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Genome-wide association study identifies two susceptibility loci for osteosarcoma

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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Figure 1: Regional plots of loci associated with 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 WWW.W (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.

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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.

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Correspondence to Sharon A Savage.

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Savage, S., Mirabello, L., Wang, Z. et al. Genome-wide association study identifies two susceptibility loci for osteosarcoma. Nat Genet 45, 799–803 (2013). https://doi.org/10.1038/ng.2645

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