Genome-wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients

Roelof Koster, Orestis A. Panagiotou, William A. Wheeler, Eric Karlins, Julie M. Gastier-Foster, Silvia Regina Caminada de Toledo, Antonio S. Petrilli, Adrienne M. Flanagan, Roberto Tirabosco, Irene L. Andrulis, Jay S. Wunder, Nalan Gokgoz, Ana Patiño-Garcia, Fernando Lecanda, Massimo Serra, Claudia Hattinger, Piero Picci, Katia Scotlandi, David M. Thomas, Mandy L. BallingerRichard Gorlick, Donald A. Barkauskas, Logan G. Spector, Margaret Tucker, D. Hicks Belynda, Meredith Yeager, Robert N. Hoover, Sholom Wacholder, Stephen J. Chanock, Sharon A. Savage, Lisa Mirabello

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Survival rates for osteosarcoma, the most common primary bone cancer, have changed little over the past three decades and are particularly low for patients with metastatic disease. We conducted a multi-institutional genome-wide association study (GWAS) to identify germline genetic variants associated with overall survival in 632 patients with osteosarcoma, including 523 patients of European ancestry and 109 from Brazil. We conducted a time-to-event analysis and estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models, with and without adjustment for metastatic disease. The results were combined across the European and Brazilian case sets using a random-effects meta-analysis. The strongest association after meta-analysis was for rs3765555 at 9p24.1, which was inversely associated with overall survival (HR = 1.76; 95% CI 1.41–2.18, p = 4.84 × 10−7). After imputation across this region, the combined analysis identified two SNPs that reached genome-wide significance. The strongest single association was with rs55933544 (HR = 1.9; 95% CI 1.5–2.4; p = 1.3 × 10−8), which localizes to the GLDC gene, adjacent to the IL33 gene and was consistent across both the European and Brazilian case sets. Using publicly available data, the risk allele was associated with lower expression of IL33 and low expression of IL33 was associated with poor survival in an independent set of patients with osteosarcoma. In conclusion, we have identified the GLDC/IL33 locus on chromosome 9p24.1 as associated with overall survival in patients with osteosarcoma. Further studies are needed to confirm this association and shed light on the biological underpinnings of this susceptibility locus.

Original languageEnglish (US)
Pages (from-to)1594-1601
Number of pages8
JournalInternational Journal of Cancer
Volume142
Issue number8
DOIs
StatePublished - Apr 15 2018

Bibliographical note

Funding Information:
This work was supported by the Bone Cancer Research Trust UK to A.M.F. Research is supported by the Chair’s Grant U10 CA98543 and Human Specimen Banking Grant U24 CA114766 of the Children’s Oncology Group from the National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Additional support for research is provided by a grant from the WWWW (QuadW) Foundation, Inc. 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, by the infrastructure and personnel of the Royal

Funding Information:
This work was supported by the Bone Cancer Research Trust UK to A.M.F. Research is supported by the Chair's Grant U10 CA98543 and Human Specimen Banking Grant U24 CA114766 of the Children's Oncology Group from the National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Additional support for research is provided by a grant from the WWWW (QuadW) Foundation, Inc. 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, by the infrastructure and personnel of the Royal National Orthopaedic Hospital Musculoskeletal Research Programme and Biobank. Support was also provided to A.M.F. (UCL) by the National Institute for Health Research UCLH Biomedical Research Centre and UCL Experimental Cancer Centre, funding from PI13/01476, FIS, ISCIII and La Fundaci?n Bancaria ?La Caixa?, Fundaci?n Caja Navarra to AP-G and AECC Project to F.L. The International Sarcoma Kindred Study was supported by the Rainbows for Kate Foundation, the Liddy Shriver Sarcoma Initiative, the Victorian Cancer Agency, the Australian National Health and Medical Research Council (APP1004017) and Cancer Australia (APP1067094).

Funding Information:
National Orthopaedic Hospital Musculoskeletal Research Programme and Biobank. Support was also provided to A.M.F. (UCL) by the National Institute for Health Research UCLH Biomedical Research Centre and UCL Experimental Cancer Centre, funding from PI13/01476, FIS, ISCIII and La Fundación Bancaria “La Caixa”, Fundación Caja Navarra to AP-G

Funding Information:
Key words: osteosarcoma, overall survival, genome-wide association study, osteosarcoma-specific survival Abbreviations: CI: confidence intervals; ENCODE: Encyclopedia of DNA Elements; eQTL: expression quantitative trait loci; GLDC: glycine dehydrogenase (decarboxylating) gene; GWAS: genome-wide association study; HR: hazard ratio; IL33: Interleukin 33 gene; ; KDM4C: lysine demethylase 4C gene; LD: linkage disequilibrium; MAF: minor allele frequency; NCBI: National Center for Biotechnology Information; NFIB: nuclear factor I B gene; SNP: single nucleotide polymorphisms; TPD52L3: tumor protein D52-like 3 gene Additional Supporting Information may be found in the online version of this article. †Sholom Wacholder is deceased. Conflict of Interest: The authors declare no competing financial interests. Grant sponsor: Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; Grant sponsor: Bone Cancer Research Trust UK; Grant sponsor: Chair’s Grant of the Children’s Oncology Group from the National Cancer Institute, National Institutes of Health; Grant number: U10 CA98543; Grant sponsor: Human Specimen Banking of the Children’s Oncology Group from the National Cancer Institute, National Institutes of Health; Grant number: U24 CA114766; Grant sponsor: WWWW (QuadW) Foundation, Inc.; Grant sponsor: Ontario Research Fund; Grant sponsor: Canadian Foundation for Innovation; Grant sponsor: Regione Emilia-Romagna; Grant sponsor: Royal National Orthopaedic Hospital Musculoskeletal Research Programme and Biobank; Grant sponsor: National Institute for Health Research UCLH Biomedical Research Centre; Grant sponsor: UCL Experimental Cancer Centre; Grant number: PI13/01476; Grant sponsor: FIS, ISCIII and La Fundación Bancaria “La Caixa”; Grant sponsor: Fundación Caja Navarra; Grant sponsor: AECC Project; Grant sponsor: Rainbows for Kate Foundation; Grant sponsor: Liddy Shriver Sarcoma Initiative; Grant sponsor: Victorian Cancer Agency; Grant sponsor: Australian National Health and Medical Research Council; Grant number: APP1004017; Grant sponsor: Cancer Australia; Grant number: APP1067094 DOI: 10.1002/ijc.31195 History: Received 20 Sep 2017; Accepted 13 Nov 2017; Online 6 Dec 2017 Correspondence to: Lisa Mirabello, PhD, Investigator, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, 9609 Medical Center Drive, Room 6E524, Bethesda, MD 20850, USA, E-mail: mirabellol@mail.nih.gov; Tel: 11-240-276-7258

Keywords

  • genome-wide association study
  • osteosarcoma
  • osteosarcoma-specific survival
  • overall survival

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