DNA methylation and transcriptomic features are preserved throughout disease recurrence and chemoresistance in high grade serous ovarian cancers

Nicole Gull, Michelle R. Jones, Pei-Chen Peng, Simon G. Coetzee, Tiago C. Silva, Jasmine T. Plummer, Alberto Luiz P. Reyes, Brian D. Davis, Stephanie S. Chen, Kate Lawrenson, Jenny Lester, Christine Walsh, Bobbie J. Rimel, Andrew J. Li, Ilana Cass, Yonatan Berg, John-Paul B. Govindavari, Joanna K. L. Rutgers, Benjamin P. Berman, Beth Y. Karlan, Simon A. Gayther

Little is known about the role of global DNA methylation in recurrence and chemoresistance of high grade serous ovarian cancer (HGSOC). We performed whole genome bisulfite sequencing and transcriptome sequencing in 62 primary and recurrent tumors from 28 patients with stage III/IV HGSOC, of which 11 patients carried germline, pathogenic BRCA1 and/or BRCA2 mutations. Landscapes of genome-wide methylation (on average 24.2 million CpGs per tumor) and transcriptomes in primary and recurrent tumors showed extensive heterogeneity between patients but were highly preserved in tumors from the same patient. We identified significant differences in the burden of differentially methylated regions (DMRs) in tumors from BRCA1/2 compared to non-BRCA1/2 carriers (mean 659 DMRs and 388 DMRs in paired comparisons respectively). We identified overexpression of immune pathways in BRCA1/2 carriers compared to non-carriers, implicating an increased immune response in improved survival (P = 0.006) in these BRCA1/2 carriers. These findings indicate methylome and gene expression programs established in the primary tumor are conserved throughout disease progression, even after extensive chemotherapy treatment, and that changes in methylation and gene expression are unlikely to serve as drivers for chemoresistance in HGSOC.