Format

Send to

Choose Destination
Int J Cancer. 2018 Apr 15;142(8):1594-1601. doi: 10.1002/ijc.31195. Epub 2017 Dec 23.

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

Author information

1
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.
2
Information Management Services (IMS), Inc. Rockville, MD.
3
Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD.
4
The Ohio State University Department of Pathology and Pediatrics, Nationwide Children's Hospital, Columbus, OH.
5
Laboratorio de Genética, Pediatric Oncology Institute, GRAACC/UNIFESP, São Paulo, Brazil.
6
UCL Cancer Institute, Huntley Street, London, United Kingdom.
7
Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, United Kingdom.
8
Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
9
Department of Pediatrics, University Clinic of Navarra, Universidad de Navarra, Pamplona, Spain.
10
Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy.
11
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
12
Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, Texas, US.
13
Keck School of Medicine, University of Southern California, Los Angeles, CA.
14
Department of Pediatrics, University of Minnesota Minneapolis, MN.

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.

KEYWORDS:

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

PMID:
29210060
PMCID:
PMC5814322
DOI:
10.1002/ijc.31195
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center