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Clin Cancer Res. 2018 Aug 14. doi: 10.1158/1078-0432.CCR-18-1199. [Epub ahead of print]

Methylomic Analysis of Ovarian Cancers Identifies Tumor-Specific Alterations Readily Detectable in Early Precursor Lesions.

Author information

1
Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland. tlw@jhmi.edu tpisanic@jhu.edu.
2
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
3
Departments of Oncology and Biostatistics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
4
Departments of Gynecology and Obstetrics and Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
5
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland.
6
Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Japan.
7
Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland.
8
Department of Mechanical Engineering, Johns Hopkins University, Baltimore, Maryland.
9
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. tlw@jhmi.edu tpisanic@jhu.edu.

Abstract

Purpose: High-grade serous ovarian carcinoma (HGSOC) typically remains undiagnosed until advanced stages when peritoneal dissemination has already occurred. Here, we sought to identify HGSOC-specific alterations in DNA methylation and assess their potential to provide sensitive and specific detection of HGSOC at its earliest stages.Experimental Design: MethylationEPIC genome-wide methylation analysis was performed on a discovery cohort comprising 23 HGSOC, 37 non-HGSOC malignant, and 36 histologically unremarkable gynecologic tissue samples. The resulting data were processed using selective bioinformatic criteria to identify regions of high-confidence HGSOC-specific differential methylation. Quantitative methylation-specific real-time PCR (qMSP) assays were then developed for 8 of the top-performing regions and analytically validated in a cohort of 90 tissue samples. Lastly, qMSP assays were used to assess and compare methylation in 30 laser-capture microdissected (LCM) fallopian tube epithelia samples obtained from cancer-free and serous tubal intraepithelial carcinoma (STIC) positive women.Results: Bioinformatic selection identified 91 regions of robust, HGSOC-specific hypermethylation, 23 of which exhibited an area under the receiver-operator curve (AUC) value ≥ 0.9 in the discovery cohort. Seven of 8 top-performing regions demonstrated AUC values between 0.838 and 0.968 when analytically validated by qMSP in a 90-patient cohort. A panel of the 3 top-performing genes (c17orf64, IRX2, and TUBB6) was able to perfectly discriminate HGSOC (AUC 1.0). Hypermethylation within these loci was found exclusively in LCM fallopian tube epithelia from women with STIC lesions, but not in cancer-free fallopian tubes.Conclusions: A panel of methylation biomarkers can be used to accurately identify HGSOC, even at precursor stages of the disease. Clin Cancer Res; 1-12. ©2018 AACR.

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