ECE2023 Rapid Communications Rapid Communications 5: Adrenal and Cardiovascular Endocrinology 1 (6 abstracts)
Analysis of germline mutations in patients with non-syndromic adrenocortical carcinoma
Massimo Terzolo 1 , Salvatore Grisanti 2 , Maria Scatolini 3 , Pasquale Tomaiuolo 3 , Enrico Grosso 3 , Vittoria Basile 1 , Deborah Cosentini 2 , Soraya Puglisi 1 , Marta Laganà 2 , Paola Perotti 1 , Elisa Rossini 4 , Sandra Sigala 4 , Marco Volante 5 & Alfredo Berruti 2
1Internal Medicine, Department of Clinical and Biological Sciences, S. Luigi Gonzaga Hospital, University of Turin, 10043, Orbassano, Italy; 2Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, ASST Spedali Civili, 25123, Brescia, Italy; 3Molecular Oncology Laboratory, Fondazione Edo ed Elvo Tempia, 13875, Ponderano; 4Department of Molecular & Translational Medicine, Section of Pharmacology, University of Brescia, 25123, Brescia, Italy; 5Pathology Unit, Oncology Department, S. Luigi Gonzaga Hospital, University of Turin, Regione Gonzole 10, 10043 Orbassano, Turin, Italy
Background: Adrenocortical carcinoma (ACC) is a rare cancer associated with hereditary syndromes in 10% of cases. However, data on germline variants (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 1998-2019. 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 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 were found in 14/150 patients (9.3%). 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 combined pathologic features of ACC and 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. 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 adrenal hyperplasia to ACC. Finally, the present findings suggest that GVs can affect ACC progression and survival of affected patients.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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