Abstract B18: MEG3 and MEG8 aberrant methylation associated with worst prognosis in an infant with neuroblastoma
Bibliographic record
Abstract
Abstract Background: Neuroblastoma (NB) is an extremely rare pediatric cancer accounting for about 12% of childhood cancer-related deaths, due to its dismal prognosis in patients diagnosed over 18 months of age with disseminated disease. However, neonates and infants with neuroblastoma are expected to have a better evolution despite their stage and even unfavorable molecular characteristics. Here, we report an unusual case of low-risk neuroblastoma (stage 2B, nonamplified MYCN) in a 9-month-old girl with unfavorable outcome despite favorable prognostic factors. Material and Methods: We investigated the coding genes expression (mRNA) and long noncoding RNAs (lncRNAs) in primary and relapse tumors of this patient to look for genomic and epigenetic alterations that could explain the clinical evolution. The cytogenetic profiles of the primary and relapse tumor samples were also obtained. Three primary tumors from patients with neuroblastoma, all classified as stage 1 (INSS) and low-risk (below 18 months of age at diagnosis, nonamplified-MYCN, all alive and free of disease 60 months after diagnosis) were used as controls in RNA sequencing (RNA-Seq. Illumina®) and DNA methylation arrays (Illumina Infinium HumanMethylation450 BeadChip). Somatic copy number alterations were investigated in the primary and relapsed sample using the array-CGH methodology in a 180K platform (Agilent). Results: The cytogenetic profiles of both samples were quite identical, with few copy number alterations. No numerical chromosomal alterations (aneuploidies) were detected; both tumors carry segmental copy number alterations in common, most of them probably present in a nonmosaic state. The differential gene expression analysis based on fold-change (≤ -2 and ≥ 2), p < 0.005, and FDR < 0.05 was used in RNA-seq to identified gene differential expression in primary and relapsed tumors. Interestingly, only two lncRNA, the imprinted maternally expressed genes MEG3 and MEG8, were downregulated in both primary and relapse tumors. MEG3 targets p53 by either directly interacting with p53 or indirectly suppressing the negative regulator MDM2. In the case of MEG8, their functions in cancer remain unknown. Our study then focused on MEG3 and MEG8 methylation analysis. DNA methylation status of the study groups (primary, relapse tumors, and controls) strongly suggested that DMR that covers promoters was responsible for silencing MEG3 and MEG8 genes in primary and relapse tumors, resulting in downregulation of MEG3 and MEG8. Tumor samples from the patient were also used to perform methylation-specific MLPA (MSMLPA) (SALSA® probemix, MRC-Holland). Hypermethylated probes at MEG3 were identified in primary and relapse tumors when compared with controls. Conclusion: Furthermore, we hypothesized that the methylation gain of the MEG3 and MEG8 locus may be accentuated during cancer progression and therefore, the increased degree of MEG3 and MEG8 suppression was associated with the overall aggressiveness of neuroblastoma. Citation Format: Estela M. Novak, Thamiris Magalhaes Gimenez, Nathalia Halley Neves, Carolina Sgarioni Camargo Vince, Ana Cristina Victorino Krepischi, Rainer Marco Lopez Lapa, Lilian M. Cristofani, Israel Bendit, Vicente Odone Filho. MEG3 and MEG8 aberrant methylation associated with worst prognosis in an infant with neuroblastoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B18.
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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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".