A method for early diagnosis of lung cancer from tumor originated DNA fragments using plasma cfDNA methylome and fragmentome profiles. (December 2022)

• Record Type: Journal Article
• Authors: Kim, Yeo Jin; Jeon, Hahyeon; Jeon, Sungwon; Lee, Sung-Hun; Kim, Changjae; Ahn, Ji-Hye; Um, Hyojin; Woo, Yeong Ju; Jeong, Seong-ho; Kim, Yeonkyung; Park, Ha-Young; Oh, Hyung-Joo; Cho, Hyun-Ju; Bae, Jin-Han; Kim, Ji-Hoon; An, Seolbin; Kang, Sung-Bong; Jho, Sungwoong; Biro, Orsolya; Kis, David; Kim, Byung Chul; Kim, Yumi; Kim, Jae Hyun; Kim, Byoung-Chul; Bhak, Jong; Oh, In-Jae
• Is Part Of: Molecular and cellular probes. Volume 66(2022)
• Publication Date: 2022-12
• Subjects: cfDNA fragmentome -- cfDNA methylome -- Lung cancer -- Liquid biopsy -- Early cancer diagnosis -- Tumor originated fragments (TOF) score; cfDNA cell-free DNA -- ctDNA circulating tumor DNA -- TOF tumor originated fragment -- ctCandi ctDNA candidate count index -- RMD read methylation density -- SFR short fragment ratio -- NSCLC non-small cell lung cancer -- SCLC small cell lung cancer -- AUC area under the receiver operating characteristic curve -- LDCT low-dose computed tomography -- EM-seq enzymatic methyl-sequencing -- NGS next generation sequencing -- WGS whole genome sequencing -- TCGA The Cancer Genome Atlas -- GEO Gene Expression Omnibus -- KGP Korean Genome Project; Molecular probes -- Diagnostic use -- Periodicals; Pathology, Cellular -- Technique -- Periodicals; Cell Biology -- Periodicals; Molecular Biology -- Periodicals; Sondes moléculaires -- Utilisation diagnostique -- Périodiques; Cytopathologie -- Technique -- Périodiques; 572
• DOI: 10.1016/j.mcp.2022.101873
• Languages: English
• ISSNs: 0890-8508

Abstract

Abstract: Early detection is critical for minimizing mortality from cancer. Plasma cell-free DNA (cfDNA) contains the signatures of tumor DNA, allowing us to quantify the signature and diagnose early-stage tumors. Here, we report a novel tumor fragment quantification method, TOF (Tumor Originated Fragment) for the diagnosis of lung cancer by quantifying and analyzing both the plasma cfDNA methylation patterns and fragmentomic signatures. TOF utilizes the amount of ctDNA predicted from the methylation density information of each cfDNA read mapped on 6243 lung-tumor-specific CpG markers. The 6243 tumor-specific markers were derived from lung tumor tissues by comparing them with corresponding normal tissues and healthy blood from public methylation data. TOF also utilizes two cfDNA fragmentomic signatures: 1) the short fragment ratio, and 2) the 5′ end-motif profile. We used 298 plasma samples to analyze cfDNA signatures using enzymatic methyl-sequencing data from 201 lung cancer patients and 97 healthy controls. The TOF score showed 0.98 of the area under the curve in correctly classifying lung cancer from normal samples. The TOF score resolution was high enough to clearly differentiate even the early-stage non-small cell lung cancer patients from the healthy controls. The same was true for small cell lung cancer patients. Highlights: A novel tumor fragment quantification method for the diagnosis of lung cancer. Machine learning models using ctDNA methylome and fragmentome profiles. Tumor Originated Fragment (TOF) scoring system to diagnose early-stage lung cancer.