Abstract B064: Prevalence and clinical relevance of clonal hematopoiesis in metastatic urologic malignancies
Notice bibliographique
Résumé
Abstract Introduction: Clonal hematopoiesis (CH) is an age-related process whereby hematopoietic progenitor cells with specific mutations gain a proliferative advantage, resulting in populations that can be detected in blood. CH is a major confounder in plasma cell-free DNA (cfDNA) assays that do not profile patient-matched white blood cell (WBC) DNA to distinguish circulating tumor DNA (ctDNA) somatic mutations from those with hematopoietic origin. We aimed to characterize CH in patients with advanced urologic cancers and clarify the potential for CH to interfere with plasma-based tumor genotyping. Methods: We applied error-corrected targeted DNA sequencing (median 2200X) to matched cfDNA and WBC DNA from 301 patients with advanced urothelial cancer (UC) or renal cell carcinoma (RCC) enrolled in a provincial biobank, using a 57 gene panel capturing key CH and urologic cancer genes. CH mutations were defined as those detected in both WBC and cfDNA with a variant allele frequency (VAF) exceeding a 0.25% limit of detection and supported by at least 5 mutant reads. In contrast, ctDNA mutations were required to be exclusively detected in plasma, with a cfDNA VAF ≥5 times the VAF in WBC. Results: 73% (221/301) of patients had ≥1 CH mutation with a VAF above 0.25% (35% of patients had a variant above 2% VAF), and CH- patients were younger than CH+ (RCC: 56 vs 68.5, p<0.01; UC: 63 vs 72, p<0.01). There was no difference in CH prevalence by biological sex. There was no difference in overall survival according to CH status (UC: [CH+] 13 vs [CH-] 16 months, p=0.98; RCC: [CH+] 33 vs [CH-] 49 months, p=0.77), in contrast to the presence of ctDNA mutations which is an established prognostic factor linked with shorter overall survival (UC: [ctDNA+] 10 vs [ctDNA-] 23 months, p<0.01; RCC: [ctDNA+] 15 vs [ctDNA-] 49 months, p<0.01). CH+ patients carried CH mutations most commonly within hematologic malignancy-associated genes (e.g. DNMT3A [58%] and TET2 [26%]), although genes linked to DNA damage response such as TP53 (10%) and ATM (9%) were also mutated. PPM1D was mutated more frequently in UC compared to RCC within CH+ patients (UC: 22%, RCC: 9%, p<0.01), likely attributable to platinum chemotherapy exposure prior to blood collection in 50% of the UC cohort. Importantly, a notable proportion of mutations in UC- or RCC-relevant driver genes originated from CH rather than cancer, including 28% and 65% of mutations falling in TP53 and ATM, respectively. Finally, randomly downsampling sequencing reads from WBC DNA suggested that 500X coverage is sufficient to resolve 90% of CH events with >1% VAF. Conclusion: CH was highly prevalent in patients with advanced urologic malignancies but had no impact on survival in this heterogeneous real-world cohort. CH commonly affected clinically-relevant driver genes that are also altered in solid cancers, potentially causing false-positive genotyping and inflating tumor mutation burden estimates in plasma-only ctDNA assays. Incorporating WBC sequencing to liquid biopsy assays can help correctly identify tumor-originating mutations. Citation Format: Aslı D Munzur, Jack V W Bacon, Francine Fishbein, Gráinne Donnellan, Cecily Q Bernales, Karan Parekh, Gillian Vandekerkhove, David C Müller, Cameron Herberts, Lucia Nappi, Corinne Maurice-Dror, Kim N Chi, Bernhard J Eigl, Christian Kollmannsberger, Maryam Soleimani, Alexander W Wyatt. Prevalence and clinical relevance of clonal hematopoiesis in metastatic urologic malignancies [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B064.
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 | 0,002 |
| 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) | 0,003 | 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 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 ».