LB-002 Liquid biopsy identifies somatic KRAS mutations in paediatric cranio-spinal arterio-venous malformations: preliminary results
Notice bibliographique
Résumé
Introduction Vascular malformations frequently contain somatic mutations of vascular endothelium. Brain arterio-venous malformations (AVMs) have been shown via surgically resected tissues to contain somatic activating mutations in the KRAS gene, coding for a GTPase controlling the mitogen activating protein kinase (MEK/MAP2K) pathway. However, many complex paediatric cranio-spinal AVMs are not amenable to surgical resection due to the high risk of bleeding. An alternative method of identifying such mutations is via a liquid biopsy. Liquid biopsy involves sampling of blood, either from the draining vein of the AVM or from a peripheral vein, to obtain circulating cell-free DNA (from necrotic endothelial cells). Liquid biopsy has been used successfully to identify mutations in peripheral body AVMs. We hypothesized that liquid biopsy would be a feasible method of identifying somatic mutations in complex paediatric cranio-spinal AVMs, including Vein of Galen Malformation. Methods Our Paediatric AVM Somatic Mutation Study received institutional ethics approval. Enrolled paediatric patients (age </= 18 years) underwent endoluminal liquid biopsy from the draining vein of the AVM at the time of planned embolization, with matched peripheral blood samples; or via peripheral blood alone if no endovascular treatment was being undertaken. Cell-free DNA was extracted and underwent next generation sequencing (NGS) for our bespoke panel of genes associated with vascular malformations: KRAS, HRAS, NRAS, RASA1, BRAF, MAP2K1, MAP2K2, EPHB4, ACVRL1, SMAD4, ENG, GNAQ, PTEN, PIK3CA, TEK, and MAP3K3. Orthogonal confirmation of positive results was undertaken using digital droplet PCR testing. Patients with identified mutations underwent consultation with our paediatric oncology team for consideration of genotype-directed pharmacotherapy. Results Of n=18 patients enrolled, n=11 patients had AVMs involving the cranio-spinal axis, and n=7 have completed NGS testing. At this preliminary stage, three patients have been identified with somatic mosaic mutations, all involving the KRAS gene. Patient 1 was diagnosed antenatally with Vein of Galen Malformation and underwent staged embolization as a neonate and infant. Liquid biopsy of the draining vein (via a microcatheter advanced across an AV fistula into the venous sac) identified a somatic activating mutation of KRAS (G12S). Patient 2 is a teenager with cervical spinal arterio-venous metameric syndrome who presented with progressive paraparesis and became wheelchair-dependent. Peripheral blood liquid biopsy identified a somatic KRAS mutation (G12D). They were commenced on the MEK inhibitor trametinib and after six months was walking independently. Patient 3 is a teenager with extensive deforming AVM of the nose and periorbital tissues. Draining vein liquid biopsy identified a somatic KRAS mutation (G12D). They were also commenced on trametinib and demonstrated marked reduction in AVM size and reduced pain. Discussion Our preliminary results support our hypothesis that liquid biopsy is a feasible method of identifying somatic mutations in complex cranio-spinal AVMs. They also suggest that somatic activating KRAS mutations play a role in a variety of AVM phenotypes, including Vein of Galen Malformation. These results highlight potential use of genotype-directed pharmacotherapy for these disabling lesions. Disclosures K. Bhatia: 1; C; Sydney Aneurysm Pty Ltd. 4; C; Sydney Aneurysm Pty Ltd. D. Lord: None. G. McCowage: None. D. Sylvester: None. J. Karpelowsky: None. G. Olsson: None. C. Bateman: None. B. Padhye: None. P. Muthusami: None. T. Krings: None. S. Kahana-Edwin: None.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».