THU616 Analysis Of Germline Mutations In Patients With Sporadic Adrenocortical Carcinoma
Authors: Terzolo Massimo , Grisanti Salvatore , Scatolini Maria , Tomaiuolo Pasquale , Grosso Enrico , Basile Vittoria , Cosentini Deborah , Puglisi Soraya , Laganà Marta , Perotti Paola , Saba Laura , Rossini Elisa , Sigala Sandra , Volante Marco , Berruti Alfredo 
Published: October 2023

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