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 ). 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 ), 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.

The Pro-tumorigenic IL-33 Involved in Antitumor Immunity: A Yin and Yang Cytokine

“…Moreover, the level of IL-33 protein has been inversely correlated with tumor grade and size in patients with pulmonary adenocarcinoma, showing an association of low IL-33 expression level with a poor prognosis ( 70 – 72 ). Likewise, a genome-wide association study unveiled a correlation between high IL-33 expression and a good prognosis in patients with osteosarcoma ( 73 ). However, if IL-33 can have a pro-tumor effect by directly targeting cancer cells, the tumor suppressor functions displayed by IL-33 are indirectly promulgated by immune surveillance as we will show hereafter.…”

Relationship of common variants in Interleukin 33 gene with susceptibility and prognosis of osteosarcoma in Han Chinese population

“…A recent genome-wide association study (GWAS) involving 632 OS patients, including 523 European patients and 109 from Brazilian patients, produced highly significant association of GLDC/IL33 locus at 9p24.1 with the risk of OS. Using publicly available data, Koster et al found that the OS susceptible single nucleotide polymorphism (SNP) in GLDC/IL33 locus associated with low expression of IL-33, which was also significantly correlated with poor survival in OS patients 18 . This result suggested that IL-33 might play some roles in the pathogenesis of OS.…”

IL-33 in Tumor Immunity: Nothing to Sneeze At

“…It turns out that low IL-33 expression is associated with poor survival in patients with osteosarcoma. 98 Interestingly, IL-33/ST2 induces osteoclast apoptosis in animal models. 99 In chronic lymphocytic leukemia and multiple myeloma, cancers that arise in bone marrow, patients have reduced IL-33 plasma expression, suggesting that loss of IL-33 may damper immune surveillance in bone marrow.…”