Clinical syndromes linked to biallelic germline variants in <i>MCM8</i> and <i>MCM9</i>
Notice bibliographique
Résumé
Abstract Background MCM8 and MCM9 are newly proposed cancer predisposition genes, linked to polyposis and early-onset cancer, in addition to their association with hypogonadism. Given the uncertain range of phenotypic manifestations and unclear cancer risk estimates, this study aimed to delineate the molecular and clinical characteristics of individuals with biallelic germline MCM8 / MCM9 variants. Methods Population allele frequencies and biallelic variant carrier frequencies were calculated using data from gnomAD, and a variant enrichment analysis was conducted across multiple cancer and non-cancer phenotypes using data from the 100K Genomes Project and the 200K exome release of the UK Biobank. A case series was conducted, including previously reported variant carriers with and without updated clinical data and newly identified carriers through the European Reference Network (ERN) initiative for rare genetic tumor risk syndromes (GENTURIS). Additionally, mutational signature analysis was performed on tumor data from our case series and publicly available datasets from the Hartwig Medical Foundation and TCGA Pan-Cancer Atlas to identify mutational signatures potentially associated with MCM8/MCM9 deficiency. Results Predicted loss of function and missense variants in MCM8 (1.4 per 100,000 individuals) and MCM9 (2.5 per 100,000 individuals) were found to be rare in gnomAD. However, biallelic MCM9 variants showed significant enrichment in cases from the 100K Genomes Project compared to controls for colonic polyps (odds ratio (OR) 6.51, 95% confidence interval (CI) 1.24–34.11; P = 0.03), rectal polyps (OR 8.40, 95% CI 1.28–55.35; P = 0.03), and gastric cancer (OR 27.03, 95% CI 2.93– 248.5; P = 0.004). No significant enrichment was found for biallelic MCM8 variant carriers or in the 200K UK Biobank. In our case series, which included 26 biallelic MCM8 and 28 biallelic MCM9 variant carriers, we documented polyposis, gastric cancer, and early-onset colorectal cancer in 6, 1, and 6 biallelic MCM9 variant carriers, respectively, while these phenotypes were not observed in biallelic MCM8 variant carriers. Additionally, our case series indicates that, beyond hypogonadism—which was present in 23 and 26 of the carriers, respectively—biallelic MCM8 and MCM9 variants are associated with early-onset germ cell tumors (occurring before age 15) in 2 MCM8 and 1 MCM9 variant carriers. Tumors from MCM8 / MCM9 variant carriers with available germline sequencing data predominantly displayed clock-like mutational processes (single base substitution signatures 1 and 5), with no evidence of signatures associated with DNA repair deficiencies. Discussion Our data indicates that biallelic MCM9 variants are associated with polyposis, gastric cancer, and early-onset CRC, while both biallelic MCM8 and MCM9 variants are linked to hypogonadism and the early development of germ cell tumors. These findings underscore the importance of including MCM8 / MCM9 in diagnostic gene panels for certain clinical contexts and suggest that biallelic carriers may benefit from cancer surveillance.
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 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,002 | 0,001 |
| Études des sciences et des technologies | 0,001 | 0,001 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,001 |
| Intégrité de la recherche | 0,001 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 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 ».