HRD-IA signatures in pancreatic ductal adenocarcinoma

胰腺导管腺癌中的 HRD-IA 特征

基本信息

批准号：
10515859
负责人：
Michael T Barrett
金额：
$ 31万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10515859
关键词：
Address American Aneuploidy BRCA mutations BRCA1 gene BRCA2 gene Base Excision Repairs Biological Assay Biological Models Biopsy CLIA certified Cancer Etiology Cells Cellularity Cessation of life Chemotherapy-Oncologic Procedure Chromosome abnormality Clinic Clinical Clinical Research Clinical Trials Complex Copy Number Polymorphism DNA Damage DNA Double Strand Break DNA Repair Development Diagnosis Disease Environment Flow Cytometry Formalin Freezing Genome Genomic Instability Genomics Genotype Lesion Malignant Neoplasms Measures Mediating Mediator of activation protein Methods Molecular Morphology Nature Necrosis PALB2 gene Pancreatic Ductal Adenocarcinoma Paraffin Embedding Pathogenicity Patients Phase Phenotype Ploidies Poly(ADP-ribose) Polymerases Population Prediction of Response to Therapy Procedures Protocols documentation Publishing Quality Control Research Resistance Resources Sampling Series Solid Neoplasm Sorting - Cell Movement Tissue Embedding Tissues Variant Work base brca gene cancer cell cancer genome chemotherapy clinical application clinically relevant detection assay genome analysis genomic aberrations genomic signature homologous recombination inhibitor interstitial neoplastic neoplastic cell novel patient biomarkers patient response personalized medicine predictive signature prospective response standard of care targeted agent targeted treatment triple-negative invasive breast carcinoma tumor whole genome

项目摘要

ABSTRACT Tumors deficient in homologous recombination display high levels of copy number variants (CNVs) including amplifications, deletions, and breakpoints in their genomes. This homologous recombination deficiency (HRD) phenotype has been associated with pathogenic BRCA mutations in multiple cancers and can be exploited clinically through a synthetic lethal interaction with agents, such as inhibitors of poly ADP- ribose polymerase (PARP) and chemotherapy regimens such as FOLFIRINOX, that increase the level of DNA damage in tumor genomes. Strikingly, subsets of tumors that are wild type for BRCA1 and BRCA2 have shown similar clinical responses to these agents. Preliminary studies suggest that responder tumors have elevated numbers of genomic aberrations even in the absence of variants in the BRCA genes or in other mediators of homologous recombination mediated DNA repair (e.g. PALB2, ATM, and BRIP1). Thus the nature and extent of these lesions in tumor genomes, regardless of genotype, provides a biomarker for patients who will respond to DNA damage and repair targeting therapies. It is estimated that in 2019, 56,770 Americans will be diagnosed with pancreatic ductal adenocarcinoma (PDA) and 45,750 will die from the disease, making PDA the third most common cause of cancer death. Recent clinical trials have made modest improvements in overall survival. Studies suggest that similar to other tumors, elevated numbers of chromosomal aberrations define a HRD signature in a subset of PDAs. A fundamental hypothesis is that this genomic signature predicts those PDA patients likely to respond to PARP inhibitors and to DNA damaging agents. However PDA biopsies are difficult to characterize due to complex genomes and heterogeneous cellularity, as cancer cells represent on average only 25% of the cells within the tumor. Furthermore, biopsies frequently contain multiple neoplastic populations that cannot be distinguished by morphology based methods. To address these clinical challenges we validated DNA content based flow sorting of PDA tissues. Our published methods yield highly purified (>95%) samples suitable for whole genome analyses from a variety of clinical samples. These include both fresh frozen and formalin fixed paraffin embedded (FFPE) tissues with low tumor cell content (<10-20%) and high amounts (>90%) of necrosis and debris. We have identified PDAs with extensive numbers of interstitial aberrations (IAs) in their genomes similar to those observed in HRD-positive BRCAmut tumors. Our results suggest that elevated numbers of IAs correlate with clinical response in PDA. In this study we will establish analytical and processing procedures for our HRD-IA assay then establish a score that distinguishes HRD+ BRCAmut tumors. We will then exploit samples treated with FOLFIRINOX to validate the application of our HRD-IA assay to identify those PDA patients, BRCAmut and BRCAwt, who respond to DNA damage targeting agents. The final phase of this work will validate our sorting and CNV based HRD-IA assay for CLIA application and clinical use.

摘要缺乏同源重组的肿瘤表现出高水平的拷贝数变异（CNV），包括基因组中的扩增、缺失和断点。这种同源重组缺陷（HRD）表型与多种癌症中的致病性 BRCA 突变有关可以通过与药物（例如聚 ADP-抑制剂）的合成致死相互作用在临床上利用核糖聚合酶 (PARP) 和化疗方案（例如 FOLFIRINOX）可提高 DNA 水平肿瘤基因组的损伤。引人注目的是，BRCA1 和 BRCA2 野生型肿瘤子集已显示对这些药物的类似临床反应。初步研究表明，反应性肿瘤已升高即使在 BRCA 基因或其他介导物中不存在变异的情况下，基因组畸变的数量同源重组介导的 DNA 修复（例如 PALB2、ATM 和 BRIP1）。因此性质和程度无论基因型如何，肿瘤基因组中这些病变的数量都为患者提供了生物标志物响应 DNA 损伤和修复靶向治疗。预计2019年将有56,770名美国人被诊断出胰腺导管腺癌 (PDA) 和 45,750 人将死于该疾病，使 PDA 成为癌症死亡的第三大常见原因。最近的临床试验在总体生存率方面取得了一定的改善。研究表明，类似于在其他肿瘤中，染色体畸变数量的增加定义了 PDA 子集中的 HRD 特征。一个基本假设是，这种基因组特征可以预测那些可能对 PDA 患者做出反应的 PDA 患者。 PARP 抑制剂和 DNA 损伤剂。然而，PDA 活检很难表征，因为复杂的基因组和异质细胞结构，因为癌细胞平均仅占细胞的 25% 肿瘤内。此外，活组织检查经常包含多个肿瘤群体，而这些肿瘤群体无法被通过基于形态学的方法来区分。为了应对这些临床挑战，我们验证了 DNA 含量基于PDA组织的流式分选。我们发布的方法可产生高度纯化 (>95%) 的样品，适用于来自各种临床样本的全基因组分析。这些包括新鲜冷冻和福尔马林固定石蜡包埋 (FFPE) 组织，肿瘤细胞含量低 (<10-20%)，坏死量高 (>90%) 和碎片。我们已经鉴定出 PDA 的基因组中存在大量的间质畸变 (IA) 与 HRD 阳性 BRCAmut 肿瘤中观察到的结果相似。我们的结果表明，IA 数量增加与 PDA 的临床反应相关。在本研究中，我们将建立分析和处理程序然后，我们的 HRD-IA 测定建立了区分 HRD+ BRCAmut 肿瘤的评分。然后我们将利用用 FOLFIRINOX 处理的样品，以验证我们的 HRD-IA 测定法在识别这些 PDA 方面的应用 BRCAmut 和 BRCAwt 患者对 DNA 损伤靶向药物有反应。这项工作的最后阶段将验证我们的分选和基于 CNV 的 HRD-IA 测定在 CLIA 应用和临床中的应用。