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Endocrine Abstracts (2016) 41 OC1.2 | DOI: 10.1530/endoabs.41.OC1.2


1Institut Cochin, INSERM U1016, CNRS UMR8104, Paris Descartes University, Paris, France; 2Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France; 3Endocrinology and Diabetes Unit, University Hospital of Würzburg, Würzburg, Germany; 4Department of Pathology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; 5Department of Oncogenetics, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France; 6Department of Pathology, Reinier de Graaf Hospital, Delft, The Netherlands; 7Department of Surgery, University Hospital Giessen and Marburg, Marburg, Germany; 8Department of Medicine, Charite University, Berlin, Germany; 9Department of Endocrinology, Diabetes and Metabolic Diseases, University Hospital of Bordeaux, Bordeaux, France; 10Department of Endocrinology, University Hospital of Grenoble, Grenoble, France; 11Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy; 12Department of Medicine, Endocrinology Unit, University of Padova, Padova, Italy; 13Department of Endocrinology, Brest University Hospital, Brest, France; 14Department of Nuclear Medicine and Endocrine Oncology, Institut Gustave Roussy, Villejuif, France; 15MedizinischeKlinik und Poliklinik IV, Ludwig-Maximilians-UniversitätMänchen, Mänchen, Germany; 16Biostatistics and Epidemiology Unit, HôtelDieu, Assistance Publique Hôpitaux de Paris, Paris, France.

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 I–III). 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.

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