Assessing Lung Cancer Absolute Risk Trajectory Based on a Polygenic Risk Model
Abstract
Lung cancer is the leading cause of cancer-related death globally. An improved risk stratification strategy can increase efficiency of low-dose CT (LDCT) screening. Here we assessed whether individual's genetic background has clinical utility for risk stratification in the context of LDCT screening. On the basis of 13,119 patients with lung cancer and 10,008 controls with European ancestry in the International Lung Cancer Consortium, we constructed a polygenic risk score (PRS) via 10-fold cross-validation with regularized penalized regression. The performance of risk model integrating PRS, including calibration and ability to discriminate, was assessed using UK Biobank data (N = 335,931). Absolute risk was estimated on the basis of age-specific lung cancer incidence and all-cause mortality as competing risk. To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial (N = 50,772 participants). The lung cancer ORs for individuals at the top decile of the PRS distribution versus those at bottom 10% was 2.39 [95% confidence interval (CI) = 1.92–3.00; P = 1.80 × 10−14] in the validation set (Ptrend = 5.26 × 10−20). The OR per SD of PRS increase was 1.26 (95% CI = 1.20–1.32; P = 9.69 × 10−23) for overall lung cancer risk in the validation set. When considering absolute risks, individuals at different PRS deciles showed differential trajectories of 5-year and cumulative absolute risk. The age reaching the LDCT screening recommendation threshold can vary by 4 to 8 years, depending on the individual's genetic background, smoking status, and family history. Collectively, these results suggest that individual's genetic background may inform the optimal lung cancer LDCT screening strategy.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 20, 2021
- Source ID
- 10.1158/0008-5472.can-20-1237
Entities
People
- Adonina Tardón
- Angela Risch
- Angeline S. Andrew
- Christopher I Amos
- Chu Chen
- David C. Christiani
- Demetrius Albanes
- Gad Rennert
- Geoffrey Liu
- Heike Bickeböller
- James D. Mckay
- John K. Field
- Lambertus Kiemeney
- Loic Le Marchand
- Maria Teresa Landi
- Matthew B. Schabath
- Matthew T. Warkentin
- Mattias Johansson
- Melinda C. Aldrich
- Neil E. Caporaso
- Nilanjan Chatterjee
- Paul Brennan
- Philip Lazarus
- Rayjean J Hung
- Shanbeth Zienolddiny
- Stephen Lam
- Stig E. Bojesen
- Susanne M Arnold
- Yonathan Brhane
Organizations
- Baylor College of Medicine
- Canadian Cancer Society Research Institute
- Canadian Institutes of Health Research
- Edinburgh Cancer Research Centre
- Foundation for the Promotion of Applied Scientific Research and Technology in Asturias
- Harvard University
- Johns Hopkins University
- National Cancer Institute
- National Center for Advancing Translational Sciences
- National Center for Research Resources
- Sinai Health System
- United States Department of Defense
- University of Copenhagen
- University of Toronto
- Vanderbilt University
- Vanderbilt University Medical Center