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OR04-5 Circulating Cell-Free DNA-Based Biomarkers For Prognostication and Disease Surveillance in Adrenocortical Carcinoma

Adrenocortical carcinoma (ACC) is a rare aggressive cancer with heterogeneous behaviour. Disease surveillance relies on frequent imaging, which comes with significant radiation exposure. Here, we investigated the role of circulating cell-free DNA (ccfDNA)-related biomarkers for prognostication and m...

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Autores principales: Altieri, Barbara, Appenzeller, Silke, Arlt, Wiebke, Asia, Miriam, Chortis, Vasileios, Elhassan, Yasir S, Fassnacht, Martin, Kircher, Stefan, Landwehr, Laura-Sophie, Lippert, Juliane, Prete, Alessandro, Smith, Gabrielle, Steinhauer, Sonja, Urlaub, Hanna, Ronchi, Cristina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9700284/
http://dx.doi.org/10.1210/jendso/bvac150.169
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author Altieri, Barbara
Appenzeller, Silke
Arlt, Wiebke
Asia, Miriam
Chortis, Vasileios
Elhassan, Yasir S
Fassnacht, Martin
Kircher, Stefan
Landwehr, Laura-Sophie
Lippert, Juliane
Prete, Alessandro
Smith, Gabrielle
Steinhauer, Sonja
Urlaub, Hanna
Ronchi, Cristina
author_facet Altieri, Barbara
Appenzeller, Silke
Arlt, Wiebke
Asia, Miriam
Chortis, Vasileios
Elhassan, Yasir S
Fassnacht, Martin
Kircher, Stefan
Landwehr, Laura-Sophie
Lippert, Juliane
Prete, Alessandro
Smith, Gabrielle
Steinhauer, Sonja
Urlaub, Hanna
Ronchi, Cristina
author_sort Altieri, Barbara
collection PubMed
description Adrenocortical carcinoma (ACC) is a rare aggressive cancer with heterogeneous behaviour. Disease surveillance relies on frequent imaging, which comes with significant radiation exposure. Here, we investigated the role of circulating cell-free DNA (ccfDNA)-related biomarkers for prognostication and monitoring of ACC. We investigated 79 patients with ACC (29M/50F, 52±14yrs; 35 primary tumors [ACC-P] and 44 recurrences [ACC-R]); while 27 patients with adrenocortical adenomas [ACA] (9M/18F, 56±16yrs) and 19 healthy subjects (HS; 9M/10F, 37±9yrs) served as controls. We extracted ccfDNA from 1-4 ml EDTA-plasma using Nonacus Cell3 Xtract or Qiagen QIAamp MinElute kit and quantified by fluorimeter (ccfDNA concentrations, Biomarker 1). Targeted next-generation sequencing (Illumina NextSeq500) was performed in a first subgroup of 52 baseline ccfDNA samples (23 ACC-P, 20 ACC-R, 8 ACA) using a customised panel of 30 ACC-specific genes (Cell3 Target Nonacus). Leucocyte DNA was sequenced to discriminate germline from somatic variants (Biomarker 2). Sequencing data from matched tumor DNA were available for 28 ACC (20 ACC-P, 8 R-ACC). A combined Biomarker score was calculated for prediction of clinical outcome. ACC-P had the highest ccfDNA concentrations (mean±SD 1.08±1.50 ng/µl) compared to ACC-R (0.29±0.23 ng/µl, P<0.05), ACA (0.17±0.13 ng/µl, P<0.005) and HS (0.11±0.07 ng/µl, P<0.005). Using a cutoff of 0.204 (median HS+2SD), 68% of ACC-P were postitive for Biomarker 1 (vs. ACC-R 55%, ACA 28%, HS 5%; P<0.0001 by Chi square test). At ccfDNA sequencing, 43% of ACC-P showed at least one somatic mutation (=positive Biomarker 2), vs. 15% in ACC-R and 0% in ACA. Mutational status at ccfDNA level matched with tumor DNA in 80% of cases. In 23 ACC-P with available sequencing data, the combined Biomarker score was strongly associated with both progression-free and overall survival (P<0.0001, HR 8.56, 95%CI 2.55-58.7, and P=0.0008, HR 13.3, 95%CI 3.77-47.1, respectively). 10 ACC-P were followed up for at least 6 months: 6 patients tumor-free at last CT scan were negative for Biomarker 1 whereas 3 out of 4 patients with early disease relapse were positive. In two recurrent cases, somatic mutations in ACC driver genes, i.e. MEN1 and ZNRF3, observed at baseline in both tumour and ccfDNA, remained detectable during monitoring. In conclusion, ccfDNA-related biomarkers are frequently detected in patients with primary ACC. They may represent a promising, non-invasive tool to predict early disease progression and complement imaging in disease surveillance. Our findings on ccfDNA-based liquid biopsy will be validated in a larger cohort of ACCs with long-term follow up. Presentation: Saturday, June 11, 2022 12:30 p.m. - 12:45 p.m.
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spelling pubmed-97002842022-11-29 OR04-5 Circulating Cell-Free DNA-Based Biomarkers For Prognostication and Disease Surveillance in Adrenocortical Carcinoma Altieri, Barbara Appenzeller, Silke Arlt, Wiebke Asia, Miriam Chortis, Vasileios Elhassan, Yasir S Fassnacht, Martin Kircher, Stefan Landwehr, Laura-Sophie Lippert, Juliane Prete, Alessandro Smith, Gabrielle Steinhauer, Sonja Urlaub, Hanna Ronchi, Cristina J Endocr Soc Adrenal Adrenocortical carcinoma (ACC) is a rare aggressive cancer with heterogeneous behaviour. Disease surveillance relies on frequent imaging, which comes with significant radiation exposure. Here, we investigated the role of circulating cell-free DNA (ccfDNA)-related biomarkers for prognostication and monitoring of ACC. We investigated 79 patients with ACC (29M/50F, 52±14yrs; 35 primary tumors [ACC-P] and 44 recurrences [ACC-R]); while 27 patients with adrenocortical adenomas [ACA] (9M/18F, 56±16yrs) and 19 healthy subjects (HS; 9M/10F, 37±9yrs) served as controls. We extracted ccfDNA from 1-4 ml EDTA-plasma using Nonacus Cell3 Xtract or Qiagen QIAamp MinElute kit and quantified by fluorimeter (ccfDNA concentrations, Biomarker 1). Targeted next-generation sequencing (Illumina NextSeq500) was performed in a first subgroup of 52 baseline ccfDNA samples (23 ACC-P, 20 ACC-R, 8 ACA) using a customised panel of 30 ACC-specific genes (Cell3 Target Nonacus). Leucocyte DNA was sequenced to discriminate germline from somatic variants (Biomarker 2). Sequencing data from matched tumor DNA were available for 28 ACC (20 ACC-P, 8 R-ACC). A combined Biomarker score was calculated for prediction of clinical outcome. ACC-P had the highest ccfDNA concentrations (mean±SD 1.08±1.50 ng/µl) compared to ACC-R (0.29±0.23 ng/µl, P<0.05), ACA (0.17±0.13 ng/µl, P<0.005) and HS (0.11±0.07 ng/µl, P<0.005). Using a cutoff of 0.204 (median HS+2SD), 68% of ACC-P were postitive for Biomarker 1 (vs. ACC-R 55%, ACA 28%, HS 5%; P<0.0001 by Chi square test). At ccfDNA sequencing, 43% of ACC-P showed at least one somatic mutation (=positive Biomarker 2), vs. 15% in ACC-R and 0% in ACA. Mutational status at ccfDNA level matched with tumor DNA in 80% of cases. In 23 ACC-P with available sequencing data, the combined Biomarker score was strongly associated with both progression-free and overall survival (P<0.0001, HR 8.56, 95%CI 2.55-58.7, and P=0.0008, HR 13.3, 95%CI 3.77-47.1, respectively). 10 ACC-P were followed up for at least 6 months: 6 patients tumor-free at last CT scan were negative for Biomarker 1 whereas 3 out of 4 patients with early disease relapse were positive. In two recurrent cases, somatic mutations in ACC driver genes, i.e. MEN1 and ZNRF3, observed at baseline in both tumour and ccfDNA, remained detectable during monitoring. In conclusion, ccfDNA-related biomarkers are frequently detected in patients with primary ACC. They may represent a promising, non-invasive tool to predict early disease progression and complement imaging in disease surveillance. Our findings on ccfDNA-based liquid biopsy will be validated in a larger cohort of ACCs with long-term follow up. Presentation: Saturday, June 11, 2022 12:30 p.m. - 12:45 p.m. Oxford University Press 2022-11-01 /pmc/articles/PMC9700284/ http://dx.doi.org/10.1210/jendso/bvac150.169 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Adrenal
Altieri, Barbara
Appenzeller, Silke
Arlt, Wiebke
Asia, Miriam
Chortis, Vasileios
Elhassan, Yasir S
Fassnacht, Martin
Kircher, Stefan
Landwehr, Laura-Sophie
Lippert, Juliane
Prete, Alessandro
Smith, Gabrielle
Steinhauer, Sonja
Urlaub, Hanna
Ronchi, Cristina
OR04-5 Circulating Cell-Free DNA-Based Biomarkers For Prognostication and Disease Surveillance in Adrenocortical Carcinoma
title OR04-5 Circulating Cell-Free DNA-Based Biomarkers For Prognostication and Disease Surveillance in Adrenocortical Carcinoma
title_full OR04-5 Circulating Cell-Free DNA-Based Biomarkers For Prognostication and Disease Surveillance in Adrenocortical Carcinoma
title_fullStr OR04-5 Circulating Cell-Free DNA-Based Biomarkers For Prognostication and Disease Surveillance in Adrenocortical Carcinoma
title_full_unstemmed OR04-5 Circulating Cell-Free DNA-Based Biomarkers For Prognostication and Disease Surveillance in Adrenocortical Carcinoma
title_short OR04-5 Circulating Cell-Free DNA-Based Biomarkers For Prognostication and Disease Surveillance in Adrenocortical Carcinoma
title_sort or04-5 circulating cell-free dna-based biomarkers for prognostication and disease surveillance in adrenocortical carcinoma
topic Adrenal
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9700284/
http://dx.doi.org/10.1210/jendso/bvac150.169
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