Study
NLST
(Learn more about this study)
Project ID
NLST-1358
Initial CDAS Request Approval
Nov 19, 2024
Title
Improving risk stratification for lung cancer screening using peripheral blood leukocyte DNA methylation: an investigation in the National Lung Screening Trial (NLST)
Summary
Lung cancer is the leading cause of cancer death in the US, accounting for approximately 22% of all cancer deaths. Annual screening with low-dose computed tomography (LDCT) is recommended in adults aged 50-80 years who have a history of pack-years to 20 and are current smokers or quit in the past 15 years, but screening with LDCT remains controversial due to the very high false-positive rates, increased radiation exposures, and costs. Moreover, many adults are diagnosed with lung cancer who are not eligible for screening. In the 2021 USPSTF recommendation statement, the task force identified “Future Research Needs,” which includes conducting more research on biomarkers, noting that: “Biomarkers could potentially be used to identify high-risk candidates for screening with LDCT”. For this project, we propose to measure DNA methylation levels in blood leukocytes obtained from samples that were collected prior to screening (and at multiple time points) in participants of the National Lung Screening Trial (NLST). Our first objective is to develop a pre-screening tool that would classify high-risk participants into additional risk categories to reduce number of scans needed. Our second objective is to examine whether differences in DNA methylation markers can distinguish participants with positive screening results who developed lung cancer from those with false positives (i.e., did not develop cancer). Our third objective is to examine whether differences in DNA methylation markers can discriminate participants who had a negative scan and were diagnosed with lung cancer during follow-up from those with a negative scan who did not develop lung cancer. Using the NLST archived samples will allow us to efficiently evaluate whether DNA methylation markers can improve models for risk stratification, thus reduce unnecessary scans needed to be performed, as well as potentially assist in identifying true positive and false negative LDCT scans.
Aims
Specific Aims:
1. We will develop a composite epigenetic score using previously identified epigenetic markers for smoking, other lung cancer risk factors (reflecting the biological dose of lung cancer risk factors throughout the lifecourse), and methylation-predicted immune cell composition, and compare its 5-year lung cancer risk prediction performance accuracy with the 5-year lung cancer risk prediction performance accuracy of: 1) epigenetic scores previously developed for lung cancer risk prediction (including our own), and 2) age and packyears of smoking. We will include 445 lung cancer cases irrespective of whether the case was detected by LDCT or CXR and 2 matched controls selected among subjects with all negative screens (both trial arms).
2. We will test whether epigenome-wide DNA methylation signatures in peripheral blood can discriminate individuals who had true positive screens in the LDCT or CXR arms (i.e., lung cancer cases diagnosed after a positive screen; n=259 with blood samples) from subjects who had a false positive screen with LDCT or CXR (i.e., no evidence of cancer during NLST follow-up or to the end of 2014; matching 2 per case).
3. We will examine whether epigenome-wide DNA methylation signatures can discriminate individuals who had a false negative at the baseline visit (i.e., were diagnosed with lung cancer during follow-up) to subjects who had a negative screen at baseline and did not develop lung cancer over the follow-up period or through end of 2014 (i.e., true negatives).
Collaborators
Elizabeth Platz, Johns Hopkins University
Karl Kelsey, Brown University
Ilana Gareen, Brown University
JoRean Sick, Brown University
Devin Koestler, Kansas University
