Abstract 6002: Characterizing dynamic landscape of DNA methylation in ovarian high-grade serous carcinoma

Abstract

Abstract Dysregulated DNA methylation (DNAm) is a hallmark of all cancer types, though the precise role of these aberrations in tumor progression and treatment response remains elusive. Advances in whole-genome bisulfite sequencing (WGBS) have enabled profiling methylomes at full resolution and stimulated interest to explore dynamics of DNAm across tumor sites and cancer treatment. A major challenge in the analysis of patient data is that a surgically removed tumor sample represents a mixture of cancer cells and microenvironment, and that the insights on DNAm changes are intertwined due to mixed effects from patient epigenomic background, tissue context, and treatment pressure. By using a computational approach, these effects can be decomposed into patient background, tissue site, and treatment phase specific changes, and controlled for natural microenvironment variation. retion, and action, as well as in several oncogenic signaling cascades. The analysis of the tissue profiles indicated that the progression of HGSC from the tissues-of-origin to the metastatic deposits is accompanied by drastic changes in DNAm profiles. Thus, when comparing ovaries and peritoneum, intra-abdominal tissues mesentery and omentum featured prominent change of promoter DNAm: loss in 10% and gain in 20% of genes. Interestingly, the genes with aberrant DNAm included ABC transporters implicated in pumping drugs across the cell membrane, as well as the members of MAPK and PI3K signaling cascades. The joint analysis of both treatment and tissue contributions suggests that the overall modest effect of NACT is further reduced in metastases, mediated via DNAm changes in genes involved in multidrug resistance. Citation Format: Alexandra Lahtinen, Giovanni Marchi, Daria Afenteva, Susanna Holmström, Kaisa Huhtinen, Anni Virtanen, Johanna Hynninen, Antti Häkkinen, Sampsa Hautaniemi. Characterizing dynamic landscape of DNA methylation in ovarian high-grade serous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6002.