Abstract A04: Molecular characterization of undifferentiated pleomorphic sarcomas
Notice bibliographique
Résumé
Abstract Objective: Undifferentiated pleomorphic sarcomas (UPS) are high-grade soft-tissue sarcomas (STS) with no apparent line of differentiation. Despite overall gains in the management of STS, progress in therapies based on molecular targets and understanding the unknown genetic diversity is needed, especially in UPS where response to therapy is limited. Using integrated multi-omic analysis, we aim to characterize UPS for recurrent genetic mutations, altered pathways, and the mutational spectrum. These insights into UPS may enable robust classification, identify prognostic markers, and lead to novel treatment approaches. Methods: Clinically well-annotated cases of UPS with matched blood specimens were retrieved from the Sarcoma Tumor Bank at Mount Sinai Hospital, Toronto. Using current World Health Organization histopathologic classification, reevaluated cases were subjected to whole-genome (WGS) or whole-exome sequencing (WES) and RNA sequencing (RNA-seq). Cell lines and/or mouse xenografts were established from some of the UPS tumors. The goal of this study was to integrate annotated somatic mutations, expressed transcripts, mRNA fusions, structural rearrangements, and copy number aberrations to detect recurrent molecular features in UPS. Results: At present, 43 UPS tumor, 8 matched metastatic samples, 6 mouse xenografts, and 4 cell lines have been sequenced by WGS or WES and RNA-seq. Among the 34 cases analyzed by WES, known cancer genes TP53, LRP1B, ATRX, and RB1 are found to recurrently contain somatic variants. Among these genes, nonsilent somatic variants were found in 18/34 tumors. The somatic variant burden among the WES tumors is approximately 5 muts/Mb. Two UPS cases were hypermutated with a somatic variant burden >10 muts/Mb. In examining the base changes in the hypermutated cases, the two display a C>A bias, in which the 5' and 3' bases flanking the C>A alterations in the hypermutated cases have a distinct pattern (TpCpN, CpCpA) that differ from the other samples. These somatic C>A biases in their trinucleotide context were not detected in >10K tumor cases across 33 cancer types sequenced by TCGA. An RB1 and ATXN10 fusion transcript that lacks the RB1 tumor-suppressing domain was confirmed in one case, while the derived cell line also expressed the RB1-ATXN10 fusion. The cell lines and xenograft models retained 8-71% of their matched tumors' somatic variants. The metastatic samples contained between 13-63% of the somatic variants also identified in their matched primary tumors, among the 4 WES metastatic samples analyzed thus far. Conclusion: Initial analyzes of UPS tumors has identified recurrently mutated cancer-related genes and a unique pattern of C>A bias not previously seen. Ongoing multi-omic analysis, integrating the RNA-seq with the somatic alterations, of UPS tumors may reveal further genomic events that may aid in stratification of UPS, understand the drivers of the disease, identify actionable targets, and realize novel therapeutics. Citation Format: Andrew Seto, Nalan Gokgoz, Qingxia Wei, Yael Babichev, Brendan C. Dickson, Benjamin Alman, Rebecca A. Gladdy, Adam Shlien, Jay Wunder, Irene L. Andrulis. Molecular characterization of undifferentiated pleomorphic sarcomas [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A04.
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 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 | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,002 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 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) | 0,002 | 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 ».