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

Koster, R; Panagiotou, OA; Wheeler, WA; Karlins, E; Gastier-Foster, JM; Caminada de Toledo, SR; Petrilli, AS; ... Mirabello, L; + view all (2018) Genome-wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients. International Journal of Cancer , 142 (8) pp. 1594-1601. 10.1002/ijc.31195. Green open access

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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.

Type: Article
Title: Genome-wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/ijc.31195
Publisher version: https://doi.org/10.1002/ijc.31195
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Osteosarcoma; overall survival; genome-wide association study; osteosarcoma specific survival
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Pathology
URI: https://discovery.ucl.ac.uk/id/eprint/10085298
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