Abstract 717: Pan-cancer analysis of <i>TRIM37</i> copy-number and development of fit-for-screening in situ hybridization tools
Notice bibliographique
Résumé
Abstract Background: Elevated TRIM37 protein levels, often driven by genomic copy number (CN) gains in cancer cells, lead to loss of the pericentriolar material during mitosis and increased dependence on PLK4-mediated centriole assembly. This synthetic lethal hypothesis is being tested in a phase I clinical trial evaluating the activity of the PLK4 inhibitor, RP-1664, in advanced solid tumors with TRIM37 CN gains or overexpression (LIONS, NCT06232408). In support of this clinical study, we characterized TRIM37 CN and RNA expression across a large genomic database and by imaging-based DNA and RNA in-situ hybridization. Methods: Whole exomes and transcriptomes from >12,000 adult solid tumors were analyzed for TRIM37 CN gain (CN > ploidy) or amplification (amp, CN ≥ ploidy + 2), respectively, or TRIM37 RNA expression (BostonGeneTM). Locus specific probes for fluorescence in-situ hybridization (FISH) were developed for TRIM37 and centromere 17 (CEP17). TRIM37 RNA-ISH was developed using the RNAscopeTM system (ACD BioTM). Results: Across adult solid tumors, TRIM37 amps, were most frequent in breast (9%), lung adenocarcinoma (5%), and melanoma (5%). Using the lower cutoff inclusive of TRIM37 gains, CN events were most often observed in urinary tract cancer (33%), lung adenocarcinoma (32.2%), breast cancer (26%), and squamous cell lung carcinoma (24.2%). TRIM37 CN levels were correlated with TRIM37 RNA expression in all indications examined. TRIM37 CN level was inversely correlated with segment length (coef -1.76, p-value = 6.1e-20). ERBB2 (HER2) is located approximately 19 megabases (mb) from TRIM37 and was often co-amplified, with 73% of ERBB2 gain/amps also having TRIM37 gain/amps. TRIM37 focal amps (<5.6 mb) were enriched in samples with co-occurring ERBB2 focal amps, even though these events were on different segments. HER2-enriched breast cancer had the highest percentage of focal TRIM37 amps (56%) and high-level amps (≥ 5 copies; 60%). To identify TRIM37 high patients clinically, we developed RNA and DNA ISH assays. TRIM37 DNA FISH ratio and ploidy corrected CN by NGS were strongly correlated (N=16, Pearson correlation = 0.89, p-value = 3.4x10-6). DNA FISH ratio was positively associated with RNA-ISH scores (Jonckheere-Terpstra test, P = 0.03), and of 16 TRIM37 FISH positive DNA-FISH samples, 14 were scored 2-3+ (≥4 copies/cell), while 2, scored 1+ (1-3 copies per cell) by RNA-ISH. Conclusions: A considerable population of adult solid tumors are TRIM37-high. Creation of fit-for-screening tools employing in-situ hybridization techniques may provide enhanced sensitivity for identification of patients with TRIM37-high tumors. Citation Format: Isabel Soria-Bretones,Joseph D. Schonhoft,Esha Jain,Nikita Kotlov,Parham Nejad,Daria F. Goncharova,Oleg A. Baranov,Jessica K. Scher,Elizabeth A. Sheehan,Vladimir A. Kushnarev,Konstantin Chernyshov,Gary Marshall,Ian M. Silverman,Victoria Rimkunas. Pan-cancer analysis of TRIM37 copy-number and development of fit-for-screening in situ hybridization tools [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 717.
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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| 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) | 0,009 | 0,002 |
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 ».