A novel approach for the non-invasive diagnosis of pulmonary nodules using low-depth whole-genome sequencing of cell-free DNA

Abstract

Background: Differentiating between benign and malignant pulmonary nodules is a diagnostic challenge, and inaccurate detection can result in unnecessary invasive procedures. Cell-free DNA (cfDNA) has been successfully utilized to detect various solid tumors. In this study, we developed a genome-wide approach to explore the characteristics of cfDNA sequencing reads obtained by low-depth whole-genome sequencing (LD-WGS) to diagnose pulmonary nodules.Methods: LD-WGS was performed on cfDNA extracted from 420 plasma samples from individuals with pulmonary nodules that were no more than 30 mm in diameter, as determined by computed tomography (CT). The sequencing read distribution patterns of cfDNA were analyzed and used to establish a model for distinguishing benign from malignant pulmonary nodules.Results: We proposed the concept of weighted reads distribution difference (WRDD) based on the copy number alterations (CNAs) of cfDNA to construct a benign and malignant diagnostic (BEMAD) algorithm model. In a training cohort of 360 plasma samples, the model achieved an average area under the receiver operating characteristic (ROC) curve (AUC) value of 0.84 in 10-fold cross-validation. The model was validated in an independent cohort of 60 plasma samples, obtaining an AUC value of 0.87. The BEMAD model could distinguish benign from malignant nodules at a sensitivity of 74% and a specificity of 86%.Furthermore, analysis of the critical features of the cfDNA using the BEMAD model identified repeat regions that were associated with microsatellite instability, which is an important indicator of tumorigenesis.

Liquid Biopsy in Clinical Oncology

“…Янус работ в данной области является поиск отдельных разновидностей опухолей в группах высокого риска -больных с наследственными опухолевыми синдромами, хронических курильщиков с большим стажем употребления табака и т.д. [43,44].…”

DNA‐Guided Extracellular‐Vesicle Metallization with High Catalytic Activity for Accurate Diagnosis of Pulmonary Nodules

“…Recent circulating tumor cells (CTCs), cell-free (cfDNA), and microRNAs have proven to be useful in the identification of malignant nodules from benign ones. [7,[9][10][11][12][13] Nevertheless, methods for analyzing them often require advanced apparatus to perform complicated assays and data processing, because of the extreme scarcity of CTCs and cfDNA in the bloodstream and the high sequence homology of microRNAs. [14,15] Extracellular vesicles (EVs) are lipid-membrane-enclosed vesicles 30-1000 nm in diameter, which are secreted by most mammalian cells and circulate in various body fluids.…”