Abstract C051: Impact of population pharmacogenomics on cisplatin-induced neurotoxicities
Notice bibliographique
Résumé
Abstract Background: Studies have shown that taxane-treated breast cancer patients with African (AFR) ancestry experience worse peripheral sensory neuropathy (PSN), while African American vincristine-treated leukemia patients have less PSN than Europeans (EUR). We hypothesized that ancestral disparities may exist for cisplatin-induced neurotoxicities and may relate to differences in allele frequency and resultant gene expression of SNPs associated with these toxicities. Methods: In our Platinum Study of 1680 genotyped testicular cancer survivors (TCS), multidimensional scaling scores were anchored by the 1000 Genomes population to classify geographic ancestry. PSN (EORTC-CIPN20) and other toxicities plus clinical and lifestyle variables were examined for associations between geographic ancestry and phenotypes using logistic regression and Wilcoxon rank sum test. Genotyped SNPs with Fst > 0.25 in 1000 Genomes were identified and evaluated with GTEx data to find expression or splicing quantitative trait loci in nerve/brain tissue or for cisplatin-associated candidate genes, across all tissues. LDmatrix was used to find linkage disequilibrium. If a block of SNPs had R2 > 0.75, one independent SNP was kept for association analysis. Logistic regression with age at questionnaire completion and 10 genetic principal components as covariates was used to calculate the association between genotype and toxicity. Results: In an analysis of patients who received 400-450 mg/m2 of cisplatin including EUR (n=681), Asian (ASN) axis (n=44) and AFR (n=13), the odds ratio (OR) for any neuropathy vs. none in the AFR vs. EUR was 7.8 (P=0.049) and in the AFR vs. ASN axis (including East Asian 1000 Genomes populations) was 10.0 (P=0.034). TCS with AFR ancestry had significantly more vertigo. There were 19,874 SNPs for analysis from the genome-wide approach and 118 SNPs from the candidate gene approach. While associations between genotype and toxicity did not reach Bonferroni threshold, some SNPs had p-values in the 10-5 range. For PSN, one SNP had increased frequency of a risk allele in the AFR population while the other had increased frequency of a protective allele, while for vertigo, four SNPs had increased frequency of risk alleles in the AFR population. Of interest was rs34904346, in which the TT vs. AA genotype had an OR of 1.9 (p=2x10-5) for any vs. no PSN, with the T allele having 90% frequency in AFR ancestry patients versus ∼60% in other populations. This SNP and three other independent SNPs associated with PSN incidence (p∼10-3) are eQTLs for RNF24 in nerve tissue, which interacts with membrane proteins that regulate intracellular calcium levels. Conclusions: We show preliminary evidence for the role of differing risk allele frequencies across populations in explaining disparities in cisplatin-induced PSN and vertigo, likely in combination with structural and environmental factors. Genotyping risk alleles could customize dosing, treatment, and post-treatment monitoring to benefit all cisplatin-treated patients. Citation Format: Swetha Nakshatri, Paul C. Dinh, Darren R. Feldman, Robert J. Hamilton, Chunkit Fung, David J. Vaughn, Christian Kollmannsberger, Robert Huddart, Lawrence H. Einhorn, Nancy J. Cox, Lois B. Travis, Eileen Dolan. Impact of population pharmacogenomics on cisplatin-induced neurotoxicities [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C051.
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 | 0,002 | 0,004 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,001 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,001 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,001 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,006 | 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 ».