Cass, I. | bioRxiv Science

bioRxiv2021

A cellular and molecular portrait of endometriosis subtypes

Endometriosis is a common, benign condition characterized by extensive heterogeneity in lesion appearance and patient symptoms. We profiled transcriptomes of 207,949 individual cells from endometriomata (n=7), extra-ovarian endometriosis (n=19), eutopic endometrium (n=4), unaffected ovary (n=1) and endometriosis-free peritoneum (n=4) to create a cellular atlas of endometrial-type epithelial cells, endometrial-type stromal cells and microenvironmental cell populations across tissue sites. Signatures of endometrial-type epithelium and stroma differed markedly across eutopic endometrium, endometrioma, superficial extra-ovarian disease and deep infiltrating endometriosis, suggesting that extensive transcriptional reprogramming is a core component of the disease process. Endometriomas were notable for the dysregulation of pro-inflammatory pathways and upregulation of complement proteins C3 and C7. Somatic ARID1A mutation in epithelial cells was associated with upregulation of pro-angiogenic factor SOX17 and remodeling of the endothelial cell compartment. Finally, signatures of endometriosis-associated endometrial-type epithelial clusters were enriched in ovarian cancers, reinforcing the epidemiologic associations between these two diseases.

genomics↗

bioRxiv2020

DNA methylation landscapes of matched primary and recurrent high grade serous ovarian cancers are preserved throughout disease progression and chemoresistance.

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 (WGBS) and whole transcriptome sequencing (RNA-seq) to establish methylation and gene expression signatures in 62 primary and recurrent tumors from 28 patients diagnosed with stage III/IV HGSOC. Eleven of these patients carried pathogenic germline BRCA1/BRCA2 mutations. Genome-wide methylation and transcriptomic features identified in primary tumors were largely preserved in matched recurrent tumors from the same patient (P-value = 7.16 x 10-7 and 1.41 x 10-3 in BRCA1/2 and non-BRCA1/2 cases respectively). Tumors from BRCA1/2 carriers displayed high levels of heterogeneity, with significantly more shared methylation changes identified between primary and recurrent tumors from non-BRCA1/2 patients, which may be related to the poorer survival we observe in HGSOCs from non-BRCA1/2 carriers (P-value = 0.0056). Partially methylated domains (PMDs) dominated the epigenetic variation across all tumors, and were more hypomethylated in BRCA1/2 than non-BRCA1/2 cases. Differential gene expression analysis identified upregulation of genes from immune pathways including antigen processing and presentation in tumors from BRCA1/2 carriers, implicating increased immune response in the improved survival observed in these patients. In summary, this study shows a previously unreported conservation of methylation and gene expression in recurrent HGSOCs. These data have implications for the possible effectiveness of epigenetic based therapies to treat both primary and recurrent ovarian cancers.

genomics↗