CHARACTERIZATION OF RECURRENT ADJACENT GENE TRANSLOCATIONS IN BREAST CANCER

描述(由申请人提供)：由染色体易位引起的基因融合是导致癌症的一种重要的遗传异常，它为许多类型的癌症提供了治疗靶点。然而，在绝大多数雌激素受体(ER)阳性的乳腺癌中，尚未发现肿瘤基因融合。最近，癌症基因组计划公布了大量关于这种癌症的下一代测序和基因组数据。对这些数据的分析揭示了大约一半的体细胞易位是在相邻或几乎相邻的基因组座位之间进行的。这一发现表明，这些体细胞相邻基因易位(AGT)可能比人们意识到的要常见得多，我们推测这些AGT的子集可能是乳腺癌的病理事件。事实上，在我们的初步研究中已经发现了一种肿瘤AGT，它涉及雌激素受体基因ESR1和邻近的基因CCDC170。这种融合赋予了肿瘤侵袭性和内分泌抵抗力，似乎在最致命的ER+乳腺癌亚型--腔B癌中常见，这种亚型在临床上特别难定义或处理。因此，我们假设ESR1-CCDC170和其他复发的AGT可能在乳腺癌的发生、发展或治疗耐药中发挥关键作用。目的1利用体外基因敲除和过表达模型进一步研究ESR1-CCDC170在乳腺癌进展、侵袭和内分泌耐药中的作用，并通过系统的蛋白质组学研究和集中的机制研究来探索参与的途径和关键的效应因子。目的2通过询问独立的患者队列，确定ESR1-CCDC170在ER+乳腺癌中的发生率，阐明其临床病理相关性，并在体内证实其在肿瘤形成、转移和内分泌耐药中的作用。目的3将通过对几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新的AGT。我们将解剖导致乳腺癌的真正复发的AGT，确定它们的发病率，并调查它们的遗传来源和作用机制。这一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产生的转录本通常被淹没在绝大多数非基因组转录诱导的嵌合体(TICs)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在很大程度上可能被以前的基因融合筛查所忽视。这项研究揭示的新的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。

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.