Abstract B030: DNA methylation profiling identifies subset of low-grade endometrial neoplasms with poor response to progestin therapy

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Abstract Purpose: We aimed to investigate the DNA methylation profile of low-grade endometrial neoplasms before and after progestin therapy. Methods: This is a retrospective cohort of patients with endometrial intraepithelial neoplasia/atypical hyperplasia (EIN/AH) and grade 1 endometrial endometrioid carcinoma (EEC) treated with progestin therapy. DNA was extracted from 24 formalin-fixed paraffin-embedded (FFPE) tumors before and 19 tumors after progestin therapy (median interval between specimens: 12.1 months). Methylation profiling was performed using the Illumina Infinium Methylation EPIC array. Laser-capture microdissection was used to enrich samples with low tumor content. Results: Twenty-four patients with a median age of 38 years were included. Majority of patients were nulligravid (58%), and self-identified as non-Hispanic (83%) and white (42%). Ten patients had a diagnosis of EIN/AH, while 14 were grade 1 EEC. Ten cases showed complete response, 7 partial responses, 8 showed no response between the pre- and post-treatment samples. Ten patients had regression of disease on follow-up, while 9 showed persistent tumor. In 5 patients, clinical outcome could not be assessed due to short time of exposure (<6 months). Unsupervised clustering based on top 3,000 differentially methylated sites (DMS) in 24 pre-treated tumors identified 2 different groups. Cluster 1 (n= 11) was composed of significantly older patients (p=0.047; median age: 39 vs 37 years) and more likely to have EEC on histologic examination (p=0.016; 100% vs 54%). Tumors in Cluster 1 were more likely to show absence of pathologic response following progestin therapy (p= 0.038; 55% vs 8%). Although no statistical significance was reached regarding clinical outcome (p=0.2), patients in Cluster 1 showed regression of disease in only 29% of cases (2/7), while in Cluster 2, 67% of patients showed regression of tumor (8/12). There was no difference regarding gravidity, race/ethnicity, body mass index, type of progestin, and follow-up time. KEGG pathways analysis revealed that the most significantly different pathways between the 2 clusters were: maturity onset diabetes of young, neuroactive ligand-receptor interaction, and signaling pathways regulating pluripotency of stem cells. Pairwise differential DNA methylation analysis between 15 pairs of pre- and post-treatment samples that passed quality control showed a hypermethylation effect of progestin therapy in the majority of DMS, including sites in open sea, northern and southern shores and shelves. Although there were sites in CpG islands with a hypermethylation pattern after treatment, progestin therapy had a predominantly hypomethylation effect on CpG islands. The gene set enrichment based on DMS showed significant change in genes mostly related to cell-cell adhesion following progestin therapy. Conclusion: DNA methylation profiling identifies a subset of EIN/AH and grade 1 EEC with poor response to progestin therapy. The methylation landscape of these low-grade neoplasms undergoes changes after progestin treatment. Citation Format: Lawrence H. Lin, Kyriaki Founta, Nyasha Chambwe, Deborah F. DeLair. DNA methylation profiling identifies subset of low-grade endometrial neoplasms with poor response to progestin therapy [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B030.