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

利用高风险浸润前卵巢癌基因组不稳定性标记

• 批准号: 10719535
• 负责人: Sohrab Shah
• 金额: $ 73.45万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-06 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719535
• 关键词: Adjuvant Chemotherapy; Aneuploidy; Architecture; BRCA1 gene; BRCA2 gene; Biological Markers; Biological Process; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Patient; Carcinoma; Carcinoma in Situ; Carcinomatosis; Cell Nucleus; Cells; Characteristics; Chromosomal Instability; Classification; Clinical Management; Consensus; DNA; DNA Repair; DNA biosynthesis; Data; Development; Disease; Early Diagnosis; Endowment; Epithelium; Event; Excision; Exhibits; Fimbriated End of the Fallopian Tube; Foundations; Future; Genetic Carriers; Genomic Instability; Genomics; Goals; Granzyme; Guidelines; Histology; Immune; Immune Evasion; Immunofluorescence Immunologic; Inherited; Invaded; Invasive Lesion; Lesion; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Measures; Mediating; Mitotic; Modeling; Molecular; Natural Killer Cells; Neoplastic Cell Transformation; Operative Surgical Procedures; Ovarian Carcinoma; Ovary; Paraffin Embedding; Pathogenicity; Pathologic; Patient Care; Patient risk; Patients; Pattern; Peritoneal; Process; Proteins; Recommendation; Recurrence; Regulatory T-Lymphocyte; Risk; Risk Assessment; Risk Reduction; Salpingo-Oophorectomy; Sampling; Serous; Stage at Diagnosis; Stains; Statistical Models; Syndrome; TP53 gene; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Training; Tubal Excisions; Tumor-associated macrophages; Variant; Work; biomarker identification; brca gene; cancer cell; cancer initiation; cancer invasiveness; cell type; chromosome missegregation; cohort; early detection biomarkers; exhaustion; experience; genetic testing; genome sequencing; genomic biomarker; high risk; imaging biomarker; improved; intraepithelial; intraperitoneal; micronucleus; molecular marker; next generation; patient stratification; peritoneal cancer; prevent; programmed cell death ligand 1; programmed cell death protein 1; prophylactic; prospective; risk stratification; treatment guidelines; tumor-immune system interactions; whole genome

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.

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 由于遗传综合征引起的卵巢癌风险-最明显的是致病性变异的携带者， BRCA 1/BRCA 2-建议进行预防性降低输卵管卵巢切除术（RRSO） 因为没有有效的卵巢癌监测。尽管接受了卵巢切除手术， 输卵管，10-20%的患者将经历原发性腹膜癌，卵巢癌相关 恶性肿瘤因此，迫切需要了解HGSC发展的早期事件，以改善 高危患者的治疗决策。重要的是，最近的一项研究发现，浆液性输卵管炎的存在， RRSO时发生上皮内癌（STIC）与10.5%的原发性腹膜炎风险相关。 与手术时输卵管组织学正常的患者相比，患前列腺癌（PPC）的风险为0.3%。 HGSC的特征是由持续的染色体错误分离引起的基因组不稳定性的高发生率 由于有丝分裂机制缺陷或DNA修复和复制错误。我们假设基因组 不稳定性是STIC和侵袭性HGSC之间转变的关键事件， 具有入侵和免疫逃避所需的核型多样性。我们将调查这一假设， 1)定量cGAS，一种细胞溶质DNA的标记物，在固定的患者样品中作为染色体的生物标志物， 不稳定2)询问STIC和HGSC中局部免疫微环境的破坏是 3）定量单细胞中非整倍性的比率作为早期转化的标志物，和4） 整合分子和成像标记物，以识别和验证与侵袭性STIC相关的特征。 了解介导非侵入性STIC向侵入性HGSC转变的过程， 为发现早期检测标记奠定基础。此外，随着基因检测的增加， RRSO的高风险患者和甚至正常风险患者更常接受机会性输卵管切除术， 我们很可能会发现STIC患者。该项目将使我们能够专注于有证据表明 基因组不稳定的STIC可能有更大的风险发展后续PPC，因此可能需要 密切监测和/或辅助化疗。此外，开发了FFPE耐受scWGS技术 作为这项建议的一部分，将使我们能够询问基因组不稳定性和克隆关系的时间 在STIC和HGSC之间。这将从根本上增强我们对卵巢癌事件的理解 启动并为进一步改善患者中HGSC的早期检测奠定基础。