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.

抽象的 高级浆液卵巢癌（HGSC）占卵巢癌死亡率的80％，并且该疾病没有靶向疗法。先前的研究已经搜索了驱动HGSC的突变和基因融合，但是临床上可行的发现令人难以置信。尽管突变和基因融合一直是癌症遗传学的重要重点，但已知其他类型的正在研究的基因组畸变是癌症驱动的，例如基因内遗传重排（IGRS）会导致基因中的外显子复制或删除。据报道，一些IGR会促进肿瘤的生长，例如EGFR和ERBB2外显子重排，这些重排会引起这些激酶的激活。我们对TCGA PAN-CACTER数据的分析表明，HGSC比所有其他癌症都表现出更高的IGR事件的频率。进一步的分析表明，ephrin受体蛋白蛋白 - 酪氨酸激酶EPHA3的潜在内部重复可能存在于HGSC肿瘤的8.3％中。 Epha3在许多癌症类型中过表达，在许多癌症类型中，它被提出为癌症驱动器。我们已经在两个卵巢癌细胞系中验证了这种异常转录本，包括HGSC细胞系。 HGSC细胞系中这种异常转录本的特定敲低有效地降低了细胞活力，这表明EPHA3的框架重复可能促进癌细胞的生长。我们假设Epha3外显子的重复可能在激活这种酪氨酸激酶中起关键作用，从而促进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学抗性的关联，表征了潜在的基因组畸变和蛋白质产物，并检查了其在激活EPHA3信号传导和HGSC进展方面的功能。

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

Are cis-spliced fusion proteins pathological in more aggressive luminal breast cancer?

• DOI: 10.18632/oncotarget.28438
• 发表时间: 2023-06-12
• 期刊: Oncotarget