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

摘要 高级别浆液性卵巢癌(HGSC)是最致命的妇科恶性肿瘤。增加的患者 遗传性综合征导致卵巢癌的风险--最明显的是携带致病变种 BRCA1/BRCA2-建议接受预防性风险降低输卵管卵巢切除术(RRSO) 因为没有有效的卵巢癌监测。尽管接受了卵巢摘除手术和 输卵管中，10%-20%的患者会经历原发性腹膜癌，与卵巢癌有关 恶毒。因此，迫切需要了解HGSC开发中的早期事件以改进 针对高危患者的治疗决策。重要的是，最近的一项研究发现浆液性输卵管的存在 RRSO的上皮内癌(STIC)与10.5%的原发腹膜相关 与之相比，手术时输卵管组织学正常的患者患癌(PPC)的风险为0.3%。 HGSC的特征是由于持续的染色体错误分离而导致的高基因组不稳定性。 由于有丝分裂机制的缺陷或DNA修复和复制中的错误。我们假设基因组 不稳定性是STIC和侵袭性HGSC之间过渡的关键事件，赋予癌细胞 具有入侵和免疫逃避所需的核型多样性。我们将通过以下方式研究这一假设 1)在固定的患者样本中定量cGAS作为染色体的生物标记物 不稳定。2)询问STIC和HGSC局部免疫微环境的破坏 非整倍体3)单细胞非整倍体率的量化作为早期转化的标志和4) 整合分子和成像标记以识别和验证与侵袭性STIC相关的特征。 了解非侵袭性STIC向侵袭性HGSC过渡的过程将 为发现早期检测标记奠定基础。此外，随着基因检测的增加和识别 RRSO的高危患者甚至正常风险患者更多地接受机会性输卵管切除术， 我们很可能会识别出患有STIC的患者。这个项目将使我们能够专注于有证据的患者 基因不稳定的STIC，他们可能有更大的风险发展成后续的PPC，因此可能需要 更密切的监测和/或辅助化疗。此外，还开发了耐FFPE的scWGS技术 作为这项提议的一部分，我们将能够询问基因组不稳定和克隆关系的时间 在STIC和HGSC之间。这将从根本上增强我们对卵巢癌事件的了解 为进一步提高HGSC患者的早期检测水平奠定了基础。

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.