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

adrenocortical carcinoma chromosome alterations intratumor heterogeneity methylation somatic mutations

Journal

Endocrine connections
ISSN: 2049-3614
Titre abrégé: Endocr Connect
Pays: England
ID NLM: 101598413

Informations de publication

Date de publication:
Jul 2020
Historique:
received: 09 06 2020
accepted: 01 07 2020
pubmed: 23 7 2020
medline: 23 7 2020
entrez: 23 7 2020
Statut: ppublish

Résumé

The prognosis of adrenocortical carcinoma (ACC) is heterogeneous. Genomic studies have identified ACC subgroups characterized by specific molecular 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. Two different tissue samples (primary tumor, local recurrence or metastasis) were analyzed in 26 patients who underwent surgery for primary or recurrent ACC. DNA-related biomarkers with prognostic role were investigated in 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). 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 anarchic alterations) in 8/14 and 'Chromosomal' (extended patterns of loss of heterozygosity) in 5/14 of the study samples. For these profiles, no intratumor heterogeneity was observed. Methylation profiles were hypermethylated in 5/12 and non-hypermethylated in 7/12 of the study samples. Intratumor heterogeneity of methylation profiles was observed in 2/12 patients (17%). Intratumor heterogeneity impacts DNA-related molecular markers. While somatic mutation can differ, prognostic DNA methylation and chromosome alteration profile seem rather stable and might be more robust for the prognostic assessment.

Sections du résumé

BACKGROUND BACKGROUND
The prognosis of adrenocortical carcinoma (ACC) is heterogeneous. Genomic studies have identified ACC subgroups characterized by specific molecular 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 METHODS
Two different tissue samples (primary tumor, local recurrence or metastasis) were analyzed in 26 patients who underwent surgery for primary or recurrent ACC. DNA-related biomarkers with prognostic role were investigated in 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 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 anarchic alterations) in 8/14 and 'Chromosomal' (extended patterns of loss of heterozygosity) in 5/14 of the study samples. For these profiles, no intratumor heterogeneity was observed. Methylation profiles were hypermethylated in 5/12 and non-hypermethylated in 7/12 of the study samples. Intratumor heterogeneity of methylation profiles was observed in 2/12 patients (17%).
CONCLUSIONS CONCLUSIONS
Intratumor heterogeneity impacts DNA-related molecular markers. While somatic mutation can differ, prognostic DNA methylation and chromosome alteration profile seem rather stable and might be more robust for the prognostic assessment.

Identifiants

DOI: 10.1530/EC-20-0228 PMID: 32698135 PMC: PMC7424337
pubmed: 32698135
doi: 10.1530/EC-20-0228
pii: EC-20-0228.R1
pmc: PMC7424337
doi:
pii:

Types de publication

Journal Article

Langues

eng

Pagination

705-714

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Auteurs

Anne Jouinot (A)

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 (J)

Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, Germany.

Martin Fassnacht (M)

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 (B)

Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.

Amandine Septier (A)

Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.

Mario Neou (M)

Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.

Karine Perlemoine (K)

Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.

Silke Appenzeller (S)

Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, Germany.

Mathilde Sibony (M)

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 (S)

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 (B)

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 (R)

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 (L)

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 (CL)

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 (G)

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 (J)

Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.
Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France.

Classifications MeSH