Abstract PR10: Ionizing radiation-induced tumorigenesis is associated with exome-wide mutational signatures conserved in mice and humans
Notice bibliographique
Résumé
Abstract Objective: Ionizing radiation (IR) is utilized in diagnostic and therapeutic medical applications, but is also a well-recognized mutagen. The in vivo genetic events promoting malignancy formation after IR exposure are not understood in detail. The mutational landscape of IR-induced tumorigenesis may yield insights into how IR-induced genomic injury leads to cancer and the important endogenous mechanisms that safeguard genomic integrity. We previously developed mouse models of IR-induced malignancies initiated by focal, fractionated irradiation similar to clinical radiotherapy. Whole exome sequencing (WES) of these mouse model-derived malignancies revealed stable trinucleotide-based (comprised of a somatic single nucleotide variant and the 5' and 3' flanking bases) mutational signatures that were independent of tumor type or genetic background, suggestive of a unique IR-specific imprint on tumor exomes. On the basis of these findings, we hypothesized that clinically derived IR-induced malignancies (secondary cancers, distinguishable from recurrent primary cancers) from patients also harbor distinct mutational signatures mirroring those identified in our mouse models. Our goal is to determine whether IR-induced malignancies from patients harbor mutational signatures similar to experimentally derived IR-induced malignancies arising in mice. Methods: WES was performed on genomic DNA isolated from two separate clinical IR-induced malignancies, both sarcomas arising in patients who were survivors of pediatric cancers. Radiotherapy exposure was verified by review of volumetric dosimetry. A UV-induced cutaneous squamous cell carcinoma (clinical patient sample) was included as a negative control and also analyzed by WES utilizing the same bioinformatics pipeline. Matched germline and tumor DNA were analyzed. Exome capture, high throughput sequencing (Illumina), read alignment and variant calling were performed using standard industry-accepted approaches. IR-induced tumors from mice and clinical samples were analyzed separately, then pooled into a single analysis to identify mutational signatures common to mice and humans. For all samples, single nucleotide variants (SNVs) were analyzed using non-negative matrix factorization (NMF) to estimate trinucleotide-based mutational signatures. Results: The two IR-induced clinical malignancies harbored 194 somatic SNVs and 361 somatic SNVs. The UV-induced cutaneous carcinoma harbored 2,113 somatic SNVs. NMF analysis of the pooled somatic SNVs from human tumor samples only support the extraction of two signatures, one of which clearly is exclusive to the UV-induced skin cancer, while the other is present almost exclusively in IR-induced malignancies (the number of mutations assigned to the signatures differs between the skin cancer and IR samples with p-value = 8.3x10-179 by a likelihood ratio test). Despite being extracted from a single tumor sample, the UV signature was virtually identical to previously published UV signature. To determine whether IR-associated mutational signatures were stable across species we pooled mouse and human IR-induced tumor SNVs for NMF analysis, which identified common signatures that are not highly correlated with each other, suggesting that they represent separate biological processes. Conclusions: IR-induced tumorigenesis is associated with stable trinucleotide-based mutational signatures that are conserved in human malignancies and mouse malignancies. These signatures are highly distinguishable from that associated with UV. These conserved signatures, developing in multiple irradiated tissue types, may reflect mutational processes associated with in vivo IR exposure and possibly demonstrate non-lethal but pathogenic somatic variants related to DNA repair. This abstract is also being presented as Poster B42. Citation Format: Philip Davidson, Amy Sherborne, Barry Taylor, Alice Nakamura, Jean Nakamura. Ionizing radiation-induced tumorigenesis is associated with exome-wide mutational signatures conserved in mice and humans [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr PR10.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
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 tête enseignante, 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 ».