Transcriptome in paraffin samples for the diagnosis and prognosis of adrenocortical carcinoma

Jouinot, Anne; Lippert, Juliane; Sibony, Mathilde; Violon, Florian; Jeanpierre, Lindsay; Murat, D. De; Armignacco, Roberta; Septier, Amandine; Perlemoine, Karine; Letourneur, Franck; Izac, Brigitte; Ragazzon, Bruno; Leroy, Karen; Pasmant, Éric; North, Marie-Odile; Gaujoux, Sébastien; Dousset, B.; Groussin, Lionel; Libé, Rossella; Terris, Benoı̂t; Fassnacht, Martin; Ronchi, Cristina L.; Bertherat, Jérôme; Assié, Guillaume

doi:10.1530/eje-21-1228

Cited by 2 publications

(1 citation statement)

References 39 publications

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“…The libraries were prepared using 100 to 500 ng of RNA. Subsequently, single-read sequencing with a read length of 75 bases (1 × 75bp) was carried out on a NextSeq 550 platform from Illumina (San Diego, CA, USA) ( 16 ).…”

Section: Methodsmentioning

confidence: 99%

PPARG dysregulation as a potential molecular target in adrenal Cushing's syndrome

Vetrivel,

Tamburello,

Oßwald

et al. 2023

Front. Endocrinol.

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BackgroundWe performed a transcriptomic analysis of adrenal signaling pathways in various forms of endogenous Cushing’s syndrome (CS) to define areas of dysregulated and druggable targets.MethodologyNext-generation sequencing was performed on adrenal samples of patients with primary bilateral macronodular adrenal hyperplasia (PBMAH, n=10) and control adrenal samples (n=8). The validation groups included cortisol-producing adenoma (CPA, n=9) and samples from patients undergoing bilateral adrenalectomy for Cushing’s disease (BADX-CD, n=8). In vivo findings were further characterized using three adrenocortical cell-lines (NCI-H295R, CU-ACC2, MUC1).ResultsPathway mapping based on significant expression patterns identified PPARG (peroxisome proliferator-activated receptor gamma) pathway as the top hit. Quantitative PCR (QPCR) confirmed that PPARG (l2fc<-1.5) and related genes – FABP4 (l2fc<-5.5), PLIN1 (l2fc<-4.1) and ADIPOQ (l2fc<-3.3) – were significantly downregulated (p<0.005) in PBMAH. Significant downregulation of PPARG was also found in BADX-CD (l2fc<-1.9, p<0.0001) and CPA (l2fc<-1.4, p<0.0001). In vitro studies demonstrated that the PPARG activator rosiglitazone resulted in decreased cell viability in MUC1 and NCI-H295R (p<0.0001). There was also a significant reduction in the production of aldosterone, cortisol, and cortisone in NCI-H295R and in Dihydrotestosterone (DHT) in MUC1 (p<0.05), respectively.OutcomeThis therapeutic effect was independent of the actions of ACTH, postulating a promising application of PPARG activation in endogenous hypercortisolism.

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Section: Methodsmentioning

confidence: 99%

PPARG dysregulation as a potential molecular target in adrenal Cushing's syndrome

Vetrivel,

Tamburello,

Oßwald

et al. 2023

Front. Endocrinol.

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Performance of DNA-based biomarkers for classification of adrenocortical carcinoma: a prognostic study

Lippert,

Dischinger,

Appenzeller

et al. 2023

European Journal of Endocrinology

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Objective Adrenocortical carcinoma (ACC) is a rare aggressive malignancy with heterogeneous clinical outcomes. Recent studies proposed a combination of clinical/histopathological parameters (S-GRAS score) or molecular biomarkers (BMs) to improve prognostication. We performed a comparative analysis of DNA-based BMs by evaluating their added prognostic value to the S-GRAS score. Design and Methods 194 formalin-fixed, paraffin-embedded (FFPE) ACC samples were analysed, including a retrospective training cohort (n=107) and a prospective validation cohort (n=87). Targeted DNA sequencing and pyrosequencing were used to detect somatic single nucleotide variations in ACC-specific genes and methylation in the promoter region of PAX5. ENSAT tumour stage, age, symptoms at presentation, resection status, and Ki-67 were combined to calculate S-GRAS. Endpoints were overall (OS), progression-free (PFS), and disease-free survival (DFS). Prognostic role was evaluated by multivariable survival analysis and their performance compared by Harrell’s C index. Results In training cohort, an independent prognostic role was confirmed at multivariate analysis for two DNA-based BMs: alterations in Wnt/β-catenin and Rb/p53 pathways, and hypermethylated PAX5 (both P<0.05 for PFS and DFS, HR 1.47-2.33). These were combined to S-GRAS to obtain a combined score (COMBI). At comparative analysis, the best discriminative prognostic model was COMBI score in both cohorts for all endpoints, followed by S-GRAS score (C index for OS 0.724 and 0.765, PFS 0.717 and 0.670, DFS 0.699 and 0.644, respectively). Conclusions Targeted DNA-based BM evaluated on routinely available FFPE samples improves prognostication of ACC beyond routinely available clinical and histopathological parameters. This approach may help to better individualise patient’s management.

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Transcriptome in paraffin samples for the diagnosis and prognosis of adrenocortical carcinoma

Cited by 2 publications

References 39 publications

PPARG dysregulation as a potential molecular target in adrenal Cushing's syndrome

PPARG dysregulation as a potential molecular target in adrenal Cushing's syndrome

Performance of DNA-based biomarkers for classification of adrenocortical carcinoma: a prognostic study

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