Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma

Anne Jouinot; Juliane Lippert; Martin Fassnacht; Bruno de La Villeon; Amandine Septier; Mario Neou; Karine Perlemoine; Silke Appenzeller; Mathilde Sibony; Sébastien Gaujoux; Bertrand Dousset; Rossella Libe; Lionel Groussin; Cristina L Ronchi; Guillaume Assié; Jérôme Bertherat

doi:10.1530/EC-20-0228

Endocrine Connections (Aug 2020)

Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma

Anne Jouinot,
Juliane Lippert,
Martin Fassnacht,
Bruno de La Villeon,
Amandine Septier,
Mario Neou,
Karine Perlemoine,
Silke Appenzeller,
Mathilde Sibony,
Sébastien Gaujoux,
Bertrand Dousset,
Rossella Libe,
Lionel Groussin,
Cristina L Ronchi,
Guillaume Assié,
Jérôme Bertherat

Affiliations

Anne Jouinot: Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France; Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Juliane Lippert: Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, Germany
Martin Fassnacht: Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, Germany; Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany
Bruno de La Villeon: Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
Amandine Septier: Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
Mario Neou: Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
Karine Perlemoine: Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
Silke Appenzeller: Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, Germany
Mathilde Sibony: Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France; Department of Pathology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Sébastien Gaujoux: Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France; Department of Digestive and Endocrine Surgery, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Bertrand Dousset: Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France; Department of Digestive and Endocrine Surgery, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Rossella Libe: Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France; Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Lionel Groussin: Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France; Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Cristina L Ronchi: Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, Germany; Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
Guillaume Assié: Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France; Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Jérôme Bertherat: Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France; Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

DOI: https://doi.org/10.1530/EC-20-0228
Journal volume & issue: Vol. 9, no. 7
pp. 705 – 714

Abstract

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Background: The prognosis of adrenocortical carcinoma (ACC) is heterogeneous. Genomic studies have identified ACC subgroups characterized by specific m olecular alterations, including features measured at DNA level (somatic mutations, chromosome alterations, DNA methylation), which are closely associated with outcome. The aim of this study was to evaluate intratumor heterogeneity of prognostic molecular markers at the DNA level. Methods: Two different tissue samples (primary tumor, local recurrence o r metastasis) were analyzed in 26 patients who underwent surgery for primary or recurrent ACC. DNA-related biomarkers with prognostic role were investigated i n frozen and paraffin-embedded samples. Somatic mutations of p53/Rb and Wnt/β-catenin pathways were assessed using next-generation sequencing (n = 26), chromosome alteration profiles were determined using SNP arrays (n = 14) and methylation profiles were determined using four-gene bisulfite pyrosequencing (n = 12). Results: Somatic mutations for ZNRF3, TP53, CTNN1B and CDKN2A were found in 7, 6, 6 and 4 patients, respectively, with intratumor heterogeneity in 8/26 patients (31%). Chromosome alteration profiles were ‘Noisy’ (numerous and anarch ic alterations) in 8/14 and ‘Chromosomal’ (extended patterns of loss of heterozygo sity) in 5/14 of the study samples. For these profiles, no intratumor heterogenei ty was observed. Methylation profiles were hypermethylated in 5/12 and non-hyperm ethylated in 7/12 of the study samples. Intratumor heterogeneity of methylation p rofiles was observed in 2/12 patients (17%). Conclusions: Intratumor heterogeneity impacts DNA-related molecular markers. While somatic mutation can differ, prognostic DNA methylation and chro mosome alteration profile seem rather stable and might be more robust for the prog nostic assessment.

Published in Endocrine Connections

ISSN: 2049-3614 (Online)
Publisher: Bioscientifica
Country of publisher: United Kingdom
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the endocrine glands. Clinical endocrinology
Website: http://www.endocrineconnections.com/

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