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Optimizing Ultrasensitive DNA methylation detection for lung cancer and other malignancies

优化肺癌和其他恶性肿瘤的超灵敏 DNA 甲基化检测

基本信息

批准号：
10705752
负责人：
JAMES G. HERMAN
金额：
$ 87.97万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2022-09-16 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10705752
关键词：
Address Age Apoptotic Benign Bioinformatics Biological Biological Assay Biological Markers Blood Cancer Detection Cancer Diagnostics Cancer Etiology Categories Cessation of life Classification Clinical Clinical Pathology Communication Complement DNA DNA Markers DNA Methylation DNA Sequence DNA analysis Data Detection Diagnosis Diagnostic Procedure Diameter Dreams Early Detection Research Network Early Diagnosis Event Frequencies Funding Genes Goals Healthcare High Prevalence Histology Human Hypermethylation Laboratories Lung Lung Neoplasms Lung nodule Malignant Neoplasms Malignant neoplasm of lung Measures Methods Methylation Molecular Necrosis Nodule Nucleic Acids Organ Participant Patients Performance Plasma Population Preparation Process Prospective cohort Protocols documentation Radiology Specialty Reagent Reporting Reproducibility Research Personnel Risk Sampling Screening for cancer Sensitivity and Specificity Signal Transduction Site Source Specimen Standardization Testing The Cancer Genome Atlas Time United States Work biomarker development bisulfite cell free DNA circulating DNA clinical practice cohort computed tomography screening cost detection assay detection method detection platform improved laboratory development lung cancer screening methylation biomarker mortality neoplastic cell novel novel strategies operation prospective screening tumor tumor DNA wasting

项目摘要

This proposal for a Biomarker Characterization Center (BCC) for the Early Detection Research Network (EDRN) seeks to improve the management of lung cancer through detection of cancer- specific DNA methylation. This effort includes a Biomarker Development Laboratory (BDL) which will optimize the methylation detection methods, implementation of these methods for clinical use through a Biomarker Reference Laboratory (BRL) with a longstanding record of molecular testing in a clinical setting, and an Administrative Core facilitating the interactions between the BDL and BRL, and with other EDRN investigators and the NCI. Previous work by the applicants has demonstrated the potential of DNA methylation detection for cancer diagnostics, and they have developed extremely sensitive assays for the detection of hypermethylated DNA sequences and optimized the isolation and processing of circulating cell-free DNA from tumors for these novel assays. The approach has been used to detect circulating cancer-specific DNA methylation changes for the early diagnosis of lung cancer in patients with screen-detected pulmonary nodules. Although sensitivity and specificity of the assay are promising, additional improvements in the performance are required for implementation of this approach in the setting of cancer screening. In this BCC, detection of cancer-specific DNA methylation changes in the plasma will be further improved, and new approaches developed and implemented to address the challenges of ultrasensitive detection of DNA methylation in the blood. In addition, we will assess the potential of these methods to detect other common and lethal malignancies. Our bioinformatic analysis of DNA methylation from The Cancer Genome Atlas (TCGA) has identified novel highly frequent cancer-specific methylation events common to all cancers, including lung cancer, that will be developed into universal cancer detection assays. The use of TCGA data has also resulted in the identification of other methylation alterations that allow determination of the origin (organ site) of this cancer-specific signal. The combination of optimal sample processing, ultrasensitive methylation detection, developed with universal cancer and histology specific loci detection, will allow improved lung cancer early detection in the setting of CT screening and management of detection of other cancer-specific DNA methylation from blood.

这一建议的生物标志物表征中心（BCC）的早期检测研究网络（EDRN）旨在通过检测癌症来改善肺癌的管理- DNA甲基化。这项工作包括一个生物标志物开发实验室（BDL），将优化甲基化检测方法，实现这些方法的临床应用通过具有长期分子检测记录的生物标志物参考实验室（BRL）在临床环境中，以及促进BDL与 BRL，以及其他EDRN调查人员和NCI。申请人以前的工作证明了DNA甲基化检测在癌症诊断中的潜力，开发了用于检测高甲基化DNA序列的极其灵敏的测定方法，优化了从肿瘤中分离和处理循环无细胞DNA的方法，测定。该方法已被用于检测循环癌症特异性DNA甲基化肺癌早期诊断中的变化结节尽管该测定的灵敏度和特异性是有希望的，但额外的改进是可行的。在癌症的情况下实施这种方法所需的性能筛选在这种BCC中，检测血浆中的癌症特异性DNA甲基化变化将进一步改进，并制定和执行新的办法，以应对挑战对血液中DNA甲基化的超灵敏检测。此外，我们还将评估这些方法来检测其他常见和致命的恶性肿瘤。我们的生物信息学分析来自癌症基因组图谱（TCGA）的DNA甲基化已经确定了新的高度频繁的癌症特异性甲基化事件常见于所有癌症，包括肺癌，发展成通用的癌症检测方法。TCGA数据的使用也导致了鉴定其他甲基化改变，从而可以确定这种癌症特异性信号。结合最佳的样品处理，甲基化检测，与通用癌症和组织学特异性位点检测一起开发，将允许在CT筛查和管理的背景下改善肺癌的早期检测。从血液中检测其他癌症特异性DNA甲基化。