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

Abstract

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.

Cellular landscape of adrenocortical carcinoma at single-nuclei resolution

“…Cellular landscape of adrenocortical carcinomas. Tourigny,Altieri et al,5 We conducted single-nuclei transcriptomic sequencing (snRNA-seq) on twelve tumour samples (six primary, three metastatic and three recurrent) from a total of eight patients (7F/1M, median age 58.5 yrs) with histologically confirmed diagnosis of ACC (Table 1 and Materials and Methods). Patients displayed a variety of steroid profiles at the time of resection, including four with mixed cortisol and androgens excess, one with cortisol excess alone, two with endocrine inactive tumours, and a single male patient with a rare, estrogen-secreting tumour.…”

“…Adrenocortical carcinoma (ACC) is a rare yet highly aggressive tumour of the adrenal gland (annual incidence 0.7-2 cases per million in USA; 5-year survival 50-60% early stage detection, 10-30% in later stages) with a molecular pathology that remains incompletely understood, which poses significant management challenges [1][2][3][4][5]. ACC is often associated with hypersecretion of various adrenocortical steroid hormones (usually cortisol and androgens) although can also be endocrinologically inactive meaning that clinical detection can be delayed until the later stages of disease [6].…”

Identification of Molecular Subtypes and Prognostic Characteristics of Adrenocortical Carcinoma Based on Unsupervised Clustering

“…Some tumors can be cured by complete surgery, while others cannot be removed, and they grow rapidly. The possibility of metastasis and diffusion is great, resulting in a poor prognosis [28]. Despite the utilization of various clinical biomarkers in the assessment of ACC prognosis [29][30][31], the adequacy of risk stratification for ACC is still lacking.…”

High Filamin a Expression in Adrenocortical Carcinomas Is Associated with a Favourable Tumour Behaviour: A European Multicentric Study

“…However, both tumour stage and Ki67 are not always able to discriminate between patients with a good or bad prognosis; therefore, more reliable prognostic factors are required. Recently, a high prognostic performance of the S-GRAS score, which combines the ENSAT stage, Ki67, resection status, age, and presence of symptoms has been demonstrated [8][9][10].…”