Abstract C004: Colonic Tissue Renewal, Retinoic Acid Signaling, Early-onset CRC
Notice bibliographique
Résumé
Abstract The current rise in early-onset colorectal cancer (EOCRC) has been attributed to a Westernized lifestyle, but a definitive lifestyle factor or genetic etiology has yet to be discovered. Still, genetic studies do show that APC mutations are initiating events in both EOCRC and later-onset CRC (LOCRC). So, a key question is why do somatic APC mutations occur at a relatively young age in EOCRC patients? Hence, we surmise that something is retarding tissue renewal in colonic crypts so that somatic mutations are retained instead of being extruded during tissue turnover. Thus, we conjecture that EOCRC involves an essential nutrient required for tissue renewal. Accordingly, we investigated vitamin A (retinol, retinoic acid), which is an essential vitamin requiring adequate dietary intake. Indeed, vitamin A is essential for tissue homeostasis because germline mutations in retinoid receptors and vitamin A deficiency during pregnancy can lead to fetal malformations. Moreover, population-based studies report vitamin A deficiency in pre-school-aged children. Consequently, young-aged individuals might be prone to cancer-initiating effects of vitamin A deficient diets. Our Goal is to determine how aberrant retinoid receptor expression might promote EOCRC development through dysregulated retinoic acid signaling. Rationale: Our previous studies show that retinoic acid (RA) signaling pathway plays an essential role in regulating cell differentiation in the colon. Moreover, we reported that CRC cells harboring mutations in RA receptors (RAR, RXR) have drug resistance to all-trans RA (ATRA). So, mutation or aberrant expression of RA receptors could lead to incomplete differentiation and promote CRC initiation. Hypothesis: Aberrant RA receptor expression leads to dysregulated RA signaling that contributes to EOCRC development. Results: Our bioinformatics analyses show that retinoid receptors are often abnormally expressed and mutated in human CRCs. We found that up to 22% of CRCs have RA receptor mutations, but mutation status did not predict patient survival. However, we did find that frequency of retinoid receptor mutation was higher (>2X-fold) in EOCRC (age < 45) compared to LOCRC. Specifically, a high frequency of somatic mutations (2x-fold) occurred in receptors for vitamin A (STRA6) and retinoic acid (RARG, PPARG) in EOCRCs. We also found RARG hypermethylation occurs frequently in EOCRCs (p<0.05). Conclusions Since the rate of retinoid receptor alteration was increased in EOCRCs, aberrant RA signaling may be a predisposing factor for early CRC development and contribute to the etiology of EOCRCs. Based on this view, reduced retinoid signaling could lead to incomplete differentiation which provides a mechanism that may explain how delayed tissue renewal causes retention of acquired APC mutations in colonic epithelium: Thus, we put forth the idea that aberrant vitamin A (retinol) metabolism and APC mutation-induced activation of WNT signaling are co-factors in promoting EOCRC. Citation Format: Bruce Boman, Brian Osmond, Anh Nguyen, Chi Zhang. Colonic Tissue Renewal, Retinoic Acid Signaling, Early-onset CRC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr C004.
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 | 0,000 |
| 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 | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,015 | 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 ».