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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的高级别浆液性卵巢癌（HGSC）是最致命的妇科恶性肿瘤，患者死亡率增加。遗传综合征导致卵巢癌的风险——最显着的致病性变异携带者 BRCA1/BRCA2——建议进行预防性风险降低输卵管卵巢切除术 (RRSO) 因为尽管进行了卵巢切除手术，但仍没有有效的卵巢癌监测。输卵管，10-20%的患者会出现原发性腹膜癌，这是一种与卵巢癌相关的癌症因此，迫切需要了解 HGSC 发展的早期事件以改善。重要的是，最近的一项研究发现输卵管浆液的存在。 RRSO 的上皮内癌 (STIC) 与发生原发性腹膜癌的风险为 10.5% 相比之下，手术时输卵管组织学正常的患者患癌 (PPC) 的风险为 0.3%。 HGSC 的特点是由于持续的染色体错误分离而导致基因组不稳定的发生率很高由于有丝分裂机制有缺陷或 DNA 修复和复制错误，我们在基因组方面遇到了困难。不稳定性是 STIC 和侵袭性 HGSC 之间转变的关键事件，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) 定量固定患者样本中的 cGAS（胞质 DNA 标记物）作为染色体生物标记物 2) 探究 STIC 和 HGSC 中局部免疫微环境的破坏作为函数。非整倍性 3) 量化单细胞中非整倍性的比率，作为早期转化的标记；4) 整合分子和成像标记物来识别和验证与侵入性 STIC 相关的特征。了解介导非侵入性 STIC 到侵入性 HGSC 之间过渡的过程将此外，随着基因检测的增加和识别，为发现早期检测标记奠定了基础。 RRSO 的高风险患者甚至正常风险患者更常接受机会性输卵管切除术，我们很可能会识别出 STIC 患者，该项目将使我们能够重点关注有 STIC 证据的患者。基因组不稳定的 STIC 可能更有可能发生后续 PPC，因此可能需要此外，还开发了 FFPE 耐受性 scWGS 技术。作为该提案的一部分，我们将能够探究基因组不稳定性和克隆关系的发生时间 STIC 和 HGSC 之间的合作将从根本上增强我们对卵巢癌事件的理解。启动并为进一步提高患者 HGSC 的早期检测奠定基础。