CHARACTERIZATION OF RECURRENT ADJACENT GENE TRANSLOCATIONS IN BREAST CANCER

乳腺癌中复发性邻近基因易位的特征

基本信息

批准号：
9093728
负责人：
Xiaosong Wang
金额：
$ 32.27万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9093728
关键词：
ABL1 gene Anchorage-Independent Growth Apoptosis Area Automobile Driving Benign Biological Biological Assay Biological Markers Breast Cancer Cell Breast Cancer Genetics Breast Cancer Treatment Breast Cancer cell line Breast Epithelial Cells Cancer Etiology Cancer Patient Cell Cycle Cell Proliferation Cell fusion Cell model Cells Chimera organism Chromosomal translocation Clinical Cytogenetics DNA Sequence Rearrangement Darkness Data Data Analyses Data Set Dependence Drug Targeting ESR1 gene Ectopic Expression Endocrine Engineering Epithelial Estrogen Receptors Estrogen receptor positive Event GAB1 gene Gene Fusion Genes Genetic Genetic Transcription Genomics Image In Vitro Incidence Lead Light Malignant Neoplasms Malignant neoplasm of lung Mammary Neoplasms Mass Spectrum Analysis Modeling Molecular Monitor Mus Neoplasm Metastasis Oncogenic Open Reading Frames Oral Pathologic Pathway interactions Patient Selection Patient-Focused Outcomes Patients Pharmaceutical Preparations Phase Phenotype Play Population Protein Array Proteins Proteomics Receptor Gene Recurrence Recurrent tumor Resistance Reverse Transcription Role Signal Pathway Signaling Molecule Solid Neoplasm Techniques Testing Time Tissues Transcript Transplantation Universities Variant Western Blotting Xenograft procedure base biomarker selection breast tumorigenesis cancer genome cancer initiation cancer type cell motility clinically relevant cohort foot gene discovery gene translocation genome sequencing genomic data genomic profiles hormone therapy in vivo individualized medicine innovation knock-down leukemia lymph nodes malignant breast neoplasm mouse model nano-string neoplastic new therapeutic target next generation sequencing non-genomic overexpression public health relevance scaffold small hairpin RNA success therapy resistant transcriptome sequencing tumor tumor progression tumorigenesis ultra high resolution whole genome

项目摘要

DESCRIPTION (provided by applicant): Gene fusions resulting from chromosome translocations are a crucial class of genetic aberrations causing cancer, which have provided treatment targets for a number of cancer types. However, neoplastic gene fusions have not yet been found in the vast majority of estrogen receptor (ER) positive breast cancers. Recently, the cancer genome projects released a large quantity of next-generation sequencing and genomic data for this cancer. Analysis of these data revealed about half of the somatic translocations to be between adjacent or nearly adjacent genomic loci. This finding suggests that these somatic adjacent gene translocations (AGTs) may be far more common than realized, and we speculate that a subset of these AGTs could be pathological events in breast cancer. Indeed, one neoplastic AGT has already been discovered in our preliminary studies, which involves the estrogen receptor gene, ESR1, and a neighboring gene, CCDC170. This fusion endows tumor aggressiveness and endocrine resistance, and appears to be frequent in the most deadly subtype of ER+ breast cancer, luminal B, that is particularly hard to clinically define or manage. We thus hypothesize that ESR1-CCDC170 and other recurrent AGTs may play a crucial role in breast cancer initiation, progression, or therapeutic resistance. The following studies are proposed to test the hypothesis: Aim 1 will further study the role of ESR1-CCDC170 in breast cancer progression, invasion, and endocrine resistance using in vitro knockdown and overexpression models, and will explore the engaged pathways and key effectors by systematic proteomic studies and focused mechanistic studies. Aim 2 will establish the incidence of ESR1-CCDC170 in ER+ breast cancer by interrogating independent patient cohorts, elucidate its clinicopathological relevance, and substantiate its role in tumor formation, metastasis, and endocrine resistance in the in vivo context. Aim 3 will systematically discover new AGTs in breast cancer by integrative analysis of several kinds of genomic profiling and next generation sequencing datasets. We will dissect out true recurrent AGTs driving breast cancer, determine their incidence, and investigate their genetic origins and mechanisms of action. Successful accomplishment of this project may uncover a dark area of breast cancer genetics. Transcripts resulting from AGTs are usually submerged in the overwhelming number of non-genomic transcription-induced chimeras (TICs), whereas conventional cytogenetic assays are insensitive to such close-range translocations. Thus AGTs could have been largely overlooked by the previous gene fusion screens. The new AGTs revealed by this study will not only shed new light on the genetic causes of breast cancer, but will also provide new biomarkers for the prediction of patient outcome and individualized therapy, and attractive drug targets for new and specific breast cancer treatment.

描述（由申请人提供）：由染色体易位产生的基因融合是导致癌症的一类关键的遗传畸变，它为多种癌症类型提供了治疗靶点。然而，在绝大多数雌激素受体（ER）阳性乳腺癌中尚未发现肿瘤性基因融合。近期，癌症基因组计划发布了大量该癌症的下一代测序和基因组数据。对这些数据的分析表明，大约一半的体细胞易位发生在相邻或几乎相邻的基因组基因座之间。这一发现表明，这些体细胞邻近基因易位（AGT）可能比我们想象的要常见得多，我们推测这些 AGT 的一部分可能是乳腺癌中的病理事件。事实上，我们的初步研究中已经发现了一种肿瘤性 AGT，它涉及雌激素受体基因 ESR1 和邻近基因 CCDC170。这种融合赋予了肿瘤侵袭性和内分泌抵抗力，并且似乎在最致命的 ER+ 乳腺癌亚型 Luminal B 中很常见，这种亚型在临床上特别难以定义或管理。因此，我们假设 ESR1-CCDC170 和其他复发性 AGT 可能在乳腺癌的发生、进展或治疗耐药中发挥关键作用。提出以下研究来检验这一假设：目标 1 将利用体外敲低和过表达模型进一步研究 ESR1-CCDC170 在乳腺癌进展、侵袭和内分泌抵抗中的作用，并通过系统方法探索其参与途径和关键效应因子。蛋白质组学研究和重点机制研究。目标 2 将通过询问独立的患者队列来确定 ESR1-CCDC170 在 ER+ 乳腺癌中的发病率，阐明其临床病理学相关性，并证实其在体内肿瘤形成、转移和内分泌抵抗中的作用。目标3将通过对多种基因组图谱和下一代测序数据集的综合分析，系统地发现乳腺癌中的新AGT。我们将剖析导致乳腺癌的真正复发性 AGT，确定其发病率，并研究其遗传起源和作用机制。该项目的成功完成可能会揭示乳腺癌遗传学的一个黑暗领域。 AGT 产生的转录本通常淹没在大量非基因组转录诱导嵌合体 (TIC) 中，而传统的细胞遗传学分析对这种近距离易位不敏感。因此，AGT 可能在很大程度上被之前的基因融合筛选所忽视。这项研究揭示的新AGT不仅将为乳腺癌的遗传原因提供新的线索，而且还将为预测患者预后和个体化治疗提供新的生物标志物，并为新的和特定的乳腺癌治疗提供有吸引力的药物靶点。