Prognostic role of targeted methylation analysis in paraffin-embedded samples of adrenocortical carcinoma

Juliane Lippert, Barbara Altieri, Breanna Morrison, Sonja Steinhauer, Gabrielle Smith, Antonia Lorey, Hanna Urlaub, Stefan Kircher, Alice Sitch, Martin Fassnacht*, Cristina L Ronchi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

Context: Adrenocortical carcinoma (ACC) is a rare aggressive disease with heterogeneous prognosis. Previous studies identified hypermethylation in the promoter region of specific genes to be associated with poor clinical outcome.

Objective: Comparative analysis of promising hypermethylated genes as prognostic markers and evaluation of their added value to established clinical prognostic tools.

Design: We included 237 patients with ACCs. Tumor DNA was isolated from formalin-fixed paraffin-embedded (FFPE) samples. Targeted pyrosequencing was used to detect promoter region methylation in 5 preselected genes (PAX5, GSTP1, PYCARD, PAX6, G0S2). The prognostic role of hypermethylation pattern was compared to S-GRAS score. Primary endpoints were progression-free (PFS) and overall survival (OS), with disease-free (DFS) as secondary endpoint.

Results: 27.9%, 13.9%, 49%, 49% and 25.3% of cases showed hypermethylation in PAX5, GSTP1, PYCARD, PAX6, and G0S2, respectively. Hypermethylation in all individual genes – except GSTP1 – was significantly associated with both PFS and OS - with Hazard Ratios (HR) between 1.4 and 2.3. However, only hypermethylation of PAX5 remained significantly associated with OS (p=0.013; HR=1.95, 95%CI 1.2-3.3) in multivariable analysis. A model for risk stratification was developed, combining PAX5 methylation status and S-GRAS groups, showing improved prognostic performance compared to S-GRAS alone (Harrell’s C index: OS=0.751, PFS=0.711, DFS=0.688).

Conclusions: This study demonstrated that hypermethylation in PAX5 is associated with worst clinical outcome in ACC, even after accounting for S-GRAS score. Assessing methylation in FFPE material is straightforward in the clinical setting and could be used to improve accuracy of prognostic classification, enabling the direction of personalized management.
Original languageEnglish
Article numberdgac470
Pages (from-to)1-8
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Volume107
Issue number10
DOIs
Publication statusPublished - 4 Aug 2022

Bibliographical note

Final Version of Record not yet available as of 25/08/2022.

Keywords

  • adrenal cancer
  • biomarkers
  • molecular oncology
  • personalized medicine
  • prognosis

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