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European Journal of Cancer
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Letter to the Editor
Letter Re: Germline NGS targeted analysis in adult patients with sporadic adrenocortical carcinoma
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Dear Editor,
We have read with great interest the article by Maria Scatolini and colleagues, entitled «Germline NGS targeted analysis in adult patients with sporadic adrenocortical carcinoma» [1]. The authors report three different germline ARMC5 variants found in five patients with adreno- cortical carcinoma (ACC), including one missense variant (NM_001105247.2: c.2192C>G) found in three index patients. ARMC5 is known to predispose to Primary Bilateral Macronodular Adrenal Hy- perplasia (PBMAH), a benign condition characterized by bilateral ad- renal nodules associated with variable levels of cortisol excess [2]. In PBMAH, ARMC5 follows Knudson’s two-hit inactivation model of tumor suppressor genes: patients harbor a germline heterozygous inactivating mutation, associated with a second hit at the somatic level on the other allele, whether through a point mutation, a deletion, or a loss-of-heterozygosity [3]. Before its description in PBMAH in 2013, ARMC5 had never been related to any other human disease. Since then, it has been reported in a few cases of meningioma, with conclusive demonstration of a two-hit inactivation [2], but no other type of benign nor malignant tumor, especially ACC.
As described in the manuscript, the c.2192C>G variant is found in the general population with a minor allele frequency (MAF) around 0.2 %, which is much higher than expected for such rare diseases as ACC and PBMAH, and has been reported in seven different PBMAH index cases in the literature [4-7], with no conclusive demonstration of its pathogenic nature. Scatolini et al precise that they did not find any second hit in the somatic DNA extracted from one of the three patients, which would be very unusual for a disease-causing pathogenic variant of ARMC5 [8]. To date, in PBMAH, no second somatic hit has been asso- ciated with this germline variant either. No familial segregation of PBMAH has been observed with this variant, and most of the in silico prediction softwares classifies c.2192C>G as a benign variant. For all these reasons, in the light of the current knowledge, c.2192C>G must be considered as a likely benign variant and not disease causing until further demonstrations, according to the guideline of the American College of Medical Genetics (ACMG) [9]. This assumption, and the fact that the two other germline ARMC5 variants described in the article are also likely benign according to ACMG criteria, should prevent from associating ARMC5 with ACC. More than 100 different ARMC5 germline variants in nearly 200 unrelated PBMAH index patients have been re- ported in the literature at present, with no description of ACC. To our knowledge, a single patient with concomitant diagnosis of PBMAH and ACC has been reported in the literature by our group [10], and this patient did not harbor any germline ARMC5 variant. Based on the existing literature and our decades-long experience with more than 500 PBMAH patients investigated and followed in our center, we recom- mend that the data of Scatolini and colleagues should be interpreted
with extreme caution, and we strongly believe that ARMC5 should not be considered as a predisposing gene for ACC. This is important to avoid that PBMAH patients having an ARMC5 pathogenic variant would be managed as having ACC favoring tumors.
Funding sources
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
Jerome Bertherat: Formal analysis, Writing - review & editing. Bruno Ragazzon: Formal analysis, Writing - review & editing. Anne Jouinot: Formal analysis, Writing - review & editing. Victor Gravrand: Formal analysis, Writing - review & editing. Lucas Bouys: Formal analysis, Writing - original draft.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References
[1] Scatolini M, Grisanti S, Tomaiuolo P, Grosso E, Basile V, Cosentini D, et al. Germline NGS targeted analysis in adult patients with sporadic adrenocortical carcinoma. Eur J Cancer 2024;205:114088. https://doi.org/10.1016/j. ejca.2024.114088.
[2] Bertherat J, Bourdeau I, Bouys L, Chasseloup F, Kamenický P, Lacroix A. Clinical, pathophysiologic, genetic, and therapeutic progress in primary bilateral macro- nodular adrenal hyperplasia. Endocr Rev 2023;44:567-628. https://doi.org/ 10.1210/endrev/bnac034.
[3] Assié G, Libé R, Espiard S, Rizk-Rabin M, Guimier A, Luscap W, et al. ARMC5 mutations in macronodular adrenal hyperplasia with Cushing’s syndrome. N Engl J Med 2013;369:2105-14. https://doi.org/10.1056/NEJMoa1304603.
[4] Bouys L, Vaczlavik A, Jouinot A, Vaduva P, Espiard S, Assié G, et al. Identification of predictive criteria for pathogenic variants of primary bilateral macronodular adrenal hyperplasia (PBMAH) gene ARMC5 in 352 unselected patients. Eur J Endocrinol 2022;187:123-34. https://doi.org/10.1530/EJE-21-1032.
[5] Morelli V, Elli FM, Frigerio S, Vena W, Palmieri S, Lucca C, et al. Prevalence and clinical features of armadillo repeat-containing 5 mutations carriers in a single center cohort of patients with bilateral adrenal incidentalomas. Eur J Endocrinol 2023;189:242-51. https://doi.org/10.1093/ejendo/Ivad088.
[6] Albiger NM, Regazzo D, Rubin B, Ferrara AM, Rizzati S, Taschin E, et al. A multicenter experience on the prevalence of ARMC5 mutations in patients with primary bilateral macronodular adrenal hyperplasia: from genetic characterization to clinical phenotype. Endocrine 2017;55:959-68. https://doi.org/10.1007/ s12020-016-0956-z.
[7] Mariani BM de P, Nishi MY, Wanichi IQ, Brondani VB, Lacombe AMF, Charchar H, et al. Allelic variants of ARMC5 in patients with adrenal incidentalomas and in
https://doi.org/10.1016/j.ejca.2025.115276
patients with cushing’s syndrome associated with bilateral adrenal nodules. Front Endocrinol (Lausanne) 2020;11:36. https://doi.org/10.3389/fendo.2020.00036.
[8] Violon F, Bouys L, Vaduva P, Chansavang A, Vaquier L, Letourneur F, et al. Somatic molecular heterogeneity in bilateral macronodular adrenocortical disease (BMAD) differs among the pathological subgroups. Endocr Pathol 2024. https://doi.org/ 10.1007/s12022-024-09824-1.
[9] Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recom- mendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-24. https://doi.org/ 10.1038/gim.2015.30.
[10] Libe R, Jazeron J-F, Louiset E, Groussin L. 18F-FDG PET reveals an adrenocortical carcinoma in a bilateral adrenal multinodular disease. Endocrine 2019;63:188-9. https://doi.org/10.1007/s12020-018-1757-3.
Lucas Bouys İD Department of Endocrinology and National Reference Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité, Paris, France Victor Gravrand Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité, Paris, France
Anne Jouinot D Department of Endocrinology and National Reference Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité, Paris, France Bruno Ragazzon Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité, Paris, France
Jérôme Bertherat* Department of Endocrinology and National Reference Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité, Paris, France
Correspondence to: Department of Endocrinology, National Reference Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique- Hôpitaux de Paris, 27 rue du Faubourg Saint-Jacques, Paris F-75014, France. E-mail address: jerome.bertherat@aphp.fr (J. Bertherat).