Detection of Circulating Tumor-specific DNA Methylation Markers in the Blood of Patients with Pituitary Tumors

Genome-wide DNA methylation aberrations are pervasive and associated with clinicopathological features across pituitary tumors (PT) subtypes. The feasibility to detect CpG methylation abnormalities in circulating cell-free DNA (cfDNA) has been reported in central nervous system tumors other than PT. Here, we aimed to profile and identify methylome-based signatures in the serum of patients harboring PT (n =13). Our analysis indicated that serum cfDNA methylome from patients with PT are distinct from the counterparts in patients with other tumors (gliomas, meningiomas, colorectal carcinomas, n =134) and nontumor conditions (n = 4). Furthermore, the serum methylome patterns across PT was associated with functional status and adenohypophyseal cell lineage PT subtypes, recapitulating epigenetic features reported in PT-tissue. A machine learning algorithm using serum PT-specific signatures generated a score that distinguished PT from non-PT conditions with 100% accuracy in our validation set. These preliminary results underpin the potential clinical application of a liquid biopsy-based DNA methylation profiling as a noninvasive approach to identify clinically relevant epigenetic markers that can be used in the management of PT. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Henry Ford Health System, Department of Neurosurgery, and the Hermelin Brain Tumor Center. MSM and MC are supported by the Sao Paulo Research Foundation (FAPESP), Brazil ( #16/11039-3; #17/10357-4,#14/03989-6); AVC and KPA by Henry Ford Hospital (A30935, A30957; GME 202199); LMP, HN, AD, MW, and AM by the National Institutes of Health (R01CA222146), HN, TSS, TMM, LMP, and AD are supported by the Department of Defense (CA170278). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Active IRB # 12490 Epigenetic liquid biopsy detection in a pan-central nervous system (pan-CNS) tumor cohort All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data will be available under the accession code GSEXXXX. All the other data supporting the findings of this study are available within the article and supplemental information and from the corresponding author upon reasonable request.