Abstract
Ovarian cancer is the most deadly gynecologic malignancy worldwide and it is warranted to dissect the critical gene regulatory network in ovarian cancer. N6-methyladenosine (m6A) RNA methylation, as the most prevalent RNA modification, is orchestrated by the m6A RNA methylation regulators and has been implicated in malignant progression of various cancers. In this study, we investigated the genetic landscape and expression profile of the m6A RNA methylation regulators in ovarian cancer and found that several m6A RNA methylation regulators were frequently amplified and up-regulated in ovarian cancer. Utilizing consensus cluster analysis, we stratified ovarian cancer samples into four clusters with distinct m6A methylation patterns and patients in these subgroups displayed the different clinical outcomes. Moreover, multivariate Cox proportional hazard model was used to screen the key m6A regulators associated with the prognosis of ovarian cancer and the last absolute shrinkage and selection operator (LASSO) Cox regression was used to construct the gene signature for prognosis prediction. The survival analysis exhibited the risk-gene signature could be used as independent prognostic markers for ovarian cancer. In conclusion, m6A RNA methylation regulators are associated with the malignant progression of ovarian cancer and could be a potential in prognostic prediction for ovarian cancer.
Highlights
Ovarian cancer is a gynecologic malignancy with the most deaths worldwide (Narod, 2016)
METTL3 directed m6A modification of tumor suppressor gene SOCS2 and silenced its expression depending on YTHDF2-mediated degradation pathway, which promoted the progression of hepatocellular cancer (Chen et al, 2018)
According to the mRNA expression detected by the Cancer Genome Atlas (TCGA) database, 20 m6A regulators including 7 “writers” (KIAA1429, METTL3, METTL14, RBM15, RBM15B, Wilms’ tumor 1-associating protein (WTAP), ZC3H13), 2 “erasers” (ALKBH5, FTO) and 11 “readers” (YTHDC1-2, YTHDF1-3, IGF2BP1-3, HNRNPA2B1, heterogeneous nuclear ribonucleoprotein C (HNRNPC), embryonic lethal abnormal vision Drosophila like 1 (ELAVL1)) were analyzed in this study
Summary
Ovarian cancer is a gynecologic malignancy with the most deaths worldwide (Narod, 2016). Obesity-associated protein (FTO) and alkB homolog 5 (ALKBH5) act as m6A methylation “erasers” and could decrease the m6A modification in RNA (Jia et al, 2011; Zheng et al, 2013). METTL3 directed m6A modification of tumor suppressor gene SOCS2 and silenced its expression depending on YTHDF2-mediated degradation pathway, which promoted the progression of hepatocellular cancer (Chen et al, 2018). The role of m6A RNA methylation-mediated gene regulatory network in diagnosis and treatment of ovarian cancer is largely unexplored. We classified the ovarian cancer patients into four subgroups with distinct overall survivals based on the expression of 20 m6A RNA methylation regulators. Our study demonstrated that m6A RNA methylation regulators have an important value in prognostic prediction for ovarian cancer
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