DNA methylation is an independent prognostic marker of survival in adrenocortical cancer
Context: Adrenocortical cancer (ACC) is an aggressive tumor with a heterogeneous outcome. Prognostic stratification is difficult even based on tumor stage and Ki67. Recently integrated genomics studies have demonstrated that CpG islands hypermethylation is correlated with poor survival.
Objective: The goal of this study was to confirm the prognostic value of CpG islands methylation on an independent cohort.
Design: Methylation was measured by methylation-specific multiplex ligation–dependent probe amplification (MS-MLPA).
Setting: MS-MLPA was performed in a training cohort of 50 patients with ACC to identify the best set of probes correlating with disease-free survival (DFS) and overall survival (OS). These outcomes were validated in an independent cohort from 21 ENSAT centers.
Patients: The validation cohort included 203 patients (64% women, median age 50 years, 80% localized tumors).
Main Outcome Measures: DFS and OS.
Results: In the training cohort, mean methylation of 4 genes (PAX5, GSTP1, PYCARD, PAX6) was the strongest methylation marker. In the validation cohort, methylation was a significant prognostic factor of DFS (P , 0.0001) and OS (P , 0.0001). Methylation, Ki67, and ENSAT stage were combined in multivariate models. For DFS, methylation (P = 0.0005) and stage (P , 0.0001) but not Ki67 (P = 0.19) remained highly significant. For OS, methylation (P = 0.0006), stage (P , 0.0001), and Ki67 (P = 0.024) were independent prognostic factors.
Conclusions: Tumor DNA methylation emerges as an independent prognostic factor in ACC. MSMLPA is readily compatible with clinical routine and should enhance our ability for prognostication and precision medicine.
|Persistent URL||dx.doi.org/10.1210/jc.2016-3205, hdl.handle.net/1765/98640|
|Journal||Journal of Clinical Endocrinology and Metabolism|
|Grant||This work was funded by the European Commission 7th Framework Programme; grant id fp7/259735 - European Network for the Study of Adrenal Tumours - Structuring clinical research on adrenal cancers in adults (ENS@T-CANCER)|
Jouinot, A, Assié, G, Libe, R, Fassnacht, M, Papathomas, T.G, Barreau, O, … Bertherat, J. (2017). DNA methylation is an independent prognostic marker of survival in adrenocortical cancer. Journal of Clinical Endocrinology and Metabolism, 102(3), 923–932. doi:10.1210/jc.2016-3205