover
    •  & Stephen J Chanock
  2. Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, USA.

    • Zhaoming Wang
    • , Kevin Jacobs
    • , Charles C Chung
    •  & Meredith Yeager
  3. Nationwide Children's Hospital, Columbus, Ohio, USA.

    • Julie M Gastier-Foster
  4. Department of Pathology and Pediatrics, The Ohio State University, Columbus, Ohio, USA.

    • Julie M Gastier-Foster
  5. Albert Einstein College of Medicine, The Children's Hospital at Montefiore, Bronx, New York, USA.

    • Richard Gorlick
  6. Center for Cancer Research, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Chand Khanna
    • , Paul S Meltzer
    •  & Lee Helman
  7. University College London (UCL) Cancer Institute, London, UK.

    • Adrienne M Flanagan
  8. Royal National Orthopaedic Hospital National Health Service (NHS) Trust, Stanmore, UK.

    • Adrienne M Flanagan
    • , Roberto Tirabosco
    • , Maria Fernanda Amary
    •  & Dina Halai
  9. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

    • Irene L Andrulis
    • , Jay S Wunder
    •  & Nalan Gokgoz
  10. Department of Pediatrics, University Clinic of Navarra, Universidad de Navarra, Pamplona, Spain.

    • Ana Patiño-Garcia
    • , Luis Sierrasesúmaga
    •  & Fernando Lecanda
  11. Department of Pediatric Oncology, A.Y. Ankara Oncology Training and Research Hospital, Ankara, Turkey.

    • Nilgün Kurucu
    • , Inci Ergurhan Ilhan
    •  & Neriman Sari
  12. Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy.

    • Massimo Serra
    • , Claudia Hattinger
    •  & Piero Picci
  13. Department of Pediatrics, Division of Epidemiology and Clinical Research, University of Minnesota, Minneapolis, Minnesota, USA.

    • Logan G Spector
  14. Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Donald A Barkauskas
  15. Stanford University, Palo Alto, California, USA.

    • Neyssa Marina
  16. Department of Pediatric Hematology-Oncology, Lucile Packard Children's Hospital, Palo Alto, California, USA.

    • Neyssa Marina
  17. Pediatric Oncology Institute, Grupo de Apoio ao Adolescente e à Criança com Câncer (GRAACC), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.

    • Silvia Regina Caminada de Toledo
    •  & Antonio S Petrilli
  18. Sir Peter MacCallum Department of Oncology, University of Melbourne, East Melbourne, Victoria, Australia.

    • David M Thomas
  19. Harvard School of Public Health, Boston, Massachusetts, USA.

    • Chester Douglass
    • , Peter Kraft
    •  & David J Hunter
  20. Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.

    • Nuria Malats
  21. Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.

    • Manolis Kogevinas
  22. IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.

    • Manolis Kogevinas
  23. Network Biomedical Research Centre in Epidemiology and Public Health (CIBERESP), Barcelona, Spain.

    • Manolis Kogevinas
  24. National School of Public Health, Athens, Greece.

    • Manolis Kogevinas

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Contributions

S.A.S. and S.J.C. designed the project. J.M.G.-F., R.G., C.K., A.M.F., R. Tirabosco, I.L.A., J.S.W., N.G., L.G.S., D.A.B., N. Marina, A.P.-G., L.S., F.L., M.S., C.H., P.P., N.K., I.E.I., N.S., S.R.C.d.T., A.S.P., M.F.A., D.H., D.M.T., C.D., P.S.M., S.I.B., M.P.P., N.E.C., M.T., N.R., M.T.L., D.T.S., P.K., D.J.H., N. Malats, M.K., S.W., R. Troisi, L.H., J.F.F. and R.N.H. performed sample collection and clinical characterization. K.J., C.C.C., M.Y. and Z.W. performed genotyping. Z.W. and L.M. performed statistical analysis. The manuscript was written by S.A.S., L.M., Z.W. and S.J.C. and reviewed by all coauthors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Sharon A Savage.

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https://doi.org/10.1038/ng.2645

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