Abstract A34: Activation-induced cytidine deaminase links ovulation-induced inflammation and serous carcinogenesis.

Abstract

In recent years, the notion that serous ovarian carcinoma results from ovulation-induced inflammation of the fallopian tube epithelial cells (FTECs) has gained evidence. However, the mechanistic pathway that leads to mutagenesis and genomic instability has not been revealed yet. The mutator enzyme activation-induced cytidine deaminase (AID), which is known to be involved in the process of immunoglobulin somatic hypermutations, has also been recently implicated in inflammation-induced epithelial malignancies. In the current study, we propose that AID is a mechanistic link between ovulation-induced inflammation in FTECs and the genotoxic damage that leads to serous carcinogenesis. We tested at the expression of AID in human fallopian tube tissues from patients with various gynecological pathologies, as well as in cultured FTECs in an experimental model mimicking normal ovulation. We also looked at the functional effects of AID up regulation in vitro by analyzing double strand DNA breaks, abasic sites, hypomethylation and chromosomal rearrangements. We also performed a comprehensive bioinformatic analysis of somatic mutations patterns in publically available serous carcinoma sequencing data in search of AID mutational fingerprints. We show that AID, previously shown to be functional only in B lymphocytes, is expressed in human FTECs under physiological conditions, is induced in vitro upon ovulatory-like stimulation and is elevated in vivo under carcinogenesis-associated circumstances. We also report that AID activity results in epigenetic, genetic and genomic damage in FTECs. Overall, our data provides new insights on the etiology of serous ovarian carcinogenesis and may set the ground for innovative approaches aimed at prevention and early-detection. Citation Format: Stav Sapoznik, Keren Bahar-Shany, Hadar Brand, Yishay Pinto, Orshay Gabay, Efrat Glick-Saar, Chen Dor, Oranit Zadok, Iris Barshack, Adi Zundelevich, Einav Nili Gal-Yam, Yuval Yung, Ariel Hourvitz, Jacob Korach, Mario Beiner, Jasmine Jacob, Erez Y. Levanon, Michal Barak, Sarit Aviel-Ronen, Keren Levanon. Activation-induced cytidine deaminase links ovulation-induced inflammation and serous carcinogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A34.