DNA methylation patterns between tissue and blood samples in ovarian cancer

5558 Background: Altered DNA methylation pattern, with functional consequences in the activity of key carcinogenic pathways, has been shown to be involved in the carcinogenesis of ovarian cancer. Tumor DNA is released into the blood via apoptosis or necrosis. Therefore, cell-free DNA (cfDNA) methylation alteration can also be detected in blood, which has shown promising performance in ovarian cancer early detection and prognostication. However, the difference of DNA methylation patterns between the tissue and blood samples of ovarian cancer is still unclear. Methods: PERCEIVE-I study (NCT04903665) is a prospective study aimed at the early detection of gynecological malignancies. Blood and paired tissue samples from this study were collected at the Fudan University Shanghai Cancer Center. Blood samples from age-matched non-cancer controls were also collected. All the blood and paired tissue samples were sequenced by a target methylation panel covering ~490,000 CpG sites. Finally, The ovarian cancer methylation patterns were analyzed based on 11 paired cancer-adjacent tissue samples and 170 blood samples (cancer, n=48; non-cancer control, n=122). Results: In total, 7,225 differentially methylated blocks (DMBs) were identified by comparing cancer and adjacent tissues, with 5,093 hypomethylated and 2,132 hypermethylated. By contrast, there were 5,853 hypomethylated and 8,685 hypermethylated DMBs in cancer blood samples compared with non-cancer controls. Among the 7,225 DMBs in tissues, 3,962 (54.8%) blocks were also observed to be altered in blood samples, including 2,354 hypomethylated blocks and 1,114 hypermethylated blocks. GO analysis revealed that these hypomethylated blocks were mainly associated with functions such as regulation of synaptic membrane and DNA-binding transcription activator activity, while the hypermethylated blocks were mainly enriched in the pattern specification process, transcription factor complex, and the DNA-binding transcription activator activity. The alteration of the above 3,962 DMBs in tissue were highly correlated with the alteration in blood (correlation coefficient of 0.71, 0.50, 0.73 and 0.73 for stage I-IV, respectively). Furthermore, in patients carrying germline BRCA1/2 mutations (n=11), most of the above DMBs were not significantly different from those without germline BRCA1/2 mutations (n=37). Conclusions: In this study, we demonstrated that blood DNA methylation alteration was highly consistent with tissue DNA methylation alteration in ovarian cancer, indicating the sustained release of DNA methylation signals from the primary cancer sites. These results suggest that cfDNA methylation can be used as reliable biomarkers for the early detection of ovarian cancer. Clinical trial information: NCT04903665 .