Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma
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 assoc...
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| Format: | Article |
| Language: | English |
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Bioscientifica
2020-08-01
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| Series: | Endocrine Connections |
| Subjects: | |
| Online Access: | https://ec.bioscientifica.com/view/journals/ec/9/7/EC-20-0228.xml |
| _version_ | 1828410600676392960 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Anne Jouinot |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T12:15:20Z |
| format | Article |
| id | doaj.art-cedc9161880f42d1b0effb1b5ca49fbb |
| institution | Directory Open Access Journal |
| issn | 2049-3614 2049-3614 |
| language | English |
| last_indexed | 2024-12-10T12:15:20Z |
| publishDate | 2020-08-01 |
| publisher | Bioscientifica |
| record_format | Article |
| series | Endocrine Connections |
| spelling | doaj.art-cedc9161880f42d1b0effb1b5ca49fbb2022-12-22T01:49:15ZengBioscientificaEndocrine Connections2049-36142049-36142020-08-0197705714https://doi.org/10.1530/EC-20-0228Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinomaAnne Jouinot0Juliane Lippert1Martin Fassnacht2Bruno de La Villeon3Amandine Septier4Mario Neou5Karine Perlemoine6Silke Appenzeller7Mathilde Sibony8Sébastien Gaujoux9Bertrand Dousset10Rossella Libe11Lionel Groussin12Cristina L Ronchi13Guillaume Assié14Jérôme Bertherat15Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France; Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, FranceDepartment of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, GermanyDepartment of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, Germany; Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, GermanyUniversité de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, FranceUniversité de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, FranceUniversité de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, FranceUniversité de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, FranceDepartment of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, GermanyUniversité de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France; Department of Pathology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, FranceUniversité de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France; Department of Digestive and Endocrine Surgery, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, FranceUniversité de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France; Department of Digestive and Endocrine Surgery, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, FranceUniversité de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France; Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, FranceUniversité de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France; Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, FranceDepartment 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, UKUniversité de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France; Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, FranceUniversité de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France; Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, FranceBackground: 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.https://ec.bioscientifica.com/view/journals/ec/9/7/EC-20-0228.xmladrenocortical carcinomaintratumor heterogeneitymethylationchromosome alterationssomatic mutations |
| spellingShingle | 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 Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma Endocrine Connections adrenocortical carcinoma intratumor heterogeneity methylation chromosome alterations somatic mutations |
| title | Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma |
| title_full | Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma |
| title_fullStr | Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma |
| title_full_unstemmed | Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma |
| title_short | Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma |
| title_sort | intratumor heterogeneity of prognostic dna based molecular markers in adrenocortical carcinoma |
| topic | adrenocortical carcinoma intratumor heterogeneity methylation chromosome alterations somatic mutations |
| url | https://ec.bioscientifica.com/view/journals/ec/9/7/EC-20-0228.xml |
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