THU616 Analysis Of Germline Mutations In Patients With Sporadic Adrenocortical Carcinoma
Notice bibliographique
Résumé
Abstract Disclosure: M. Terzolo: None. S. Grisanti: None. M. Scatolini: None. P. Tomaiuolo: None. E. Grosso: None. V. Basile: None. D. Cosentini: None. S. Puglisi: None. M. Laganà: None. P. Perotti: None. L. Saba: None. E. Rossini: None. S. Sigala: None. M. Volante: None. A. Berruti: None. Background: Adrenocortical carcinoma (ACC) is a rare cancer associated with hereditary syndromes in 10% of cases. Germline variants (GVs) in patients with ACC have been identified mainly in pediatric patients and in family cases, while data on GVs in adult patients with sporadic ACC are limited. Methods: We analyzed germline DNA from 150 adult patients with sporadic ACC sequentially referred to our centers between 1998 and 2019. We designed a custom panel of 17 genes potentially involved in the pathogenesis of ACC: AIP, APC, ARMC5, ARNT, BRCA1, BRCA2, CTNNB1, IGF2, MEN1, MSH2, MSH6, PDE8B, PDE11A, PRKACA, PRKACB, PRKAR1A, and TP53. NGS data were analyzed by a semi-automated bioinformatic pipeline. All GVs were studied using effect predictor tools (PolyPhen and SIFT). Specific databases (ClinVar, Varsome, gnomAD, IARC TP53, HGMD) were used for variant classification according to ACMG criteria. Variants interpreted as pathogenic (P) or likely pathogenic (LP) were considered as positive. Clinical, pathological and genomic data were analyzed in different Cox models to study prognostic impact of covariates for disease-free survival (DFS), progression-free survival (PFS) and overall survival (OS). Results: We identified 21 unique GVs in 24/150 patients (16%). GVs were found in 9 genes including APC (n=3), ARMC5 (n=3), MSH2 (n=3), PDE11A (n=3), TP53 (n=3), MSH6 (n=2), PDE8B (n=2), AIP (n=1) and CTNNB1 (n=1). Eleven positive GVs including 3 GVs with deleterious potential were found in 14/150 patients (9.3%). Some variants were particularly enriched, with a frequency of 0.02% compared to an overall frequency of 0.001-0.004% in the gnomAD database. We found a new GV in TP53 (G105D) in a patient who was later found to have a sister with ACC and, for the first time, 3 GVs in ARMC5 (P731R). Patients with ARMC5 GVs had large cortisol-secreting tumors and one case displayed pathologic features of ACC and combined macronodular cortical disease. Positive GVs were associated with a shorter OS (50 vs 142 months, HR 1.81; 95%CI, 0.86-3.82, p=0.118) and PFS (8 vs 30 months, HR 3.11; 95%CI, 1.57-6.16, p=0.001) but not DFS (27 vs 32 months, HR 1.07; 95%CI, 0.52-2.22, p=0.845). At multivariate analysis, known clinical factors (age, surgery of primary ACC, ENSAT stage, hypercortisolism) were found to have prognostic impact on OS. However, GVs remained independent predictors of PFS and OS in metastatic patients. Conclusions: In a series of 150 patients with ACC, we found that 9.3% of them had positive GVs, thus confirming findings from the TCGA analysis. We describe for the first time the presence of ARMC5 GVs in patients with ACC and we found a novel pathogenic variant of TP53. Pathologic features of one ARMC5 case suggest a possible progression from macronodular hyperplasia to ACC. Finally, the present findings suggest that GVs can affect ACC progression and survival of affected patients. Presentation: Thursday, June 15, 2023
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,001 |
| Bibliométrie | 0,000 | 0,002 |
| 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) | 0,000 | 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 tête enseignante, 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 ».