Germline NGS targeted analysis in adult patients with sporadic adrenocortical carcinoma

Maria Scatolini; Salvatore Grisanti; Pasquale Tomaiuolo; Enrico Grosso; Vittoria Basile; Deborah Cosentini; Soraya Puglisi; Marta Laganà; Paola Perotti; Laura Saba; Elisa Rossini; Flavia Palermo; Sandra Sigala; Marco Volante; Alfredo Berruti; Massimo Terzolo

doi:10.1016/j.ejca.2024.114088

Germline NGS targeted analysis in adult patients with sporadic adrenocortical carcinoma

Eur J Cancer. 2024 Apr 26:205:114088. doi: 10.1016/j.ejca.2024.114088. Online ahead of print.

Authors

Maria Scatolini¹, Salvatore Grisanti², Pasquale Tomaiuolo³, Enrico Grosso¹, Vittoria Basile⁴, Deborah Cosentini², Soraya Puglisi⁵, Marta Laganà², Paola Perotti⁴, Laura Saba⁴, Elisa Rossini⁶, Flavia Palermo¹, Sandra Sigala⁶, Marco Volante⁷, Alfredo Berruti², Massimo Terzolo⁴

Affiliations

¹ Molecular Oncology Laboratory, Fondazione Edo ed Elvo Tempia, 13875 Ponderano, BI, Italy.
² Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, ASST Spedali Civili, 25123 Brescia, Italy.
³ Molecular Oncology Laboratory, Fondazione Edo ed Elvo Tempia, 13875 Ponderano, BI, Italy; Internal Medicine, Department of Clinical and Biological Sciences, S. Luigi Gonzaga Hospital, University of Turin, 10043 Orbassano, Italy.
⁴ Internal Medicine, Department of Clinical and Biological Sciences, S. Luigi Gonzaga Hospital, University of Turin, 10043 Orbassano, Italy.
⁵ Internal Medicine, Department of Clinical and Biological Sciences, S. Luigi Gonzaga Hospital, University of Turin, 10043 Orbassano, Italy. Electronic address: soraya.puglisi@unito.it.
⁶ Department of Molecular & Translational Medicine, Section of Pharmacology, University of Brescia, 25123 Brescia, Italy.
⁷ Pathology Unit, Oncology department, University of Turin, San Luigi Gonzaga University Hospital, Regione Gonzole 10, 10043 Orbassano, Turin, Italy.

PMID: 38714106
DOI: 10.1016/j.ejca.2024.114088

Abstract

Background: Adrenocortical carcinoma (ACC) is a rare cancer that arises sporadically or due to hereditary syndromes. Data on germline variants (GVs) in sporadic ACC are limited. Our aim was to characterize GVs of genes potentially related to adrenal diseases in 150 adult patients with sporadic ACC.

Methods: This was a retrospective analysis of stage I-IV ACC patients with sporadic ACC from two reference centers for ACC in Italy. Patients were included in the analysis if they had confirmed diagnosis of ACC, a frozen peripheral blood sample and complete clinical and follow-up data. Next generation sequencing technology was used to analyze the prevalence of GVs in a custom panel of 17 genes belonging to either cancer-predisposition genes or adrenocortical-differentiation genes categories.

Results: We identified 18 GVs based on their frequency, enrichment and predicted functional characteristics. We found six pathogenic (P) or likely pathogenic (LP) variants in ARMC5, CTNNB1, MSH2, PDE11A and TP53 genes; and twelve variants lacking evidence of pathogenicity. New unique P/LP variants were identified in TP53 (p.G105D) and, for the first time, in ARMC5 (p.P731R). The presence of P/LP GVs was associated with reduced survival outcomes and had a significant and independent impact on both progression-free survival and overall survival.

Conclusions: GVs were present in 6.7 % of patients with sporadic ACC, and we identified novel variants of ARMC5 and TP53. These findings may improve understanding of ACC pathogenesis and enable genetic counseling of patients and their families.

Keywords: Adrenal cancer; Genetics; Mutation; Oncogenes; Outcome; Pathogenesis; Progression; Progression.; Survival; Tumor suppressors.