Abstract : 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. MS-MLPA is readily compatible with clinical routine and should enhance our ability for prognostication and precision medicine.
