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

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.

SUBMITTER: Koster R

PROVIDER: S-EPMC5814322 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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

Koster Roelof R Panagiotou Orestis A OA Wheeler William A WA Karlins Eric E Gastier-Foster Julie M JM Caminada de Toledo Silvia Regina SR Petrilli Antonio S AS Flanagan Adrienne M AM Tirabosco Roberto R Andrulis Irene L IL Wunder Jay S JS Gokgoz Nalan N Patiño-Garcia Ana A Lecanda Fernando F Serra Massimo M Hattinger Claudia C Picci Piero P Scotlandi Katia K Thomas David M DM Ballinger Mandy L ML Gorlick Richard R Barkauskas Donald A DA Spector Logan G LG Tucker Margaret M Belynda D Hicks DH Yeager Meredith M Hoover Robert N RN Wacholder Sholom S Chanock Stephen J SJ Savage Sharon A SA Mirabello Lisa L

International journal of cancer 20171223 8

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 9 ...[more]

PMID: 29210060

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Project description:Objectives:Previous genome-wide association study showed that GLDC/IL33 loci were associated with overall survival in patients with osteosarcoma (OS). We performed a replication study to explore whether variants of GLDC/IL33 are associated with the survival of OS patients and to further verify their functional role in the gene expression. Methods:A total of 216 patients with OS were enrolled. The overall survival time was calculated from the date of diagnosis till the date of last follow-up or mortality. Two SNPs were genotyped, including rs55933544 and rs74438701. OS specimens were obtained from 72 patients during surgery. The gene expression level of IL33 and GLDC was evaluated by qPCR. Patients were classified into two groups according to the 5-year overall survival (death/survival). The chi-square test was used to analyze difference of genotype frequency. The Student t-test was used to compare the gene expression level between different genotypes. Cumulative survival time was calculated by the Kaplan-Meier method and analyzed by the log-rank test. Results:Genotype TT of rs55933544 was significantly associated with the event of death (0.176 vs. 0.061, p < 0.001). Patients with no risk allele T of rs55933544 showed a 5-year overall survival of 81.4% (110/141), which was significantly higher than an overall survival of 55.0% (29/54) for patients with one risk allele and 44.8% (12/21) for patients with two risk alleles (p < 0.01). Genotype TT of rs55933544 were indicative of remarkably lower expression of IL33 than genotype CC (0.00041 ± 0.00025 vs. 0.00065 ± 0.00031, p = 0.04). Patients with low IL33 expression presented remarkably worse survival as compared with the patients with high IL33 expression (p < .01). Conclusions:Variant rs55933544 was associated with the survival time of OS patients. IL33 may contribute to a poor prognosis of OS. Further investigation into the biological mechanisms by which IL33 influences the overall survival can shed light on the improvement of clinical outcome for OS patients.

Dataset Information

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

Publications

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

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