FAM131B-BRAF Fusion Gene Resulting From 7q34 Deletion Leads to MAPK Pathway Activation in Pilocytic Astrocytoma
Bibliographic record
Abstract
Pilocytic astrocytoma (PA, WHO Grade I) is the most common childhood brain tumor, accounting for approximately 20% of brain tumors in childhood. Recently, we and others have shown that tandem duplication at 7q34, resulting in KIAA1549-BRAF fusion genes and constitutive activation of the MAPK signaling pathway, is a hallmark genetic lesion in PA development. Alternative mechanisms of MAPK activation include BRAF and KRAS point mutations, RAF1 fusions, and Neurofibromatosis-associated NF1 mutations. To elucidate underlying genetic driver alterations leading to aberrant MAPK activation, we screened 125 primary tumors for mutations in KRAS, NRAS, PTPN11, BRAF and RAF1 and performed multiplex and long-distance inverse (LDI) PCR to identify BRAF and RAF1 fusion genes. To define the mechanism underlying the formation of novel BRAF fusion genes and understand their phenotype, we used microarray-based comparative genomic hybridization (aCGH) and performed in vitro experiments for functional assessment. Fusions targeting RAF kinases were found in 72% (90/125) of cases. Sequencing confirmed all previously reported variants of KIAA1549-BRAF and yielded novel variants of this fusion gene and of SRGAP3-RAF1 . Mutations in KRAS and BRAF , as well as RAF1 gene fusions were mostly mutually exclusive with BRAF rearrangements. Most importantly, we identified FAM131B as an alternative fusion partner of BRAF , resulting from an interstitial deletion of ˜2.5 Mb at 7q34, in 3 cases. Investigating the functional characteristics of FAM131B-BRAF, we demonstrated constitutive MEK phosphorylation and activation of MAPK downstream effectors. Furthermore, we showed that FAM131B-BRAF is able to transform NIH3T3 cells. Our results implicate RAF kinase fusions as a central oncogenic mechanism in PA tumor development and strengthen their potential role both as a tumor-specific marker for the molecular diagnosis of PA and as an ideally suited target for molecular therapeutic intervention.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".