Identification of genetic and molecular events specific to pediatric gliomas and involved in gliomagenesis
Bibliographic record
Abstract
Brain tumours are the largest group of solid neoplasms in children, and they are currently the leading cause of cancer-related mortality and morbidity in the pediatric years. In Canada, pediatric astrocytomas account for 44% of all brain tumours in children. While the low-grade tumours have significant morbidity on the developing brain, the high-grade tumours have a dismal three-year survival rate varying from 10%-30%. Although extensive documentation is available on adult astrocytomas, relatively little is known about the molecular mechanisms underlying the development and progression of pediatric astrocytomas. The main goal of the work presented in this thesis was to better characterize the molecular pathogenesis of pediatric high-grade and low-grade astrocytomas (pediatric HGA and pediatric LGA). First, we aimed to identify and characterize chromosomal alterations in pediatric HGA using the Illumina Single Nucleotide Polymorphisms (SNP)-based array. Results from this study showed an unexpectedly low frequency of genetic amplification and of complete deletions, and a high frequency of loss-of-heterozygozity in the pediatric samples. Despite some commonalities, most copy-number alterations in pediatric HGA were distinct from those described in adult HGA. This study constituted the first complete profiling of the tumour cell genome using high-resolution SNP arrays. Second, using the same technique, we identified and characterized recurrent tandem duplication on chromosome 7q34, leading to an in-frame gene fusion between 2 adjacent genes: KIAA1549 and BRAF, in a subset of pediatric LGA. Our results demonstrated that this duplication occurs mainly in sporadic juvenile pilocytic astrocytomas (JPA) and is rare in other low-grade brain tumours. Moreover, this duplication showed neuroanatomomical specificity for JPA located in the cerebellar regions. Finally, using in vivo and in vitro models of JPA, we showed up-regulation of several known senescence markers indicative of the activation of an oncogene-induced senescence (OIS) program in these tumour cells. Results from these two studies suggest that the KIAA1549-BRAF gene fusion is a biological marker of JPA, and that constitutive activation of BRAF leading to oncogene-mediated senescence may explain their tendency toward growth arrest. Collectively, these studies have uncovered new chromosomal alterations specific to pediatric low-grade and high-grade astrocytomas, and they have helped elucidate molecular mechanisms leading to the development of these tumours.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| 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".