| Title: | Clinical usefulness of polygenic risk scores in risk prediction models for lung cancer screening and lung nodule management |
| Journal: | Translational Oncology |
| Published: | 15 Apr 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41990546/ |
| DOI: | https://doi.org/10.1016/j.tranon.2026.102771 |
Publication 17992
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Abstract
BACKGROUND: Lung cancer mortality decreases as a result of low-dose computed tomography (LDCT) screening, but suffers from low uptake and high false-positive rates. The impact of integrating genetic risk using a polygenic risk score (PRS) to optimize lung cancer screening remains underexplored.</p>
METHODS: We developed a genome-wide PRS and evaluated its performance in pre- and post-screening contexts. Screening eligibility was assessed using two UK Biobank (UKB) subsets: UKBPLCO (n = 8957; PLCOm2012norace risk ≥2%) and UKBScreeningCriteria (n = 74,024 meeting screening eligibility criteria). To evaluate nodule management, we used a cohort of 669 ever-smokers with PLCO ≥2% and Lung-RADS score ≥3, referred to as SYNERGIQCPLCO_LungRADS. Multivariable Cox models, time-dependent area under the curve (AUC), and decision curve analyses (DCA) evaluated association, discrimination, and clinical net benefit.</p>
RESULTS: In UKBPLCO, the PRS was associated with a hazard ratio (HR) of 1.18 per standard deviation. In UKBScreeningCriteria, PRS showed HR of 1.34. Adding PRS to the PLCOm2012 model improved discrimination (AUC: 0.707 vs 0.696; P = 6.85e-27[likelihood ratio test]) and correctly reclassified 9.2% of incident lung cancer cases. Six-year absolute risks stratified by PRS deciles indicate 3.1-fold increase in the top compared to the bottom decile. In SYNERGIQCPLCO_LungRADS, HRPRS was 1.22. In this context, DCA indicated a modest net benefit for decision thresholds between 10% and 30%.</p>
CONCLUSION: PRS in lung cancer reveals context-dependent net benefit across studied populations. Although PRS adds limited value for determining screening eligibility, it may help reclassify borderline individuals and inform decisions regarding closer follow-up or invasive diagnostic procedures for high-risk screened groups.</p>
12 Authors
- Véronique Boumtje
- Zhonglin Li
- Nathalie Gaudreault
- Victoria Saavedra Armero
- Dominique K. Boudreau
- Sophie Plante
- Sabrina Biardel
- Aida Eslami
- Simon Martel
- Sébastien Thériault
- Philippe Joubert
- Yohan Bossé
1 Application
| Application ID | Title |
|---|---|
| 25205 | Identification and characterization of functional variants with a causal role in chronic cardiopulmonary diseases |
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