Abstract 7014: Integrative DNA methylation cancer profiling reveals patterns associated with tumor progression and treatment response
Authors: Lahtinen Alexandra , Marchi Giovanni , Afenteva Daria , Lavikka Kari , Holmström Susanna , Pöllänen Elsi , Micoli Giulia , Maarala Ilari , Li Yilin , Muranen Taru A. , Oikkonen Jaana , Hietanen Sakari , Virtanen Anni , Hynninen Johanna , Häkkinen Antti , Hautaniemi Sampsa 
Published: March 2024

Abstract
DNA methylation plays a critical role in tumor progression and response to chemotherapy. Frequently dysregulated during tumor development, it is closely intertwined with mixed effects from patient epigenetic background, tissue context, and treatment pressure. Here, we leveraged methylomic and transcriptomic profiling of 400 whole-genome sequencing samples from 125 patients with ovarian high-grade serous carcinoma (HGSC), belonging to the prospective, longitudinal, multi-region DECIDER trial (NCT04846933). This cohort included 120 samples from tubo-ovarian tumors, 209 samples from intra-abdominal metastases, and 71 ascites, representing all major sites of HGSC metastases. We profiled cancer methylome across tissues, patient groups, and various anticancer treatments using decomposition method, which allows separating the effects of tumor microenvironment and treatment, tissue, and patient specific changes, thus, facilitating integration of the heterogeneous collection of samples. First, we systematically examined the tissue-specific carcinogenesis and characterized methylomes of all types of metastases and excess fluid accumulations in the abdominal cavity. In our analyses, the cancer spread from tubo-ovarian sites to metastatic deposits involved gradual loss of DNA methylation and increase in transcriptomic levels, possibly indicating stemness. Specifically, several members of the ATP-binding-cassette (ABC) family of transporters, as well as receptor tyrosine kinases were frequently hypomethylated in bowel and omentum. The methylome of ascites showed most commonality to the tubo-ovarian tumors and peritoneum. Our results confirmed that several well-known tumor-associated genes, such as PTEN, GSK3B, ESR1, FGFR2, TNC, BCL6, HIF1A, NOTCH2 are regulated epigenetically, and this dysregulation stems early from the sites of origin. Next, we built methylomic profiles of patients with various treatment responses. Direct comparisons between good and poor responders revealed pronounced methylation differences, with refractory disease being associated with severely aberrated methylome prior to chemotherapy treatment. Neoadujuvant chemotherapy resulted in very few changes to these epigenetic aberrations and no acquired mechanisms, suggesting that intrinsic methylomes of poor responders accommodate multiple drivers for EMT, hypoxia, and chronic inflammation to resist chemotherapy-induced cell death already prior to treatment. In conclusion, using a large whole-genome sequencing DNA methylation dataset we elucidated the major underlying epigenetic mechanisms of tumorigenesis and platinum resistance, which provide possible drug targets for improving platinum sensitivity. Our multi-omics analyses enabled the identification of aberrated patterns that drive transcriptional changes, shedding light on epigenetic landscape of HGSC.
Citation Format: Alexandra Lahtinen, Giovanni Marchi, Daria Afenteva, Kari Lavikka, Susanna Holmström, Elsi Pöllänen, Giulia Micoli, Ilari Maarala, Yilin Li, Taru A. Muranen, Jaana Oikkonen, Sakari Hietanen, Anni Virtanen, Johanna Hynninen, Antti Häkkinen, Sampsa Hautaniemi. Integrative DNA methylation cancer profiling reveals patterns associated with tumor progression and treatment response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7014.