Abstract 2077: Genome-wide association study identifies the <i>GLDC/IL33</i> locus associated with survival of osteosarcoma patients
Bibliographic record
Abstract
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. To date, few prognostic factors have been identified to be associated with survival in patients with osteosarcoma. We conducted an international, multi-institutional genome-wide association study (GWAS) to identify germline genetic variants associated with overall survival in 632 patients with osteosarcoma. Subjects were genotyped as part of our previously published osteosarcoma susceptibility GWAS, including 523 patients of >80% European ancestry and 109 patients from Brazil. We performed 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. Cox models were adjusted for age at diagnosis, gender, significant principal components, and study/center. SNPs that reached P<10-4 in patients of European ancestry were followed up in patients from Brazil. The results were combined across case sets using a random-effects meta-analysis, and between-sets heterogeneity was evaluated using Cochran's Q chi-squared statistic and the I2 metric. Age (P<0.001) and presence of metastases at diagnosis (P<0.001) were associated with patient survival. In the combined analysis of 632 patients, the strongest association was SNP rs55933544, which was inversely associated with overall survival at genome-wide significance (HR=1.89 per copy of the T allele; 95% CI 1.5-2.4; P=1.3×10-8; I2=0%). Rs5593354 is located in intron 23 of the GLDC gene on chromosome 9p24.1, adjacent to the IL33 gene. This association was consistent across both the European (HR=1.9; P=1.6×10-6) and Brazilian (HR=2.1; P=8.4×10-3) case sets, and after adjustment for metastatic disease at diagnosis (combined HR=1.92; P=1.3×10-8), suggesting that this locus affects overall survival independent of metastatic disease. Kaplan-Meier curve analyses indicated a statistically significant difference between survival rates over time (log-rank test P<0.001) for both the dominant and multiplicative models for rs55933544. Using publicly available data, the risk allele was associated with lower expression of IL33, and lower expression of IL33 in osteosarcoma tumors was associated with worse survival in an independent set of 112 osteosarcomas (P<0.05). 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 biologic underpinnings of this susceptibility locus. Citation Format: Roelof Koster, Orestis A. Panagiotou, William A. Wheeler, Eric Karlins, Julie M. Gastier-Foster, Silvia Regina Caminada de Toledo, Antonio S. Petrilli, Adrienne M. Flanagan, Roberto Tirabosco, Irene L. Andrulis, Jay S. Wunder, Nalan Gokgoz, Ana Patiño-Garcia, Fernando Lecanda, Massimo Serra, Claudia Hattinger, Piero Picci, Katia Scotlandi, David M. Thomas, Mandy L. Ballinger, Richard Gorlick, Donald A. Barkauskas, Logan G. Spector, Margaret Tucker, Belynda Hicks, Meredith Yeager, Robert Hoover, Stephen J. Chanock, Sharon A. Savage, Lisa J. Mirabello. Genome-wide association study identifies the GLDC/IL33 locus associated with survival of osteosarcoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2077.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".