{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:31:41Z","timestamp":1785407501648,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,24]]},"group-title":"Genomics","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T00:00:00Z","timestamp":1776988800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["W81XWH-21-1-0281"],"award-info":[{"award-number":["W81XWH-21-1-0281"]}],"id":[{"id":"https:\/\/ror.org\/03g2zjp07","id-type":"ROR","asserted-by":"publisher"}]},{"award":["W81XWH-17-1-0141"],"award-info":[{"award-number":["W81XWH-17-1-0141"]}],"id":[{"id":"https:\/\/ror.org\/03g2zjp07","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30CA082709-25"],"award-info":[{"award-number":["P30CA082709-25"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30CA060553"],"award-info":[{"award-number":["P30CA060553"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Van Andel Research Institute - Stand Up To Cancer Epigenetics Dream Team"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>High grade serous ovarian cancer (HGSC) is initially a responsive tumor to platinum (Pt)-based therapy. Pt resistance in HGSC is associated with epigenetic modifications and hypomethylating agents (HMAs) have been studied as carboplatin resensitizing agents. As DNA methylation is detectable in cancer cells and in blood, here we aimed to develop a blood-based methylation signature associated with cancer and cancer recurrence in HGSC.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    We evaluated genome-wide DNA methylation in de-identified peripheral blood mononuclear cells (PBMCs) from women 1) without cancer (controls, n=20); 2) newly diagnosed HGSC (prior to treatment, Pt-naive, n=60) 3) Pt-resistant recurrent HGSC before and after treatment with the novel HMA\/DNA methyltransferase inhibitor (DNMTI) guadecitabine (Pt-resistant, n=30). The Pt-resistant patients were enrolled in\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT02901899\">NCT02901899<\/jats:ext-link>\n                    clinical trial testing guadecitabine and the PD-1 inhibitor pembrolizumab. DNA extracted from PBMCs was analyzed by using Infinium MethylationEPIC BeadChips. There were 30,369 differentially methylated loci (DMLs) in Pt-na\u00efve patients vs. controls (adj. p &lt; 0.05, \u03b2 &gt;10%), with most loci being demethylated. Enriched pathways in PBMCs from cancer patients included\n                    <jats:italic>mechanisms of cancer, neutrophil degranulation, and cancer-related signaling pathways (PI3K\/AKT, STAT3, HGF, interleukins)<\/jats:italic>\n                    . The number of DMLs was greater (880 DMLs; adj. p&lt;0.05, \u03b2&gt;10%) in Pt-resistant vs. Pt-na\u00efve patients, and top enriched pathways associated with Pt-resistant HGSC included pathways in\n                    <jats:italic>cancer, metabolic pathways, platelet activation, ABC transporters and signaling pathways (calcium, PI3K\/AKT, MAPK, Ras, ErbB, Hippo, Wnt)<\/jats:italic>\n                    . Massive genomewide hypomethylation 5 days after treatment with guadecitabine was observed (13,742 DMLs; adj. p&lt;0.05, \u03b2&gt;10%), which persisted 30 days after discontinuation of treatment. Pathways enriched by hypomethylated genes in PBMCs following guadecitabine treatment interestingly included pathways related to n\n                    <jats:italic>euronal signaling, such as glutaminergic receptor signaling, axonal guidance signaling, synaptic long-term depression, synaptogenesis signaling and serotonin receptor signaling<\/jats:italic>\n                    . Deconvolution analysis of the methylome data of PBMCs from Pt-resistant recurrent HGSC before versus after HMA treatment predicted\n                    <jats:italic>increased<\/jats:italic>\n                    na\u00efve B cells, memory and na\u00efve CD+ T cells, na\u00efve CD4+ T cells, and neutrophils and\n                    <jats:italic>decreased<\/jats:italic>\n                    monocytes.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>We propose new DMLs associated with Pt-naive versus Pt-resistant HGSC. These findings can lead to new biomarkers for HGSC.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.23.720362","type":"posted-content","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T21:15:16Z","timestamp":1777065316000},"source":"Crossref","is-referenced-by-count":0,"title":["Blood Based Biomarkers of DNA Methylation Associated with Platinum Resistance in High Grade Serous Ovarian Cancer"],"prefix":"10.64898","author":[{"given":"Elnaz Abbasi","family":"Farid","sequence":"first","affiliation":[{"name":"Medical Sciences Program, Indiana University School of Medicine-Bloomington, Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Medical Sciences Program, Indiana University School of Medicine-Bloomington, Bloomington, IN 47405, 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