Abstract A003: Characterizing DNA methylation patterns driving chemotherapy resistance in ovarian high-grade serous carcinoma
Authors: Lahtinen Alexandra , Marchi Giovanni , Lavikka Kari , Micoli Giulia , Holmström Susanna , Pöllänen Elsi , Maarala Ilari , Afenteva Daria , Li Yilin , Muranen Taru A. , Oikkonen Jaana , Huhtinen Kaisa , Virtanen Anni , Hynninen Johanna , Häkkinen Antti , Hautaniemi Sampsa 
Published: March 2024

Abstract
To characterize the role of DNA methylation (DNAm) in chemotherapy response, we analyzed whole-genome DNAm data integrated with transcriptome from 67 samples of 17 patients with ovarian high grade serous carcinoma (HGSC) belonging to the prospective, longitudinal, multi-region DECIDER trial (NCT04846933). We used a novel decomposition method, which allows separating the effects of tumor microenvironment and treatment, tissue, and patient specific changes, facilitating the integration of the heterogeneous collection of samples. We firstly characterized DNAm alterations between tissue sites. Our results show that the cancer spread from tubo-ovarian sites to metastatic deposits is accompanied by moderate changes that employ cell junctions and focal adhesions. The most drastic change in the tissue intrinsic DNAm profiles implicated upregulation of members of the ATP-binding-cassette (ABC) family of transporters, including such multidrug resistance-associated genes as ABCC2, ABCC3, and ABCC4 in omentum. We then proceeded to characterize the DNAm changes during treatment. Our results reveal that DNAm plays a distinct role in emergence, driving, and regulation of both preexisting and acquired resistance to chemotherapy. We observed that patient-specific DNAm background shows enormous intra- and intertumor heterogeneity and sustains multiple driver mechanisms to resist chemotherapy-induced cell death already prior to treatment. We also observed that neoadjuvant chemotherapy (NACT) results in emergence of resistance via acquired, tissue specific DNAm alterations in DNA damage repair, apoptosis, cellular senescence, and drug efflux. Pathway analyses show that treatment-naïve tumors from patients with poor treatment outcome have DNAm-induced upregulation of key resistance promoting signaling pathways, such as PI3K/Akt, mTOR, and Rap1 cascades. Hypoxic transcriptional program activated via HIF-1 signaling was significantly altered in poorly responding patients, accompanied by changes in extracellular matrix instigated by integrins ITGB1 and ITGA5. Tumors of patients with refractory disease demonstrated DNAm changes in genes involved in tumor-promoting chronic inflammation driven by elevation of tumor necrosis factor. NACT treatment resulted in very few changes to these DNA aberrations and no acquired mechanisms, suggesting that intrinsic DNAm patient profiles accommodate multiple drivers for tumor progression and chemoresistance. In conclusion, using a large whole-sequencing DNAm dataset we elucidated the major underlying mechanisms of acquired platinum resistance, which provide possible targets for improving platinum sensitivity. Validation of these results and the intrinsic ability of HGSC to resist platinum-based treatment is currently on-going in our recently sequenced DNAm batch consisting of 400 samples of 135 HGSC patients.
Citation Format: Alexandra Lahtinen, Giovanni Marchi, Kari Lavikka, Giulia Micoli, Susanna Holmström, Elsi Pöllänen, Ilari Maarala, Daria Afenteva, Yilin Li, Taru A. Muranen, Jaana Oikkonen, Kaisa Huhtinen, Anni Virtanen, Johanna Hynninen, Antti Häkkinen, Sampsa Hautaniemi. Characterizing DNA methylation patterns driving chemotherapy resistance in ovarian high-grade serous carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A003.