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LINE-1 retrotranspositions in epithelial ovarian cancer : can we use DNA “parasites” for good purpose?

University of British Columbia

High grade serous ovarian cancer (HGSC), endometrioid ovarian cancer (ENOC) and clear cell ovarian cancer (CCOC) are the three most common subtypes of epithelial ovarian cancers (EOC). While HGSC arise from serous tubal intraepithelial carcinomas (STIC) lesions in the fallopian tube, ENOC and CCOC share a common precursor lesion, endometriosis (ectopic growth of uterine lining). Effective biomarkers of early cancer development and recurrence are lacking. We performed whole genome sequencing (WGS) and observed highly recurrent retrotransposition events originating from an active LINE-1 retrotransposon (L1) in the TTC28 gene in one-third of our ENCO and CCOC cohort. L1s are mobile genetic elements that encodes their own protein machineries to “copy-and-paste” their sequences into random genomic loci. A process called 3’ transduction occur when L1s insert the unique downstream DNA sequences along with their own sequences. All these processes may fuel genomic instability, as such L1s are epigenetically silenced in normal tissues, but are found to be re-activated in cancers and cancer precursor lesions. We hypothesize that L1s activate early in EOC tumorigenesis and that TTC28-L1 3’ transductions could be used as markers of tumor development and progression. Using conventional and multiplex PCR on formalin-fixed paraffin-embedded (FFPE) tumor tissues, we found that TTC28-L1 3’ transductions occurred early and preceded many somatic mutations. We developed a probe-based target capture sequencing method that could identify novel TTC28-L1 3’ transductions in frozen tumor and FFPE tissues, and potentially in circulating tumor DNA. Using immunohistochemistry (IHC), we observed high L1 protein expressions in HGSC and its precursor lesions. Our results suggest that TTC28-L1 events occur early in EOC development and L1 protein expressions may reflect pre-malignant transformations. The use of L1 protein IHC and our target capture assay could be explored as a potential method to track such development.

Text

2019-10-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/67443

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/