Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 142, Issue 8, Pages 1594-1601Publisher
WILEY
DOI: 10.1002/ijc.31195
Keywords
osteosarcoma; overall survival; genome-wide association study; osteosarcoma-specific survival
Categories
Funding
- Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
- Bone Cancer Research Trust UK
- Chair's Grant of the Children's Oncology Group from the National Cancer Institute, National Institutes of Health [U10 CA98543]
- Human Specimen Banking of the Children's Oncology Group from the National Cancer Institute, National Institutes of Health [U24 CA114766]
- WWWW (QuadW) Foundation, Inc.
- Ontario Research Fund
- Canadian Foundation for Innovation
- Regione Emilia-Romagna
- Royal National Orthopaedic Hospital Musculoskeletal Research Programme and Biobank
- National Institute for Health Research UCLH Biomedical Research Centre
- UCL Experimental Cancer Centre [PI13/01476]
- FIS, ISCIII and La Fundacion Bancaria La Caixa
- Fundacion Caja Navarra
- AECC Project
- Rainbows for Kate Foundation
- Liddy Shriver Sarcoma Initiative
- Victorian Cancer Agency
- Australian National Health and Medical Research Council [APP1004017]
- Cancer Australia [APP1067094]
- NATIONAL CANCER INSTITUTE [P30CA016058, U10CA098543, U24CA114766, ZIACP010142] Funding Source: NIH RePORTER
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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 x 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 x 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. What's new? To date, prognostic factors associated with survival in patients with osteosarcoma are scarce. Here, the authors conducted a multi-institutional genome-wide association study to explore whether germline genetics may contribute to overall survival in osteosarcoma patients. They identified a common single nucleotide polymorphism, rs55933544, located in the GLDC gene on chromosome 9, associated with poor survival. The rs55933544 risk allele was associated with lower expression of the nearby gene, IL33. These findings, if replicated in additional populations, form the foundation for future studies of the molecular basis of the association of the GLDC/IL33 (rs55933544) variant with survival in osteosarcoma.
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