ECE2016 Oral Communications Adrenal - Basic & Clinical (5 abstracts)
Recent pan-genomic analyses of tumor DNA identified specific patterns of DNA methylation e.g. CpG islands hypermethylation in the promoter regions of genes- as pejorative prognostic markers in adrenocortical cancer (ACC). Integrated genomics clearly shows that ACC with such an hypermethylation belongs to specific subgroups of ACC with increased driver genes alterations and a poor survival.
Aim: To confirm the prognostic value of this methylation pattern on an independent cohort using a commercially available kit, and to confront methylation to tumor stage and Ki67, the two main prognostic factors validated so far.
Patients and Methods: DNA methylation was measured by methylation-specific multiplex-ligation-dependent probe amplification (MS-MLPA) in the CpG islands of 27 genes using the ME002-B1 kit (MRC-Holland). MS-MLPA marker was set up in a training cohort of 50 ACC, then validated in an independent cohort of 203 ACC from 21 ENSAT centers. The validation cohort included 64% females, median age 50 years, 80% localized tumors (ENSAT stages IIII). Univariate and multivariate survival analyses were performed with Cox models.
Results: The mean methylation of 4 genes (PAX5, GSTP1, PYCARD, PAX6) correlated well with methylation arrays (Pearson correlation coefficient 0.81). The mean methylation was a strong predictor of survival, with a hazard ratio (HR) for recurrence of 1.013 (P<10−6) and a HR for death of 1.012 (P<10−4) per 1% increase of methylation. In a multivariate model including ENSAT stage and Ki67, the mean methylation remained significant for predicting recurrence (P<10−3) and death (P<10−3).
Conclusion: Focal measurement of tumor DNA methylation is a high and independent predictor of recurrence and death in ACC patients. MS-MLPA is readily compatible with clinical routine, and should therefore complete the clinical and pathological prognostic markers for precision medicine.