Polygenic inheritance and its interplay with smoking history in predicting lung cancer diagnosis: a French-Canadian case-control cohortResearch in context
Véronique Boumtje,
Hasanga D. Manikpurage,
Zhonglin Li,
Nathalie Gaudreault,
Victoria Saavedra Armero,
Dominique K. Boudreau,
Sébastien Renaut,
Cyndi Henry,
Christine Racine,
Aida Eslami,
Stéphanie Bougeard,
Evelyne Vigneau,
Mathieu Morissette,
Benoit J. Arsenault,
Catherine Labbé,
Anne-Sophie Laliberté,
Simon Martel,
François Maltais,
Christian Couture,
Patrice Desmeules,
Patrick Mathieu,
Sébastien Thériault,
Philippe Joubert,
Yohan Bossé
Affiliations
Véronique Boumtje
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Hasanga D. Manikpurage
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Zhonglin Li
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Nathalie Gaudreault
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Victoria Saavedra Armero
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Dominique K. Boudreau
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Sébastien Renaut
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Cyndi Henry
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Christine Racine
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Aida Eslami
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Stéphanie Bougeard
Anses (French Agency for Food, Environmental and Occupational Health and Safety), 22440, Ploufragan, France
Evelyne Vigneau
Oniris, INRAE, StatSC, 44300, Nantes, France
Mathieu Morissette
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Benoit J. Arsenault
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Catherine Labbé
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Anne-Sophie Laliberté
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Simon Martel
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
François Maltais
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Christian Couture
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Patrice Desmeules
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Patrick Mathieu
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Sébastien Thériault
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Philippe Joubert
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada
Yohan Bossé
Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Quebec City, Canada; Department of Molecular Medicine, Université Laval, Quebec City, Canada; Corresponding author. Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Pavillon Marguerite-d'Youville, Y2106, 2725 Chemin Sainte-Foy, Quebec City, Québec, G1V 4G5, Canada.
Summary: Background: The most near-term clinical application of genome-wide association studies in lung cancer is a polygenic risk score (PRS). Methods: A case-control dataset was generated consisting of 4002 lung cancer cases from the LORD project and 20,010 ethnically matched controls from CARTaGENE. A genome-wide PRS including >1.1 million genetic variants was derived and validated in UK Biobank (n = 5419 lung cancer cases). The predictive ability and diagnostic discrimination performance of the PRS was tested in LORD/CARTaGENE and benchmarked against previous PRSs from the literature. Stratified analyses were performed by smoking status and genetic risk groups defined as low (80th percentile) PRS. Findings: The phenotypic variance explained and the effect size of the genome-wide PRS numerically outperformed previous PRSs. Individuals with high genetic risk had a 2-fold odds of lung cancer compared to low genetic risk. The PRS was an independent predictor of lung cancer beyond conventional clinical risk factors, but its diagnostic discrimination performance was incremental in an integrated risk model. Smoking increased the odds of lung cancer by 7.7-fold in low genetic risk and by 11.3-fold in high genetic risk. Smoking with high genetic risk was associated with a 17-fold increase in the odds of lung cancer compared to individuals who never smoked and with low genetic risk. Interpretation: Individuals at low genetic risk are not protected against the smoking-related risk of lung cancer. The joint multiplicative effect of PRS and smoking increases the odds of lung cancer by nearly 20-fold. Funding: This work was supported by the CQDM and the IUCPQ Foundation owing to a generous donation from Mr. Normand Lord.
