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Genome‐wide association study identifies the GLDC / IL33 locus associated with survival of osteosarcoma patients
Author(s) -
Koster Roelof,
Panagiotou Orestis A.,
Wheeler William A.,
Karlins Eric,
GastierFoster Julie M.,
Caminada de Toledo Silvia Regina,
Petrilli Antonio S.,
Flanagan Adrienne M.,
Tirabosco Roberto,
Andrulis Irene L.,
Wunder Jay S.,
Gokgoz Nalan,
PatiñoGarcia Ana,
Lecanda Fernando,
Serra Massimo,
Hattinger Claudia,
Picci Piero,
Scotlandi Katia,
Thomas David M.,
Ballinger Mandy L.,
Gorlick Richard,
Barkauskas Donald A.,
Spector Logan G.,
Tucker Margaret,
Belynda D. Hicks,
Yeager Meredith,
Hoover Robert N.,
Wacholder Sholom,
Chanock Stephen J.,
Savage Sharon A.,
Mirabello Lisa
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31195
Subject(s) - osteosarcoma , hazard ratio , genome wide association study , proportional hazards model , single nucleotide polymorphism , locus (genetics) , oncology , imputation (statistics) , biology , confidence interval , allele , medicine , genetic association , meta analysis , survival analysis , genetics , gene , genotype , cancer research , machine learning , missing data , computer science
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.