Developing Novel Circulating Epigenetic Biomarkers for Early Detection of Lung Cancer

The investigators aim to identify novel circulating methylated biomarkers for early lung cancer detection as well as to develop new technologies that are clinically applicable with high sensitivity and specificity.

Study Overview

• Status: Recruiting
• Conditions: Lung Cancer
• Intervention / Treatment: Diagnostic test: Blood-derived DNA methylation detection

Detailed Description

Lung cancer is the leading cause of cancer death, accounting for 2.09 million cases in 2018 worldwide. There is a huge demand globally for sensitive and reliable assays to intercept lung cancer at early stages when it can be cured. Past studies have shown that circulating cell-free tumor DNA (ctDNA) shed from tumor cells contains the same mutations and methylation patterns as the original tumor cells. Emerging evidence has indicated the presence of systemic immune dysregulation in cancer patients, and that tumor-reactive T cells carry a distinct molecular profile compared to other bystander cells. Thus, molecular abnormality of ctDNA and tumor-reactive T cells may be one of the early signs that hint the presence of malignancy, and it may serve as a promising target for development of blood-based assays in early lung cancer for its convenience and non-invasiveness as opposed to invasive tumor biopsy, or imaging-based methods that are limited by unsatisfactory sensitivity/specificity.

The investigators aim to identify novel markers for early lung cancer detection as well as to develop new technologies that are clinically applicable with high sensitivity and specificity. The objectives of this proposal are multifaceted: (1) The investigators will generate genome-wide methylation atlas of circulating cell free DNA and of circulating T cells in lung cancer patients vs. non-cancer subjects. (2) The investigators will develop an enriched method to enhance the performance of multiplex droplet digital PCR (ddPCR) technology with increased sensitivity and decreased input DNA requirement. (Enriched methylation-specific droplet digital PCR, EMS-ddPCR) (3) The investigators will develop a single-cell, locus-specific DNA methylation detection system that is bisulfite-free and non-PCR-based. The system can be coupled with flow cytometry or mass cytometry to enable cell-type specific methylation detection. (single-cell, locus-specific methylation detection, scLSM-FACS) (4) The investigators will identify a novel methylation signature consisting of tumor-derived and immune-derived biomarkers for early detection of lung cancer.

• Study Type: Observational
• Enrollment (Estimated): 900

Contacts and Locations

• Study Contact: Name: Hsing-Chen Tsai, M.D., Ph.D; Phone Number: 88797 +886-2-23123456; Email: htsai@ntu.edu.tw

Study Locations

• Taiwan
  • Taipei, Taiwan, 100225
    • Recruiting
    • National Taiwan University Hospital
    • Contact: Hsing-Chen Tsai, M.D., Ph.D; Phone Number: 88797 +886-2-23123456; Email: htsai@ntu.edu.tw

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

1. Study subjects: Patients with suspected or confirmed diagnosis of lung cancer.
2. Indeterminate subjects: Subjects who had indeterminate sub-centimeter pulmonary nodules or ground glass opacities discovered by computed tomography.
3. Control subjects: Non-cancer subjects including healthy volunteers, chronic inflammatory airway diseases such as chronic obstructive airway disease, asthma, and bronchiectasis, etc.

Description

Inclusion Criteria:

• Subjects suspected or confirmed diagnosis of lung cancer.
• Subjects who had indeterminate sub-centimeter pulmonary nodules or ground glass opacities discovered by computed tomography.
• Non-cancer subjects: including healthy volunteers and chronic inflammatory airway diseases such as chronic obstructive airway disease, asthma, and bronchiectasis, etc.
• Subjects age over 20.

Exclusion Criteria:

• Pregnancy.
• Subjects with HIV infection.
• Unable to or unwilling to give informed consent.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Lung cancer patients; Patients age over 20, with suspected or confirmed diagnosis of lung cancer.	Diagnostic test: Blood-derived DNA methylation detection; Up to 20 ml of blood will be collected from each subject, and the blood specimen will be processed to isolate plasma cell-free DNA and immune-derived cells (circulating T cells). Circulating methylated tumor/immune signature will then be identified.
Indeterminate subjects; Subjects who had indeterminate sub-centimeter pulmonary nodules or ground glass opacities discovered by computed tomography.	Diagnostic test: Blood-derived DNA methylation detection; Up to 20 ml of blood will be collected from each subject, and the blood specimen will be processed to isolate plasma cell-free DNA and immune-derived cells (circulating T cells). Circulating methylated tumor/immune signature will then be identified.
Control subjects; Non-cancer patients including healthy volunteers, chronic inflammatory airway diseases such as chronic obstructive airway disease, asthma, and bronchiectasis, etc.	Diagnostic test: Blood-derived DNA methylation detection; Up to 20 ml of blood will be collected from each subject, and the blood specimen will be processed to isolate plasma cell-free DNA and immune-derived cells (circulating T cells). Circulating methylated tumor/immune signature will then be identified.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of circulating tumor and immune methylated signature	Genome-wide methylation profile of lung cancer patients and control subjects will be measured both in circulating T cells and cell-free DNA collected from peripheral blood by using Infinium MethylationEPIC BeadChip platform.	1 year
Technology development	The investigators will develop enriched methylation-specific droplet digital PCR (EMS-ddPCR) with increased sensitivity and decreased input DNA requirement. The investigators will develop single-cell, locus-specific DNA methylation detection system for flow cytometry (scLSM-FACS) to enable cell-type specific methylation detection.	1 year
Technology validation	The investigators will validate the identified circulating methylated signature in patients with indeterminate pulmonary nodules.	1 year

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital
• Investigators: Study Chair: Hsing-Chen Tsai, M.D., Ph.D, Graduate institute of Toxicology, NTUCM; Department of Internal Medicine, NTUH

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2021
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: March 22, 2021
• First Submitted That Met QC Criteria: March 22, 2021
• First Posted (Actual): March 24, 2021

Study Record Updates

• Last Update Posted (Actual): June 18, 2024
• Last Update Submitted That Met QC Criteria: June 16, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Lung cancer; Cell-free DNA; DNA methylation; T cell methylome; cell-free tumor DNA (ctDNA)
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms
• Other Study ID Numbers: 202012096RIPC

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No