Polygenic inheritance and its interplay with smoking history in predicting lung cancer diagnosis: a French-Canadian case-control cohort.

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EBioMedicine Pub Date : 2024-08-01 Epub Date: 2024-07-05 DOI:10.1016/j.ebiom.2024.105234

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

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Abstract

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 (<20th percentile), intermediate (20-80th percentile) and high (>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.

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预测肺癌诊断的多基因遗传及其与吸烟史的相互作用：法裔加拿大人病例对照队列。

背景：全基因组关联研究在肺癌中最近期的临床应用是多基因风险评分（PRS）：肺癌全基因组关联研究最近期的临床应用是多基因风险评分（PRS）：方法：生成了一个病例对照数据集，其中包括来自 LORD 项目的 4002 例肺癌病例和来自 CARTaGENE 的 20,010 例种族匹配对照。在英国生物库（n = 5419 例肺癌病例）中得出并验证了包括超过 110 万个遗传变异的全基因组 PRS。在 LORD/CARTaGENE 中对 PRS 的预测能力和诊断鉴别性能进行了测试，并与以前文献中的 PRS 进行了比较。根据吸烟状况和低 PRS（第 80 百分位数）遗传风险组进行了分层分析：结果：全基因组 PRS 所解释的表型变异和效应大小在数量上优于以往的 PRS。与低遗传风险相比，高遗传风险个体患肺癌的几率是低遗传风险个体的 2 倍。除传统的临床风险因素外，PRS还是肺癌的独立预测因素，但在综合风险模型中，其诊断鉴别性能是递增的。吸烟会使低遗传风险人群罹患肺癌的几率增加 7.7 倍，使高遗传风险人群罹患肺癌的几率增加 11.3 倍。与从不吸烟和遗传风险低的人相比，遗传风险高的吸烟者患肺癌的几率增加了17倍：解释：遗传风险低的人无法抵御与吸烟有关的肺癌风险。PRS和吸烟的共同乘法效应使肺癌的发病几率增加了近20倍：由于 Normand Lord 先生的慷慨捐赠，这项工作得到了 CQDM 和 IUCPQ 基金会的支持。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.