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：
10551899
负责人：
Michael T Barrett
金额：
$ 33.04万
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/10551899
关键词：
Acceleration Address American Aneuploidy BRCA mutations BRCA1 gene BRCA2 gene Base Excision Repairs Biological Assay Biological Models Biopsy CLIA certified Calibration 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 DNA Repair Inhibition Development Diagnosis Disease Environment Flow Cytometry Formalin Freezing Genome Genomic Instability Genomics Genotype Lesion Malignant Neoplasms Measures Mediating Mediator Methods Molecular Morphology Nature Necrosis PALB2 gene Pancreatic Ductal Adenocarcinoma Paraffin Embedding Pathogenicity Patients Phase Phenotype Ploidies Poly(ADP-ribose) Polymerase Inhibitor Population Prediction of Response to Therapy Procedures Protocols documentation Publishing Quality Control Research Resistance Resources Sampling Series Solid Neoplasm Sorting Tissue Embedding Tissues Variant Work brca gene cancer cell cancer genome chemotherapy clinical application clinically relevant detection assay genome analysis genomic aberrations genomic signature homologous recombination improved interstitial neoplastic neoplastic cell novel patient biomarkers patient response personalized medicine predictive signature predictive test prospective response standard of care synthetic lethal interaction 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.

缺乏同源重组的抽象肿瘤显示高水平的拷贝数变体（CNV），包括其基因组中的扩增，缺失和断点。这种同源重组缺乏症（HRD）表型与多种癌症的致病性BRCA突变有关，并且可以通过与药物的合成致命相互作用（例如聚ADP-的抑制剂）进行临床利用核糖聚合酶（PARP）和化学疗法治疗方案（例如Folfirinox）增加了DNA水平肿瘤基因组的损害。令人惊讶的是，已经显示了BRCA1和BRCA2野生型肿瘤的子集对这些药物的类似临床反应。初步研究表明响应者肿瘤升高即使在BRCA基因中没有变体或其他介体中，基因组畸变的数量也同源重组介导的DNA修复（例如PALB2，ATM和BRIP1）。因此本质和程度在肿瘤基因组中的这些病变中，无论基因型如何应对DNA损伤并修复靶向疗法。据估计，在2019年，将被诊断出56,770名美国人患有胰腺导管腺癌（PDA）和45,750将死于该疾病，使PDA成为癌症死亡的第三大最常见原因。最近的临床试验使整体生存率得到了适度的改善。研究表明类似其他肿瘤，染色体畸变的数量升高会在PDA的一部分中定义了HRD签名。一个基本的假设是，该基因组签名预测了那些可能对的PDA患者 PARP抑制剂和DNA破坏剂。但是，由于PDA活检很难表征复杂的基因组和异质细胞性，因为癌细胞平均仅代表25％的细胞在肿瘤内。此外，活检经常包含多个肿瘤种群由基于形态学的方法区分。为了应对这些临床挑战，我们验证了DNA含量基于PDA组织的流动分选。我们发表的方法产生高度纯化（> 95％）样本适合整个基因组分析了各种临床样本。这些包括固定的新鲜冷冻和福尔马林肿瘤细胞含量低（<10-20％）和高量（> 90％）坏死的石蜡（FFPE）组织（FFPE）组织和碎片。我们已经确定了其基因组中大量间质畸变（IAS）的PDA 与HRD阳性BRCAMUT肿瘤中观察到的类似。我们的结果表明IAS数量升高与PDA中的临床反应相关。在这项研究中，我们将建立分析和处理程序然后，我们的HRD-IA分析建立了区分HRD+ BRCAMUT肿瘤的分数。然后我们将利用用folfirinox处理的样品以验证我们的HRD-IA分析的应用以识别这些PDA 对DNA损伤靶向剂的反应的患者Brcamut和Brcawt。这项工作的最后阶段将验证我们的分类和基于CNV的HRD-IA测定法，以供CLIA应用和临床使用。