Methylated Biomarkers of Smoking as a Selection Tool in Participants for Lung Cancer Screening (MET-SELS)

The MET-SELS study aims to revolutionize how we identify individuals for lung cancer screening by moving beyond the limitations of self-reported smoking history. Currently, eligibility for low-dose CT (LDCT) scans relies on "pack-years"-a metric often compromised by recall bias, under-reporting, and an inability to account for the biological nuances of smoke inhalation or environmental exposure. Consequently, current criteria miss nearly half of incidental lung cancers.

To bridge this gap, the study investigates DNA methylation as a stable, objective "biological footprint" of smoking. Unlike short-term biomarkers like nicotine or CO levels, specific epigenetic changes in genes such as AHRR and F2RL3 persist long after cessation and correlate accurately with cumulative tobacco exposure.

Led by Professor Dr. Annemiek Snoeckx and a multidisciplinary team at UZA and the Centre for Medical Genetics, the research will analyze saliva samples from two groups: roughly 900 participants from the ZORALCS screening trial and 150 volunteers. By comparing saliva-derived genomic signatures against both self-reported data and professional interviews, the team aims to validate a panel of methylation markers that can pinpoint high-risk individuals with far greater precision.

The ultimate vision for MET-SELS is to implement a population-based "saliva-first" triage system, similar to the FIT test used for colorectal cancer. In this model, high-risk candidates would provide a saliva sample at home; only those with a confirmed epigenetic risk profile would be invited for a LDCT scan, significantly increasing the yield of early-stage lung cancer detection while streamlining healthcare resources.

Study Overview

• Status: Recruiting
• Conditions: Epigenetics; DNA Methylation; Saliva; Lung Cancer Screening; Risk Stratification With Biomarker
• Intervention / Treatment: Genetic: DNA-methylation in saliva

Detailed Description

The MET-SELS study represents a sophisticated paradigm shift in oncology and preventive medicine, aiming to solve one of the most persistent challenges in lung cancer screening (LCS): the accurate identification of the high-risk population. Currently, global screening protocols-which rely on low-dose CT (LDCT) scans-target individuals based on "categorical smoking criteria," typically defined by age and a history of at least 30 pack-years. However, as the MET-SELS researchers argue, these criteria are fundamentally flawed. They are largely arbitrary, susceptible to significant recall and volunteer bias, and fail to capture the biological reality of smoking behavior, such as inhalation depth, nicotine retention, or the compounding effects of second-hand smoke. Because current methods only capture approximately 50% of incidental lung cancers, there is a critical need for a "bias-proof" and biologically grounded selection tool.

To address this, the study, led by Principal Investigator Professor Dr. Annemiek Snoeckx and a multidisciplinary team including Professors Ken Op de Beeck, Guy Van Camp, and Jan van Meerbeeck, turns to the cutting-edge field of epigenetics. The central hypothesis is that tobacco smoke leaves a permanent and quantifiable "molecular scar" on the human genome through DNA methylation. While traditional biomarkers like carbon monoxide in exhaled breath or cotinine in serum only reflect short-term nicotine exposure-and can be easily masked by temporary abstinence or nicotine replacement therapy-DNA methylation patterns in specific genes are remarkably robust. Specifically, the study focuses on a panel of genes including AHRR, F2RL3, and ALPPL2. Research has shown that people who smoke or used to smoke exhibit significantly lower methylation levels at the AHRR site (cg05575921) compared to people who never smoked. Crucially, while some of these epigenetic markers begin to reverse upon quitting, others remain stable for more than 30 years after cessation, providing a reliable "biological ledger" of a person's lifetime tobacco exposure and their true risk profile.

The methodology of the MET-SELS study is designed for high statistical power and clinical relevance. It utilizes two distinct cohorts: Cohort 1 consists of 850-900 participants from the ZORALCS screening implementation study at UZA, and Cohort 2 includes 150 volunteers aged 50 and older, covering a spectrum of smoking histories. Participants provide a simple 2 ml saliva sample, which is far less invasive and more cost-effective for mass screening than blood-based liquid biopsies. These samples undergo rigorous genomic and methylomic analysis at the Centre for Medical Genetics, employing techniques such as whole-genome sequencing (WGS) and quantitative methylation-specific PCR (qMSP). These biological results are then cross-referenced against two types of behavioral data: self-reported questionnaires and intensive, structured interviews led by specialized healthcare providers. By using ROC analysis and linear regression, the study aims to validate how accurately these salivary biomarkers can predict smoking status, pack-years, and duration of abstinence compared to traditional reporting.

The long-term vision of MET-SELS is nothing short of a total transformation of public health policy. The researchers aim to validate a "saliva-first" triage model for lung cancer, analogous to the FIT (Fecal Immunochemical Test) used in colorectal cancer screening. In this envisioned future, a saliva collection kit would be mailed to the target-age population; only those whose epigenetic signature reveals a high-risk profile would be invited for a clinical LDCT scan. This approach would not only improve the yield of early-stage lung cancer detection but also significantly enhance the cost-effectiveness of screening programs by excluding low-risk individuals who are currently selected based on inaccurate self-reporting. By replacing subjective anecdotes with objective genomic data, the MET-SELS study paves the way for a more precise, equitable, and effective era of cancer prevention.

• Study Type: Interventional
• Enrollment (Estimated): 1000
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Charlotte Theuns; Phone Number: +32470274088; Email: charlotte.theuns@uantwerpen.be

Study Locations

• Belgium
  • Antwerpen
    • Antwerp, Antwerpen, Belgium, 2650
      • Recruiting
      • Antwerp University Hospital
      • Contact: Charlotte Theuns; Phone Number: 0470274088; Email: charlotte.theuns@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Cohort 1: Volunteers

Inclusion Criteria:

• Age: Must be > 50 years of age
• Smoking History: Includes individuals with and without a smoking history

Cohort 2: ZORALCS-study participants

Inclusion Criteria:

• Age: 55-74 years old
• Smoking History: Includes individuals with a smoking history

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Screening
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort - volunteers; Reference group: people who smoked less than 10 years	Genetic: DNA-methylation in saliva; Participants provide a simple 2 ml saliva sample, which is far less invasive and more cost-effective for mass screening than blood-based liquid biopsies. These samples undergo rigorous genomic and methylomic analysis at the Centre for Medical Genetics, employing techniques such as whole-genome sequencing (WGS) and quantitative methylation-specific PCR (qMSP). These biological results are then cross-referenced against two types of behavioral data: self-reported questionnaires and intensive, structured interviews led by specialized healthcare providers. By using ROC analysis and linear regression, the study aims to validate how accurately these salivary biomarkers can predict smoking status, pack-years, and duration of abstinence compared to traditional reporting.
Experimental: Cohort: Lung cancer screening participants; Participants of the ZORALCS-study	Genetic: DNA-methylation in saliva; Participants provide a simple 2 ml saliva sample, which is far less invasive and more cost-effective for mass screening than blood-based liquid biopsies. These samples undergo rigorous genomic and methylomic analysis at the Centre for Medical Genetics, employing techniques such as whole-genome sequencing (WGS) and quantitative methylation-specific PCR (qMSP). These biological results are then cross-referenced against two types of behavioral data: self-reported questionnaires and intensive, structured interviews led by specialized healthcare providers. By using ROC analysis and linear regression, the study aims to validate how accurately these salivary biomarkers can predict smoking status, pack-years, and duration of abstinence compared to traditional reporting.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DNA-methylation	DNA Methylation Status, measured as a continuous variable across a panel of specific genes (e.g., AHRR, F2RL3, ALPPL2).	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparative smoking accuracy	Self-reported vs. Interview-based Accuracy: Comparing how well the DNA markers correlate with the participant's own questionnaire answers versus the data gathered by a specialized healthcare professional	2 years

Collaborators and Investigators

• Sponsor: University Hospital, Antwerp
• Collaborators: Universiteit Antwerpen
• Investigators: Principal Investigator: Annemiek Snoeckx, MD, PhD, University Of Antwerp / Antwerp University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 4, 2025
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2028

Study Registration Dates

• First Submitted: May 4, 2026
• First Submitted That Met QC Criteria: June 3, 2026
• First Posted (Actual): June 8, 2026

Study Record Updates

• Last Update Posted (Actual): June 8, 2026
• Last Update Submitted That Met QC Criteria: June 3, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Smoking; Risk stratification; Saliva; Lung Cancer Screening; DNA-methylation
• Additional Relevant MeSH Terms: Behavior; Smoking; Genetic Phenomena; Biochemical Phenomena; Chemical Phenomena; Metabolism; Methylation; Alkylation; DNA Methylation
• Other Study ID Numbers: 4607 (Other Identifier: Antwerp University Hospital)

Drug and device information, study documents

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