RF21 | PSUN07 Germline Genetic Testing in a Cohort of Adults with Adrenocortical Carcinoma : Insights From a Clinical Care Setting

• Published in: Journal of the Endocrine Society Vol. 6; no. Supplement_1; p. A139
• Main Authors: Mourot, Aurélie, Parisien-La Salle, Stefanie, Poirier, Jonathan, Olney, Harold, Lacroix, André, Haffaf, Zaki E, Bourdeau, Isabelle
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01-11-2022
• Subjects: Adrenal
• ISSN: 2472-1972; 2472-1972
• DOI: 10.1210/jendso/bvac150.283

Abstract
Context
About 5-10% of adrenocortical cancer (ACC) arise in patients with genetic predisposition syndromes, including Li-Fraumeni, Lynch, MEN1, or Familial Adenomatous Polyposis (APC). Recent European (2018) and American guidelines (2020) recommend that all adults with ACC should be offered clinical genetic counseling. There is a paucity of data regarding systematic germline testing in adults with ACC and the extent of the genetic evaluation is unclear.
Objective
To describe the germline genetic characteristics in a cohort of adult patients with ACC evaluated in a tertiary clinical care center.
Methods
Data including demographics, personal and family history of neoplasia, pathology reports, clinical features and genetic testing were retrospectively collected from charts of patients treated at Centre hospitalier de l'Université de Montréal (CHUM). After genetic counseling, genetic testing was proposed to patients with a pathologic diagnosis of ACC. From 2005 to 2015, TP53 gene analysis was performed using direct sequencing and MLPA. Since 2016, multigene testing was performed for a progressively increasing number of oncogenic genes using a custom next-generation panel for germline leucocyte DNA including at least the TP53, MSH2, MSH6, MLH1,PMS2, EPCAM, MEN1, BRCA1 and BRCA2 genes (Invitae, CA). An extended panel, based on past medical and familial history, was performed at the discretion of the geneticist. Patient data was retrospectively investigated.
Results
We analyzed data from 44 patients with available germline genetic results. Median age of the patients was 46 years (ranging from 22 to 79 years), including 11 males (25.0%) and 33 females (75.0%). Ten patients (22.7%) underwent only TP53 gene analysis and 32 patients (72.7%) were studied using the larger oncogenic genetic panel.
Germline pathogenic or likely pathogenic variants were identified in 5 of the 44 patients (11.4%) while genetic variants of unknown significance (VUS) were found in 7 of the 44 patients (15.9%). Among patients with pathogenic variants, one had a family history and known germline mutation in the BRCA2 gene (8765delAG, p.Glu2846GlyfsX23). One patient had a personal and familial medical history suggesting a MEN1 syndrome that was confirmed with the finding of a germline MEN1 mutation (c.1556delC, p.Pro519Leu fs40). Unsuspected germline pathogenic variants were found in three patients: 1) TP53 (c.425delC, p.Pro142fs), 2) MUTYH (c.536A>G, p.Tyr179Cys) and 3) MSH6 (c.3649-3655, p.Arg1217Leu fs9) genes. Variants of unknown significance (VUS) were found in the following genes: POT1, MSH3, PALB2, RAD51d, APC, ATM and BRCA2.
Conclusions
Germline pathogenic variants were found in 11.4% of our cohort of patients with ACC. VUS were found in 15.9% of patients but their significance remains to be determined. Genetic counseling and germline genetic testing should be offered to all patients with ACC; however the optimal use and extent of oncogenic gene panels need to be better defined.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 12:48 p.m. - 12:53 p.m.