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关键一类遗传畸变，其为许多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基因融合。最近，癌症基因组计划公布了大量的下一代测序和这种癌症的基因组数据。对这些数据的分析揭示了大约一半的体细胞易位发生在相邻或几乎相邻的基因组位点之间。这一发现表明，这些体细胞相邻基因易位（AGTs）可能比意识到的要普遍得多，我们推测这些AGTs的一个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。这种融合赋予肿瘤侵袭性和内分泌抗性，并且似乎在ER+乳腺癌的最致命亚型管腔型B中频繁发生，这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、进展或治疗耐药性中起关键作用。本研究拟通过以下研究来验证这一假设：目的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、侵袭和内分泌耐药中的作用，并将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效应物。 目的2将通过询问独立患者队列，确定ER+乳腺癌中ESR1-CCDC 170的发生率，阐明其临床病理学相关性，并证实其在体内肿瘤形成、转移和内分泌耐药中的作用。 目的3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新的AGTs。我们将解剖出真正的复发性AGTs驱动乳腺癌，确定其发病率，并调查其遗传起源和作用机制。 该项目的成功完成可能会揭开乳腺癌遗传学的一个黑暗领域。AGT产生的转录物通常淹没在绝大多数非基因组转录诱导的嵌合体（TIC）中，而常规的细胞遗传学检测对这种近距离易位不敏感。因此，AGTs可能在很大程度上被以前的基因融合筛选所忽视。这项研究揭示的新AGTs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结局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.