The Prognostic Significance and Mechanistic Determination of Chromatin Remodeling Biomarkers in Non-Functional Pancreatic Neuroendocrine Tumor

非功能性胰腺神经内分泌肿瘤染色质重塑生物标志物的预后意义和机制确定

• 批准号: 10451759
• 负责人: Aatur Dilip Singhi
• 金额: $ 59.71万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10451759
• 关键词: ARID1A gene; ATRX gene; Abdomen; Address; Affect; Autopsy; Behavior; Biological Assay; Biological Markers; Cells; Cessation of life; Chromatin; Chromatin Structure; Clinical; Common Neoplasm; DAXX gene; DNA Sequence Alteration; Detection; Development; Disease; Disease-Free Survival; Distant Metastasis; Epigenetic Process; Excision; Gene Expression Regulation; Genes; Genetic Transcription; Genomics; Goals; High Prevalence; Histone H3; Histones; Incidence; Individual; Indolent; International; Islet Cell Tumor; Lead; Maintenance; Metastatic to; Methods; Molecular; Molecular Chaperones; Mutation; Neoplasm Metastasis; Neoplasms; Nonmetastatic; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Pattern; Play; Postoperative Period; Prognostic Marker; Prospective Studies; Proteins; Proteomics; Recurrence; Regulation; Regulator Genes; Reporting; Resolution; Retrospective Studies; Role; Sampling; Specimen; Staging System; Stratification; System; Telomerase; Testing; United States; Validation; cancer cell; chromatin remodeling; clinical implementation; clinically significant; cohort; epigenomics; imaging modality; improved; innovation; insight; nanoscale; neoplastic cell; novel; overtreatment; pancreatic neoplasm; patient biomarkers; patient prognosis; patient stratification; patient subsets; prognostic; prognostic assays; prognostic performance; prognostic significance; prospective; radiological imaging; reconstitution; research clinical testing; response; telomere; transcriptome sequencing; tumor; tumor progression; validation studies

Project Summary/Abstract Non-functional pancreatic neuroendocrine tumors (NF-PanNETs) are a heterogeneous group of neoplasms with increasing incidence and ill-defined pathobiology. While many NF-PanNETs are indolent and remain stable for years, a significant subset may behave aggressively and metastasize widely. Thus, the increasing and frequent detection of NF-PanNETs presents a treatment dilemma. Current prognostic parameters and systems are susceptible to interpretation errors, sampling issues, and do not accurately reflect the clinical behavior of these neoplasms. Hence, additional biomarkers are needed to improve the prognostic stratification of patients with NF-PanNETs. Previously, we and others have reported recurrent genomic alterations in ATRX and DAXX are associated with metastatic progression of NF-PanNETs. Mutations in these genes result in loss of their respective proteins and coincide with the alternative lengthening of telomeres (ALT), a telomerase-independent maintenance mechanism. We have also shown that loss of ATRX/DAXX and ALT correlate with the development of metastases, are prognostic biomarkers for shorter disease-free survival and are independent of other prognostic clinicopathologic parameters. Thus, ATRX/DAXX and ALT represent promising biomarkers. However, they have not been evaluated prospectively nor in preoperative specimens, where prognostic stratification is important for patient management. In addition, only 50% of metastatic NF-PanNETs harbor inactivation of ATRX/DAXX and the presence of ALT. To identify additional biomarkers, we recently profiled ATRX/DAXX wild type metastatic NF-PanNETs and reported recurrent alterations in SETD2/H3K36me3 and ARID1A, which similar to ATRX and DAXX are chromatin regulating genes. We therefore hypothesize that the metastatic progression of NF-PanNETs is characterized by changes in chromatin regulation and determining the key genomic and epigenomic hallmarks will not only improve the prognostic stratification of patients with NF-PanNETs, but advance our understanding of the pathogenesis of this increasingly prevalent disease. Aim 1 will be to develop and clinically validate preoperative prognostic biomarker assays for NF-PanNETs. Through both retrospective and prospective studies, we will determine the prognostic performance and significance of ATRX, DAXX, ALT, H3K36me3 and ARID1A. For Aim 2, we plan to define the chromatin patterns at different epigenetic states in the metastatic progression of NF-PanNETs. Considering ATRX, DAXX, SETD2 and ARID1A are chromatin regulators, we will evaluate the nanoscale chromatin structure and affected molecular pathways of various NF-PanNET states using PathSTORM and CUT&RUN/RNA-seq assays. Finally, Aim 3 will investigate the adaptive response of ATRX/DAXX inactivation and ALT initiation. We have discovered that the histone chaperone, HIRA, can reconstitute telomeric chromatin and function of ATRX/DAXX deficiency ALT cancer cells. Within this aim, we will delineate the role of HIRA in regulating telomeric integrity, chromatin and transcription. Overall, this proposal will lead to the development of a clinically available assay for patient management, insight in the pathognomonic chromatin structural changes and identify novel drivers/pathways for not only NF-PanNETs, but likely other ALT-associated neoplasms.

项目总结/摘要 非功能性胰腺神经内分泌肿瘤（NF-PanNETs）是一组异质性肿瘤， 发病率和不明确的病理生物学。虽然许多NF-PanNET是惰性的，并且多年来保持稳定，但重要的是， 亚群可能表现为攻击性并广泛转移。因此，NF-PanNET的增加和频繁检测 呈现出治疗上的困境。目前的预测参数和系统容易受到解释错误、抽样 问题，并不能准确反映这些肿瘤的临床行为。因此，需要额外的生物标志物， 改善NF-PanNET患者的预后分层。以前，我们和其他人报告说， ATRX和DAXX的基因组改变与NF-PanNET的转移进展相关。这些基因突变 基因导致其各自蛋白质的丢失，并与端粒（ALT）的交替延长相一致， 端粒酶独立的维持机制。我们还发现ATRX/DAXX和ALT的缺失与 转移的发展，是较短的无病生存期的预后生物标志物，并且独立于其他肿瘤标志物。 预后临床病理参数。因此，ATRX/DAXX和ALT代表有希望的生物标志物。但他们 尚未进行前瞻性评估，也未在术前标本中进行评估，其中预后分层对患者很重要 管理此外，只有50%的转移性NF-PanNET具有ATRX/DAXX的失活和ATRX/DAXX的存在。 备选.为了鉴定其他生物标志物，我们最近分析了ATRX/DAXX野生型转移性NF-PanNET，并报道了 SETD 2/H3 K36 me 3和ARID 1A的重复变异与ATRX和DAXX相似，是染色质调节基因。 因此，我们假设NF-PanNETs的转移进展的特征是染色质的变化， 调控和确定关键的基因组和表观基因组标志不仅可以改善预后分层， NF-PanNETs患者，但推进我们对这种日益流行的疾病的发病机制的理解。 目的1将是开发和临床验证NF-PanNET的术前预后生物标志物测定。通过两 回顾性和前瞻性研究，我们将确定ATRX，DAXX， ALT、H3 K36 me 3和ARID 1A。对于目标2，我们计划定义不同表观遗传状态下的染色质模式， NF-PanNET的转移进展。考虑到ATRX、DAXX、SETD 2和ARID 1A是染色质调节因子，我们将 评估纳米级染色质结构和各种NF-PanNET状态的受影响分子途径， PathSTORM和CUT&RUN/RNA-seq测定。最后，目标3将研究ATRX/DAXX的自适应响应 灭活和ALT启动。我们已经发现组蛋白伴侣蛋白HIRA可以重建端粒染色质 ATRX/DAXX缺陷ALT癌细胞的功能。在此目标下，我们将描述HIRA在调节 端粒完整性、染色质和转录。总的来说，这一提议将导致开发一种临床可用的 用于患者管理的测定，了解特异性染色质结构变化并鉴定新的 不仅是NF-PanNET，而且可能是其他ALT相关肿瘤的驱动因子/途径。