Characterization of EPHA3 intragenic rearrangements in high-grade serous carcinoma progression and recurrence

EPHA3基因内重排在高级别浆液性癌进展和复发中的特征

• 批准号: 10062915
• 负责人: Xiaosong Wang
• 金额: $ 21.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062915
• 关键词: Anchorage-Independent Growth; Area; Automobile Driving; Biological Markers; Blood specimen; Brain Neoplasms; Cancer Cell Growth; Cancer Patient; Cancer cell line; Carcinoma; Cell Line; Cell Proliferation; Cell Survival; Cells; Chemoresistance; Clinical; DNA Sequence Alteration; DNA Sequence Rearrangement; Data; Development; Disease; Disease Resistance; EPHA3 gene; ERBB2 gene; ES Cell Line; Engineering; Eph Family Receptors; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Event; Exhibits; Exons; Fibronectins; Foundations; Frequencies; Gene Duplication; Gene Fusion; Genes; Genetic; Growth; Hematologic Neoplasms; In Vitro; Incidence; Investigation; Lead; Ligands; Light; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of ovary; Modeling; Molecular; Monoclonal Antibodies; Mutation; Nature; Oncogenic; Patients; Phase I Clinical Trials; Phenotype; Phosphotransferases; Platinum; Platinum Compounds; Play; Point Mutation; Population; Primary Neoplasm; Protein Tyrosine Kinase; Proteins; Quantitative Reverse Transcriptase PCR; RNA analysis; Receptor Protein-Tyrosine Kinases; Recurrence; Recurrent Malignant Neoplasm; Recurrent tumor; Reporting; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; SKOV3 cells; Serous; Signal Transduction; Small Interfering RNA; Specificity; TP53 gene; The Cancer Genome Atlas; Therapeutic Effect; Therapeutic Studies; Therapeutic antibodies; Transcript; base; cancer cell; cancer genetics; cancer genome; cancer recurrence; cancer type; chemotherapy; clinically actionable; genome-wide analysis; genomic aberrations; improved; inhibitor/antagonist; kinase inhibitor; knock-down; mortality; overexpression; patient population; peripheral blood; precision medicine; small molecule; targeted treatment; taxane; therapeutic target; therapy resistant; transcriptome sequencing; tumor; tumor progression

Abstract High grade serous ovarian cancer (HGSC) accounts for 80% of ovarian cancer mortality, and no targeted therapies are available for this disease. Previous studies have searched for mutations and gene fusions that drive HGSC, but the clinically actionable discoveries have been underwhelming. Although mutations and gene fusions have been a significant focus of cancer genetics, other types of understudied genomic aberrations are known to be cancer-driving, such as Intragenic genetic rearrangements (IGRs) that result in exons within genes being duplicated or deleted. Some IGRs have been reported to drive growth in tumors, such as EGFR and ERBB2 exon rearrangements that are known to cause activation of these kinases. Our analysis of TCGA pan-cancer data revealed that HGSC exhibits a higher frequency of unbalanced IGR events than all other cancers. Further analysis revealed a potential intragenic duplication of the ephrin-receptor protein-tyrosine kinase EPHA3 that may be present in up to 8.3% of HGSC tumors. EPHA3 is overexpressed in a number of cancer types, where it has been proposed as a cancer driver. We have verified the presence of this aberrant transcript in two ovarian cancer cell lines, including a HGSC cell line. Specific knockdown of this aberrant transcript in the HGSC cell line potently reduced cell viability, suggesting that the in-frame duplication of EPHA3 may promote cancer cell growth. We hypothesize that EPHA3 exon duplications may play a key role in activating this tyrosine kinase, which may promote HGSC progression and recurrence. This proposal seeks to assess the incidence of EPHA3 exon duplications in HGSC, explore its association with tumor recurrence and chemoresistance, characterize the underlying genomic aberrations and protein products, and examine its function in activating EPHA3 signaling and HGSC progression.

摘要 高级别浆液性卵巢癌（HGSC）占卵巢癌死亡率的80%，并且没有针对这种疾病的靶向治疗。以前的研究已经寻找了驱动HGSC的突变和基因融合，但临床上可操作的发现并不令人印象深刻。虽然突变和基因融合一直是癌症遗传学的重要焦点，但已知其他类型的未充分研究的基因组畸变是癌症驱动的，例如基因内遗传重排（IGR），其导致基因内的外显子被复制或删除。据报道，一些IGR可驱动肿瘤生长，如EGFR和ERBB2外显子重排，已知可引起这些激酶的激活。我们对TCGA泛癌症数据的分析显示，HGSC表现出比所有其他癌症更高的不平衡IGR事件频率。进一步的分析揭示了肝配蛋白受体蛋白酪氨酸激酶EPHA3的潜在基因内复制，其可能存在于高达8.3%的HGSC肿瘤中。EPHA3在许多癌症类型中过表达，其中它已被提议作为癌症驱动因素。我们已经证实了这种异常的转录存在于两个卵巢癌细胞系，包括HGSC细胞系。HGSC细胞系中这种异常转录物的特异性敲低有效地降低了细胞活力，表明EPHA3的框内复制可能促进癌细胞生长。我们推测EPHA3外显子重复可能在激活这种酪氨酸激酶中起关键作用，这可能促进HGSC的进展和复发。该提案旨在评估HGSC中EPHA3外显子重复的发生率，探索其与肿瘤复发和化疗耐药性的相关性，表征潜在的基因组畸变和蛋白产物，并检查其在激活EPHA3信号传导和HGSC进展中的功能。

项目成果

Intragenic Rearrangement Burden Associates with Immune Cell Infiltration and Response to Immune Checkpoint Blockade in Cancer.

基因内重排负担与癌症中免疫细胞浸润和对免疫检查点阻断的反应相关。

• DOI: 10.1158/2326-6066.cir-22-0637
• 发表时间: 2024
• 期刊: Cancer immunology research
• 影响因子: 10.1
• 作者: Zhang,Han;Lee,Sanghoon;Muthakana,ReneeR;Lu,Binfeng;Boone,DavidN;Lee,Daniel;Wang,Xiao-Song
• 通讯作者: Wang,Xiao-Song