Genomic classification of benign adrenocortical lesions

in Endocrine-Related Cancer
Authors:
Simon Faillot Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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Thomas Foulonneau Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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Mario Néou Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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Stéphanie Espiard Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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Simon Garinet Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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Anna Vaczlavik Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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Anne Jouinot Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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Windy Rondof Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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Amandine Septier Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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Ludivine Drougat Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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Karine Hécale-Perlemoine Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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Bruno Ragazzon Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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Marthe Rizk-Rabin Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France

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Mathilde Sibony Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
Department of Pathology, AP-HP, Hôpital Pitié-Salpétrière, Pierre et Marie Curie Université, Paris, France

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Fidéline Bonnet-Serrano Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France
Department of Hormonology, AP-HP, Hôpital Cochin, Paris, France

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Jean Guibourdenche Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
Department of Hormonology, AP-HP, Hôpital Cochin, Paris, France

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Rosella Libé Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France

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Lionel Groussin Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France

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Bertrand Dousset Department of Endocrine Surgery, AP-HP, Hôpital Cochin, Paris, France

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Aurélien de Reyniès Programme Cartes d’Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France

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Jérôme Bertherat Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France

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Guillaume Assié Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
Department of Endocrinology, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France

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Correspondence should be addressed to G Assié: guillaume.assie@inserm.fr
DOI:
https://doi.org/10.1530/ERC-20-0128
Volume/Issue:
Volume 28: Issue 1
Article Type:
Research Article
Page Range:
79–95
Online Publication Date:
Jan 2021
Copyright:
© 2021 Society for Endocrinology 2021
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Benign adrenal tumors cover a spectrum of lesions with distinct morphology and steroid secretion. Current classification is empirical. Beyond a few driver mutations, pathophysiology is not well understood. Here, a pangenomic characterization of benign adrenocortical tumors is proposed, aiming at unbiased classification and new pathophysiological insights. Benign adrenocortical tumors (n = 146) were analyzed by transcriptome, methylome, miRNome, chromosomal alterations and mutational status, using expression arrays, methylation arrays, miRNA sequencing, SNP arrays, and exome or targeted next-generation sequencing respectively. Pathological and hormonal data were collected for all tumors. Pangenomic analysis identifies four distinct molecular categories: (1) tumors responsible for overt Cushing, gathering distinct tumor types, sharing a common cAMP/PKA pathway activation by distinct mechanisms; (2) adenomas with mild autonomous cortisol excess and non-functioning adenomas, associated with beta-catenin mutations; (3) primary macronodular hyperplasia with ARMC5 mutations, showing an ovarian expression signature; (4) aldosterone-producing adrenocortical adenomas, apart from other benign tumors. Epigenetic alterations and steroidogenesis seem associated, including CpG island hypomethylation in tumors with no or mild cortisol secretion, miRNA patterns defining specific molecular groups, and direct regulation of steroidogenic enzyme expression by methylation. Chromosomal alterations and somatic mutations are subclonal, found in less than 2/3 of cells. New pathophysiological insights, including distinct molecular signatures supporting the difference between mild autonomous cortisol excess and overt Cushing, ARMC5 implication into the adreno-gonadal differentiation faith, and the subclonal nature of driver alterations in benign tumors, will orient future research. This first genomic classification provides a large amount of data as a starting point.

Supplementary Materials

    • Supplemental Table 1: Clinical data
    • Supplemental Table 2: Different types of OMICs performed for each sample
    • Supplemental Table 3: Somatic mutations identified by exome sequencing
    • Supplemental Table 4: Mutations identified in a set of 8 potential drivers of benign tumorigenesis, using a targeted NGS panel.
    • Supplemental Table 5: Molecular statuses of benign adrenocortical tumors.
    • Supplemental Table 6: Differential signatures of transcriptome groups.
    • Supplemental Table 7: Expression profile in adrenal adenomas (C2B and C2D) of genes of the C1A/C1B malignancy signature.
    • Supplemental Table 8: Aberrant expression of genes in single tumors from the C2B transcriptome group and no mutation identified in cAMP/PKA related genes. Aberrant expression was defined as a Z-score>4 in the sample, considering C2B mRNA cluster as a reference.
    • Supplemental Table 9: Differential signatures of miRNome groups.
    • Supplemental Table 10: List of genes with a significant negative correlation with miRNAs expression
    • Supplemental Table 11: List of CpGs differentially methylated
    • Supplemental Table 12: List of genes with a significant negative correlation between methylation and expression
    • Supplemental Table 13: Chromosomal alterations
    • Supplemental Figure 1: Venn diagram showing the different omics performed on the cohort
    • Supplemental Figure 2: Main driver mutations in benign adrenocortical tumors
    • Supplemental Figure 3: Mutational signatures for ACA and PMAH patients explored with exome sequencing

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Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© 2021 Society for Endocrinology 2021
Page(s):
17
Received Date:
24 Oct 2020
Accepted Date:
04 Nov 2020
Print Publication Date:
01 Jan 2021
Online Publication Date:
Jan 2021
Keywords:
genomics; adrenal; adenoma; hyperplasia

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