Genome-Wide DNA Methylation Profiling as a Prognostic Marker in Pituitary Adenomas—A Pilot Study

Author:

Møller Morten Winkler12,Andersen Marianne Skovsager23ORCID,Halle Bo12,Pedersen Christian Bonde12,Boldt Henning Bünsow24ORCID,Tan Qihua25ORCID,Jurmeister Philipp Sebastian67,Herrgott Grayson A.8,Castro Ana Valeria89ORCID,Petersen Jeanette K.24ORCID,Poulsen Frantz Rom12ORCID

Affiliation:

1. Department of Neurosurgery, Odense University Hospital, 5000 Odense, Denmark

2. Department of Clinical Research and BRIDGE (Brain Research—Inter Disciplinary Guided Excellence), University of Southern Denmark, 5000 Odense, Denmark

3. Department of Endocrinology, Odense University Hospital, 5000 Odense, Denmark

4. Department of Pathology, Odense University Hospital, 5000 Odense, Denmark

5. Department of Public Health, Odense University Hospital, 5000 Odense, Denmark

6. Institute of Pathology, Ludwig Maximilians University Hospital Munich, 80336 Munich, Germany

7. German Cancer Consortium (DKTK), Partner Site Munich, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

8. Omics Laboratory, Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Health, Detroit, MI 48202, USA

9. Department of Physiology, College of Human Medicine, Michigan State University, E. Lansing, MI 48824, USA

Abstract

Background: The prediction of the regrowth potential of pituitary adenomas after surgery is challenging. The genome-wide DNA methylation profiling of pituitary adenomas may separate adenomas into distinct methylation classes corresponding to histology-based subtypes. Specific genes and differentially methylated probes involving regrowth have been proposed, but no study has linked this epigenetic variance with regrowth potential and the clinical heterogeneity of nonfunctioning pituitary adenomas. This study aimed to investigate whether DNA methylation profiling can be useful as a clinical prognostic marker. Methods: A DNA methylation analysis by Illumina’s MethylationEPIC array was performed on 54 pituitary macroadenomas from patients who underwent transsphenoidal surgery during 2007–2017. Twelve patients were excluded due to an incomplete postoperative follow-up, degenerated biobank-stored tissue, or low DNA methylation quality. For the quantitative measurement of the tumor regrowth rate, we conducted a 3D volumetric analysis of tumor remnant volume via annual magnetic resonance imaging. A linear mixed effects model was used to examine whether different DNA methylation clusters had different regrowth patterns. Results: The DNA methylation profiling of 42 tissue samples showed robust DNA methylation clusters, comparable with previous findings. The subgroup of 33 nonfunctioning pituitary adenomas of an SF1-lineage showed five subclusters with an approximately unbiased score of 86%. There were no overall statistically significant differences when comparing hazard ratios for regrowth of 100%, 50%, or 0%. Despite this, plots of correlated survival estimates suggested higher regrowth rates for some clusters. The mixed effects model of accumulated regrowth similarly showed tendencies toward an association between specific DNA methylation clusters and regrowth potential. Conclusion: The DNA methylation profiling of nonfunctioning pituitary adenomas may potentially identify adenomas with increased growth and recurrence potential. Larger validation studies are needed to confirm the findings from this explorative pilot study.

Funder

Novo Nordisk Fonden

Publisher

MDPI AG

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