Epigenetic Resensitization to Platinum in Ovarian Cancer

Matei, Daniela; Fang, Fang; Shen, Changyu; Schilder, Jeanne M.; Arnold, Alesha; Zeng, Yan; Berry, William A.; Huang, Tim H.M.; Nephew, Kenneth P.

doi:10.1158/0008-5472.can-11-3909

Cited by 335 publications

(316 citation statements)

References 52 publications

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“…Treatment with 5-aza-2 0 -deoxycytidine restores sensitivity to carboplatin in patients with advanced ovarian cancer. 41 In addition, it has been demonstrated that defective multidrug resistance proteins lead to platinum resistance. 42 Defects in N-glycosylation also may affect tumor growth in cells with deregulated phosphatidylinositol 3-kinase/v-Akt murine thymoma viral oncogene homolog (PI3K-Akt) pathway.…”

Section: Discussionmentioning

confidence: 99%

Methylation status of TUSC3 is a prognostic factor in ovarian cancer

Pils

Horak

Vaňhara

et al. 2012

Cancer

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BACKGROUND. Current prognostic information in ovarian cancer is based on tumor stage, tumor grade, and postoperative tumor size. Reliable molecular prognostic markers are scarce. In this article, the authors describe epigenetic events in a frequently deleted region on chromosome 8p22 that influence the expression of tumor suppressor candidate 3 (TUSC3), a putative tumor suppressor gene in ovarian cancer. METHODS. Messenger RNA expression and promoter hypermethylation of TUSC3 were studied in ovarian cancer cell lines and in tumor samples from 2 large, independent ovarian cancer cohorts using polymerase chain reaction-based methods. RESULTS. The results indicated that TUSC3 expression is decreased significantly because of promoter methylation in malignant ovarian tumors compared with benign controls. Almost 33% of ovarian cancer samples had detectable TUSC3 promoter methylation. Furthermore, methylation status of the TUSC3 promoter had a significant and independent influence on progression-free and overall survival. CONCLUSIONS. TUSC3 hypermethylation predicted progression-free and overall survival in ovarian cancer. The current observations suggested a role for N-glycosylating events in ovarian cancer pathogenesis in general and identified the epigenetic silencing of TUSC3 as a prognostic factor in this disease. Cancer 2013;119:946-54. V C 2012 American Cancer Society.KEYWORDS: TUSC3, methylation, ovarian cancer, glycosylation, progression-free survival, overall survival, biomarker.. INTRODUCTIONEpithelial ovarian cancer is the most lethal gynecologic malignancy and the fourth most frequent cause of cancer-related death among women in industrialized countries. 1 Because >75% of women are diagnosed with advanced disease (International Federation of Gynecology and Obstetrics [FIGO] stages III and IV), an early diagnosis presents 1 of the challenges of this disease. Patients with advanced ovarian cancer undergo intensive multimodal therapy consisting of cytoreductive surgery and (neo)adjuvant platinum-based and taxane-based chemotherapy. Regardless of the progress made in surgical and medical therapies over recent decades, the outcome for women with advanced ovarian cancer remains grim. Innovative, hypothesis-driven approaches to biomarker development remain essential even in the era of high-throughput sequencing and various omics. Studies of promoter methylation patterns in tumor suppressor genes have yielded several promising methylated biomarker candidates. [2][3][4] In contrast to a gene or protein expression analysis, methylation can easily be detected using polymerase chain reaction (PCR)-based methods in both tumor material and body fluids. [5][6][7] TUSC3 (tumor suppressor candidate 3), originally named N33, was identified as a potential tumor suppressor gene in prostate cancer 8,9 and is located on chromosome band 8p22. Known homozygous deletions of this region in pancreatic cell lines 10,11 and prostate cancer cell lines 12,13 contain no other cancer-related genes except TUSC3, although mutations of the T...

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Section: Discussionmentioning

confidence: 99%

Methylation status of TUSC3 is a prognostic factor in ovarian cancer

Pils

Horak

Vaňhara

et al. 2012

Cancer

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“…DNA methyltransferase inhibitors (DNMTis), such as 5-azacytidine (Aza) and 5-aza-2'-deoxycytidine (Dac) are effective cancer therapies in hematologic neoplasms (Tsai et al, 2012) (Matei et al, 2012) and are FDA approved for the pre-leukemic disorder myelodysplasia (MDS) (Kaminskas et al, 2005). These cytidine analogues incorporate into DNA, block catalytic actions of DNA methyltransferases (DNMTs), and trigger their degradation (Stresemann et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

Chiappinelli¹,

Strissel²,

Desrichard³

et al. 2017

Cell

103

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SummaryWe show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of double-stranded RNA (dsRNA) causing a Type I Interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response twofold, and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV overexpression activates the response. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and the latter signature separates primary samples for multiple tumor types from The Cancer Genome Correspondence should be addressed to Reiner.Strick@uk-erlangen.de and sbaylin@jhmi.edu.. 7 Co-first authors. 8 Co-senior authors.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Author Contributions KBC, PLS, AD, TM, JW, TAC, SBB, and RS designed experiments, performed data analyses, and wrote the manuscript. KBC, PLS, CH, AD, AH, BA, and SB performed experiments. NSR provided ERV-3 env cDNA plasmid and DS provided ovarian cancer cell lines. HL, AS, VM, DMP, LMC, MWB, and CAZ assisted with data analyses. TM, TAC, SBB, and RS contributed equally to this work and are co-senior authors. HHS Public Access

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“…MLH1 promoter hypermethylation has been reported in numerous types of tumors, including colorectal (33), gastric cancer (34) and EC (35). Previous studies have also reported that MLH1 hypermethylation may be associated with poor prognosis for patients with gastric (22), ovarian (36) and colorectal cancer (37), whilst studies on the prognostic value of MLH1 methylation in Han Chinese patients with EC or ESCC are scarce. The present study demonstrated that MLH1 promoter hypermethylation is a prognostic marker of ESCC in Chinese males.…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of MLH1 promoter methylation in male patients with esophageal squamous cell carcinoma

Chen

et al. 2017

Oncology Letters

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Abstract. The DNA mismatch repair (MMR) gene MutL homolog 1 (MLH1) is critical for the maintenance of genomic integrity. Methylation of the MLH1 gene promoter was identified as a prognostic marker for numerous types of cancer including glioblastoma, colorectal, ovarian and gastric cancer. The present study aimed to determine whether MLH1 promoter methylation was associated with survival in male patients with esophageal squamous cell carcinoma (ESCC). Formalin-fixed, paraffin-embedded ESCC tissues were collected from 87 male patients. MLH1 promoter methylation was assessed using the methylation-specific polymerase chain reaction approach. Kaplan-Meier survival curves and log-rank tests were used to evaluate the association between MLH1 promoter methylation and overall survival (OS) in patients with ESCC. Cox regression analysis was used to obtain crude and multivariate hazard ratios (HR), and 95% confidence intervals (CI). The present study revealed that MLH1 promoter methylation was observed in 53/87 (60.9%) of male patients with ESCC. Kaplan-Meier survival analysis demonstrated that MLH1 promoter hypermethylation was significantly associated with poorer prognosis in patients with ESCC (P=0.048). Multivariate survival analysis revealed that MLH1 promoter hypermethylation was an independent predictor of poor OS in male patients with ESCC (HR=1.716; 95% CI=1.008-2.921). Therefore, MLH1 promoter hypermethylation may be a predictor of prognosis in male patients with ESCC.

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Epigenetic Resensitization to Platinum in Ovarian Cancer

Cited by 335 publications

References 52 publications

Methylation status of TUSC3 is a prognostic factor in ovarian cancer

Methylation status of TUSC3 is a prognostic factor in ovarian cancer

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

Prognostic value of MLH1 promoter methylation in male patients with esophageal squamous cell carcinoma

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