Abstract 1069: Interrogating the role of the cGAS/STING pathway fallopian tube transformation

Abstract

Abstract Ovarian Cancer is the deadliest gynecologic malignancy. Despite recent advances in cancer diagnostics, it is a cancer that is often detected late and the vast majority of patients are diagnosed at Stage III and Stage IV. After treatment with debulking surgery and chemotherapy, 80% of patients have tumor relapse with increasing resistance. Early detection efforts have been largely unsuccessful and the only effective prevention strategy in high risk patients is surgical removal of the fallopian tube and ovaries. Careful pathologic studies of prophylactic risk reducing bilateral salpingo-oophorectomy (RRSO) has demonstrated that HGSC originates in the fallopian tube. Within the fallopian tube, secretory cells within the fimbriae are believed to be the origin of HGSC based on numerous lines of correlative evidence including the identification of histologically and molecularly abnormal regions in the fallopian tube called serous tubal intraepithelial cancer (STIC) in 3-5% of patients undergoing RRSO, and the presence of STIC in approximately half of patients undergoing debulking surgeries for HGSC. Finally, p53 mutations have been found to be identical in STIC and in the concurrent invasive disease indicating that HGSC and the STIC likely arise from the same clone. TCGA analysis has demonstrated that HCSC is a disease characterized by genomic and chromosomal instability harboring copy number alteration, including amplifications, deletions and more complex chromosomal rearrangements which impact multiple genes and pathways. Aberrantly segregating chromosomes that lag behind the spindle apparatus fail to become part of the primary nucleus (PN) and are instead enclosed by a self-assembled nuclear membrane, creating a structure called the micronucleus (MN). Spontaneous breakdown of the MN causes cytoplasmic DNA sensing and activation of the cGAS-STING pathway, an important innate cellular defense mechanism to foreign cytoplasmic DNA. To better understand the early genomic and signaling events in the development of HGSC, we are interrogating tissue from our archives from MSKCC patients who have undergone RRSO, hormone ablation surgeries or surgical debulking and were found to have benign fallopian tube, STIC lesions or invasive HGSC with STIC. We have performed a pilot experiment of 20 patient samples of different germline genetic backgrounds. Intriguingly, cGAS signaling was observed only rarely in the STICs indicating low rates of CIN in STICs we have evaluated, however we note that even in early invasive disease, we observe cGAS positivity. Taken together, these data are consistent with a model where CIN and subsequent cGAS/STING pathway activation drives the transition from pre-invasive to invasive disease. Citation Format: Duaa Hassan Al-Rawi, Danguole Norkunaite, Samuel Bakhoum, Sohrab Shah. Interrogating the role of the cGAS/STING pathway fallopian tube transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1069.