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European Journal of Cancer
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Letter to the Editor
Response to letter to the editor on “Germline NGS targeted analysis in adult patients with sporadic adrenocortical carcinoma”
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Dear Editor,
we welcome the letter by Bouys and Colleagues for their thoughtful comment on our article [1] that allows us to better shape the interpre- tation of our findings.
Based on their large experience with patients affected by Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) and extensive research on ARMC5 gene, Bouys and Colleagues challenge our inter- pretation that the c.2192C > G variant has a potential pathogenic role for adrenocortical carcinoma (ACC).
Concerning the variant frequency, we underline that the minor allele frequency of the c.2192C > G variant in the Non-Finnish European population is currently estimated at 0.0009475 % [2]. Given that a frequency of 0.2 % was found in our cohort of 150 patients with ACC, this ARMC5 variant was very enriched compared to the general population.
Concerning the lack of a second hit, we underline that this ARMC5 variant was validated via Sanger sequencing, confirming its presence in a heterozygous state at both germline and somatic level. Although this finding lets us to exclude a loss of heterozygosity event, we were not able to detect the presence of a possible different second hit (somatic point mutation or deletion) also because we only analyzed the coding sequence of exon 6.
Concerning the lack of pathogenic potential of the c.2192C > G variant, we underline that the bioinformatic analysis conducted on this variant using the SIFT algorithm (score 0.0) [3] and the Polyphen al- gorithm (score 0.859) [4], predicts a probably deleterious impact on the ARMC5 protein. The moderately high Grantham score (103) [5] reflects a significant chemical imbalance between the substituted amino acids (proline to arginine), suggesting a likely impact on protein folding or interaction dynamic. At the time when our analysis was done, the variant was classified as conflicting interpretation of pathogenicity (CIP) according to the ClinVar database [6]. The remarkable enrichment of this variant in our patients with ACC and the results of the predictive bioinformatic tools led us to attribute a possible pathogenetic role to this variant. The classification of this variant has evolved over time, reflecting ongoing development in the interpretation of genetic data and better integration of accumulating evidence. Currently, in the ClinVar database the variant is categorized as CIP, with five submissions: three “variants of uncertain significance (VUS)” and two “likely benign (LB)“. On the other hand, the Universal Protein Knowledgebase [7] classifies the variant as pathogenic.
Therefore, we believe that the jury is still out, but we certainly share the view of Bouys and Colleagues that patients harboring an ARMC5 pathogenic variant should not be managed as having an ACC favoring condition. We did not made such a conclusion in our paper and we believe that this comment may help to interpret more correctly our
findings. Given the pathological evidence of both PBMAH and ACC in a carrier of the variant, we argued that progression from PBMAH to ACC is possible, a statement that has a completely different meaning. We believe that this condition has a striking analogy with the recently re- ported possibility of progression of an adrenal adenoma to ACC [8,9]. However, given the extreme rarity of this event, we do not consider adrenal adenomas as pre-malignant conditions [10].
Financial support
None.
Declaration of interests
None.
CRediT authorship contribution statement
Puglisi Soraya: Visualization, Writing - review & editing. Berruti Alfredo: Conceptualization, Supervision, Validation, Writing - review & editing. Tomaiuolo Pasquale: Writing - review & editing. Grisanti Salvatore: Conceptualization, Writing - original draft, Writing - review & editing. Scatolini Maria: Conceptualization, Writing - original draft, Writing - review & editing. Terzolo Massimo: Conceptualization, Su- pervision, Validation, Writing - original draft, Writing - review & editing.
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.
[2] (https://gnomad.broadinstitute.org) - Last accessed on 30 December 2024
[3] Sim NL, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC. SIFT web server: pre- dicting effects of amino acid substitutions on proteins. Nucleic Acids Res 2012;40: W452-7.
[4] Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248-9.
[5] Grantham R. Amino acid difference formula to help explain protein evolution. Science 1974;185:862-4.
[6] Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res 2018;46. D1062-D7.
[7] UniProt C. UniProt: the universal protein knowledgebase in 2025. Nucleic Acids Res 2024.
[8] Angelousi A, Jouinot A, Bourgioti C, Tokmakidis P, Bertherat J, Kaltsas G. Trans- formation of a benign adrenocortical adenoma to a metastatic adrenocortical carcinoma is rare but it happens. JCEM Case Rep 2024;2:luae131.
[9] Belmihoub I, Silvera S, Sibony M, Dousset B, Legmann P, Bertagna X, et al. From benign adrenal incidentaloma to adrenocortical carcinoma: an exceptional random event. Eur J Endocrinol 2017;176:K15-9.
[10] Fassnacht M, Dekkers OM, Else T, Baudin E, Berruti A, de Krijger R, et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European network for the study of adrenal tumors. Eur J Endocrinol 2018;179:G1-46.
Maria Scatolini
Molecular Oncology Laboratory, Fondazione Edo ed Elvo Tempia, Ponderano, BI 13875, Italy
Salvatore Grisanti D
Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, ASST Spedali Civili, Brescia 25123, Italy
Soraya Puglisi* D
Internal Medicine, Department of Clinical and Biological Sciences, S. Luigi Gonzaga Hospital, University of Turin, Orbassano 10043, Italy
Pasquale Tomaiuolo D Molecular Oncology Laboratory, Fondazione Edo ed Elvo Tempia, Ponderano, BI 13875, Italy Internal Medicine, Department of Clinical and Biological Sciences, S. Luigi Gonzaga Hospital, University of Turin, Orbassano 10043, Italy
Alfredo Berruti D Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, ASST Spedali Civili, Brescia 25123, Italy
Massimo Terzolo D Internal Medicine, Department of Clinical and Biological Sciences, S. Luigi Gonzaga Hospital, University of Turin, Orbassano 10043, Italy
* Correspondence to: Internal Medicine 1, Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, Regione Gonzole 10, Orbassano 10043, Italy.
E-mail address: soraya.puglisi@unito.it (S. Puglisi).