Exploiting markers of genomic instability in high-risk pre-invasive ovarian cancer

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ABSTRACT High grade serous ovarian cancer (HGSC) is the most lethal gynecologic malignancy. Patients with increased risk of ovarian cancer due to inherited syndromes–most notably carriers of pathogenic variants of BRCA1/BRCA2–are recommended to undergo prophylactic risk reducing salpingo-oophorectomies (RRSO) because there is no effective ovarian cancer surveillance. Despite undergoing surgical removal of ovaries and fallopian tubes, 10-20% of patients will experience primary peritoneal cancer, an ovarian cancer related malignancy. As such there is a dire need to understand the early events in HGSC development to improve therapeutic decisions for high-risk patients. Importantly, a recent study found that the presence of serous tubal intraepithelial carcinoma (STIC) at RRSO was associated with 10.5% risk of developing primary peritoneal carcinoma (PPC) compared with a 0.3% risk in patients with normal fallopian tube histology at the time of surgery. HGSC is characterized by high rates of genomic instability arising from ongoing chromosome missegregation due to defective mitotic machinery or errors in DNA repair and replication. We hypothesize that genomic instability is a critical event in the transition between STIC and invasive HGSC, endowing cancer cells with karyotypic diversity needed for invasion and immune evasion. We will investigate this hypothesis by 1) Quantifying cGAS, a marker for cytosolic DNA, in fixed patient samples as a biomarker for chromosomal instability. 2) Interrogating disruption of the local immune microenvironment in STIC and HGSC as a function of aneuploidy 3) Quantifying rates of aneuploidy in single cells as a marker for early transformation and 4) Integrating the molecular and imaging markers to identify and validate features associated with invasive STICs. An understanding of the processes that mediate the transition between non-invasive STIC to invasive HGSC will lay the groundwork for discovery of early detection markers. Moreover, as genetic testing increases and identifies high-risk patients for RRSOs and even normal risk patients more often undergo opportunistic salpingectomies, it is likely we will identify patients with STICs. This project will allow us to focus on patients with evidence of genomically unstable STICs who may be at a greater risk to develop subsequent PPC and thus may require closer surveillance and/or adjuvant chemotherapy. Moreover, the FFPE tolerant scWGS technology developed as part of this proposal will allow us to interrogate the timing of genomic instability and clonal relationships between STIC and HGSC. This will fundamentally enhance our understanding of the events in ovarian cancer initiation and lays the foundation to further improve early detection of HGSC in patients.