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.

项目摘要/摘要 非功能性胰神经内分泌肿瘤（NF-Pannets）是一组异质的肿瘤，随着增加 发病率和不确定的病理学。虽然许多NF-Pannets懒惰并且保持稳定多年，但很重要 子集的行为可能会积极进展并广泛转移。因此，NF-Pannets的增加和频繁检测 提出治疗困境。当前的预后参数和系统容易出现解释错误，采样 问题，并且不能准确反映这些肿瘤的临床行为。因此，需要其他生物标志物 改善NF-Pannets患者的预后分层。以前，我们和其他人报告了经常性 ATRX和DAXX中的基因组改变与NF-Pannets的转移性进展有关。其中的突变 基因导致其各自蛋白质的丧失，并与端粒的替代延长（ALT）相吻合，A 端粒酶无关的维护机制。我们还表明，ATRX/DAXX和ALT的损失与 转移的发展是用于较短无病生存的预后生物标志物，并且独立于其他 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。但是，他们 尚未对前瞻性或术前标本进行评估，而预后分层对患者很重要 管理。另外，只有50％的转移性NF型孔伴有ATRX/DAXX的灭活和存在 alt。为了识别其他生物标志物，我们最近介绍了ATRX/DAXX野生型转移性NF-Pannets，并报告了 与ATRX和DAXX相似的SetD2/H3K36me3和ARID1A的复发变化是调节基因的染色质。 因此，我们假设NF-Pannets的转移进展为特征是染色质的变化 调节并确定关键的基因组和表观基因组标志不仅会改善预后分层 NF-Pannets的患者，但可以提高我们对这种日益普遍疾病的发病机理的理解。 AIM 1将是开发和临床验证NF-Pannets的术前预后生物标志物测定法。通过两者 回顾性和前瞻性研究，我们将确定AT​​RX，DAXX，DAXX的预后性能和意义 Alt，H3K36me3和ARID1A。对于AIM 2，我们计划在不同表观遗传状态下定义染色质模式 NF-Pannets的转移进展。考虑ATRX，DAXX，SETD2和ARID1A是染色质调节剂，我们将 使用纳米级染色质结构评估纳米​​级染色质结构，并使用各种NF-Pannet状态的分子途径影响 路径风暴和切割/RNA-seq分析。最后，AIM 3将研究ATRX/DAXX的自适应响应 灭活和替代启动。我们发现组蛋白伴侣HIRA可以重新构建端粒染色质 ATRX/DAXX缺陷型ALT癌细胞的功能。在此目标中，我们将描述HIRA在调节中的作用 端粒完整性，染色质和转录。总体而言，该建议将导致开发临床上可用的 患者管理的测定，洞察病理学染色质结构变化并识别新颖 驱动因素/途径不仅是NF-Pannets，而且可能是其他与Alt相关的肿瘤。