ECE2021 Oral Communications Oral Communications 11: Adrenal and Cardiovascular Endocrinoloyg (6 abstracts)
Circulating cell-free DNA for prognostication and disease surveillance in adrenocortical carcinoma
Gabrielle Smith 1 , Juliane Lippert 2 , Barbara Altieri 2 , Yasir Elhassan 1 , Laura-Sophie Landwehr 2 , Alessandro Prete 1 , Silke Appenzeller 3 , Vasileios Chortis 1 , Sonja Steinhauer 2 , Miriam Asia 4 , Robert Sutcliffe 4 , Celina Whalley 5 , Wiebke Arlt 1 , Martin Fassnacht 2 & <u>Cristina Ronchi</u> & 2
1University of Birmingham, Institute of Metabolism and System Research, Birmingham, United Kingdom; 2University Hospital of Wuerzburg, Division of Endocrinology and Diabetes, Wuerzburg, Germany; 3University of Wuerzburg, Core Unit Bioinformatics, Germany; 4Queen Elizabeth University Hospital Birmingham, United Kingdom; 5University of Birmingham, Institute of Cancer and Genomic Sciences, United Kingdom
Background
Adrenocortical Carcinoma (ACC) is a rare aggressive cancer with a heterogeneous behaviour. Disease surveillance relies on frequent imaging, which has limited sensitivity and results in significant radiation exposure. Aim of the study was to investigate the role of circulating cell-free DNA (ccfDNA) as a biomarker for prognostication and disease monitoring in ACC.
Methods
ccfDNA was extracted from 1–4 ml EDTA-plasma using the Nonacus Cell3 Xtract or the Qiagen QIAamp MinElute ccfDNA kit and quantified by fluorimetry. The experimental cohort included 60 patients with ACC (22M/36F, 52 ± 15 yrs): 22 primary tumours (ACC-P) and 38 disease recurrences (ACC-R). Twenty-three patients with adrenocortical adenomas (ACA, 8M/15F, 55 ± 17 yrs) and 19 healthy subjects (9M/10F, 37 ± 9 yrs) served as controls. Targeted next generation sequencing was performed on 23 ccfDNA samples (8 ACC-P, 11 ACC-R, 4 ACA) using a customised panel of 30 ACC-specific genes (Cell3 Target Nonacus) and Illumina NextSeq500 Sequencer. Leucocyte DNA was sequenced to discriminate germline from somatic variants. Sequencing data from corresponding tumour DNA (tDNA) were available for comparison in 13/19 ACC.
Results
ACC-P had the highest ccfDNA concentrations (1.23 ± 1.56 ng/µl) compared to ACC-R (0.31 ± 0.27 ng/µl, P < 0.05), ACA (0.16 ± 0.10 ng/µl, P < 0.005) and healthy subjects (0.12 ± 0.09 ng/µl, P < 0.005). In the entire ACC cohort, ccfDNA concentrations correlated with the tumour burden, i.e. size of primary tumours or local recurrence plus size and number of metastasis (P < 0.001, R = 0.57 by linear regression). In ACC-P, the ccfDNA levels correlated with the ENSAT tumour stage (P = 0.059), but not with Ki67 index (P = 0.22). Moreover, high pre-surgery ccfDNA levels tended to be associated with shorter recurrence-free survival, but the number of cases is still limited (n = 11, P = 0.10, HR 6.23, 95% CI 0.7–55.4). Among sequenced ccfDNA samples, 3 ACC-P (37%) and 3 ACC-R (27%), but no ACA, showed somatic mutations in at least one known driver gene (2 CTNNB1, 2 TP53, 2 MEN1, 2 ZNRF3). The variant allele frequency ranged between 1.9 and 30.9%. The ccfDNA sequencing matched with the t-DNA in 9 of 13 cases (i.e. 6 without somatic variants and 3 with superimposable mutations).
Conclusion
ccfDNA concentrations correlated with tumour burden in patients with ACC and may have utility in predicting disease recurrence. Targeted ccfDNA sequencing detected ACC-specific mutations in ~30% of ACC. Serial ccfDNA quantitative and genomic analysis may represent an efficient, non-invasive tool complementary to imaging to improve the disease surveillance in ACC. This will be investigated in a large cohort of operated patients.
Volume 73
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Endocrine Abstracts
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