Molecular signatures of X chromosome inactivation and associations with clinical outcomes in epithelial ovarian cancer

Abstract

X chromosome inactivation (XCI) is a key epigenetic gene expression regulatory process, which may play a role in women’s cancer. In particular tissues, some genes are known to escape XCI, yet patterns of XCI in ovarian cancer (OC) and their clinical associations are largely unknown. To examine XCI in OC, we integrated germline genotype with tumor copy number, gene expression and DNA methylation information from 99 OC patients. Approximately 10% of genes showed different XCI status (either escaping or being subject to XCI) compared with the studies of other tissues. Many of these genes are known oncogenes or tumor suppressors (e.g. DDX3X, TRAPPC2 and TCEANC). We also observed strong association between cis promoter DNA methylation and allele-specific expression imbalance (P = 2.0 × 10−10). Cluster analyses of the integrated data identified two molecular subgroups of OC patients representing those with regulated (N = 47) and dysregulated (N = 52) XCI. This XCI cluster membership was associated with expression of X inactive specific transcript (P = 0.002), a known driver of XCI, as well as age, grade, stage, tumor histology and extent of rl disease following surgical debulking. Patients with dysregulated XCI (N = 52) had shorter time to recurrence (HR = 2.34, P = 0.001) and overall survival time (HR = 1.87, P = 0.02) than those with regulated XCI, although results were attenuated after covariate adjustment. Similar findings were observed when restricted to high-grade serous tumors. We found evidence of a unique OC XCI profile, suggesting that XCI may play an important role in OC biology. Additional studies to examine somatic changes with paired tumor-normal tissue are needed.

Interrogation of gender disparity uncovers androgen receptor as the transcriptional activator for oncogenic miR-125b in gastric cancer

“…Our results support the hypothesis that X-chromosome deregulation may affect the AR function and have relevance to female carcinogenesis (i.e., ovarian and breast cancer) 34 , 35 . Moreover, the modulation process of AR by sex chromosomal abnormalities is age-related and cell type-specific 36 , which may lead to the gender differences in GC.…”

The Emerging Role of Non-coding RNAs in Drug Resistance of Ovarian Cancer

“…At present, it is known that lncRNAs can regulate the malignant biological behavior of cells by acting as a competitive endogenous RNA (ceRNA), recruiting downstream molecules, serving as protein scaffolds, transmitting regulatory signals (Wong et al, 2018), and regulating endolysosome pH (Miller et al, 2018). A number of lncRNAs have a close relationship to the development of ovarian cancer metastasis, recurrence, and chemotherapy resistance (Winham et al, 2019;Zhang M. et al, 2019;Sun et al, 2020). Aberrantly expressed lncRNAs may participate in ovarian cancer progression through various mechanisms, including inducing autophagy, increasing DNA damage repair, changing cell cycle progression and checkpoints, inducing anti-apoptosis, regulating cell signaling pathways, and promoting EMT (Liu et al, 2015;Yan et al, 2017;Xu Q. F. et al, 2018;Wu et al, 2019).…”

trans-Acting Factors and cis Elements Involved in the Human Inactive X Chromosome Organization and Compaction

“…X-linked gene reactivation has also been observed in aged tissue [ 82 – 84 ], autoimmune diseases [ 85 ], and cancer [ 86 – 88 ]. There is evidence that, in ovarian cancer cells, there is a unique profile of X-linked gene expression and escape, suggesting that XCI may play a role in the development of ovarian cancer [ 89 ].…”