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Am J Pathol. 2018 Dec 13. pii: S0002-9440(18)30690-4. doi: 10.1016/j.ajpath.2018.11.005. [Epub ahead of print]

Long Interspersed Element 1 Retrotransposons Become Deregulated during the Development of Ovarian Cancer Precursor Lesions.

Author information

1
Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland.
2
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
3
Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
4
Department of Gynecology and Obstetrics, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
5
Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Mechanical Engineering, Johns Hopkins University, Baltimore, Maryland.
6
Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
7
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland; Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland; Department of Gynecology and Obstetrics, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
8
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland; Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland; Department of Gynecology and Obstetrics, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Electronic address: ishih@jhmi.edu.

Abstract

There is growing evidence that most high-grade serous ovarian carcinomas likely arise from local dissemination of precursor lesions of the fallopian tube. Evolution of these lesions from early p53 signatures to latter-stage, serous tubal intraepithelial carcinomas (STICs) is characterized by cytologic atypia, accumulation of somatic mutations, and genomic instability, the etiologies of which remain unclear. Long interspersed element 1 (LINE-1) retrotransposon is expressed in many carcinomas, including high-grade serous ovarian carcinoma, where it contributes to genomic instability; however, the timing of LINE-1 activation during this evolution has yet to be elucidated. In this study, we assessed LINE-1 open reading frame 1 protein expression in 12 p53 signature lesions, 32 STICs, and 112 various types of ovarian cancers via immunohistochemical staining and examined LINE-1 promoter methylation in representative cases. We found that 78% and 57% of STICs, with and without concurrent ovarian carcinomas, respectively, exhibited intense LINE-1 immunoreactivity compared with adjacent, normal-appearing fallopian tube epithelium. Hypomethylation of the LINE-1 promoter was found in all STICs exhibiting overexpression. None of the 12 p53 signatures demonstrated significant LINE-1 expression. In ovarian cancer, 84 (75%) of 112 ovarian carcinomas overexpressed LINE-1. Our results indicate that LINE-1 retrotransposons often become deregulated during progression of ovarian cancer precursor lesions from the p53 signature to STIC stages and remain highly expressed in carcinoma.

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