Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
Baylor College of Medicine, Houston, Texas.
J Thorac Oncol. 2019 Aug;14(8):1360-1369. doi: 10.1016/j.jtho.2019.04.008. Epub 2019 Apr 19.
Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer.
We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer.
We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 × 10), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 10). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate.
We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.
非吸烟者肺癌遗传易感性的机制尚不清楚。造成这一知识空白的主要原因是这种疾病相对罕见（亚洲人除外），因此难以收集到足够的研究样本。在这项研究中，我们对迄今为止最大的一组欧洲血统非吸烟者肺癌病例进行了全基因组关联研究。
我们对欧洲血统的非吸烟者进行了两阶段（发现和复制）全基因组关联研究。通过对最近 OncoArray 研究中的非吸烟者进行荟萃分析，进一步增加了样本量，最终共有 3636 例病例和 6295 例对照。我们还将我们的研究结果与吸烟者的研究结果进行了比较。
我们发现三个全基因组统计学上显著的单核苷酸多态性 rs31490（比值比[OR]：0.769，95%置信区间[CI]：0.722-0.820；p 值 5.31×10）、rs380286（OR：0.770，95% CI：0.723-0.820；p 值 4.32×10）和 rs4975616（OR：0.778，95% CI：0.730-0.829；p 值 1.04×10）。这三个单核苷酸多态性均映射到染色体 5 的 CLPTM1L-TERT 区域，该区域先前与吸烟者和非吸烟者亚洲女性的肺癌风险以及乳腺癌、卵巢癌、结直肠癌和前列腺癌等其他癌症的风险有关。
我们发现，非吸烟者的肺癌遗传易感性与泛癌风险相关的遗传变异有关。与吸烟者的比较表明，先前与肺癌风险相关的顶级变异仅在暴露于烟草的情况下才会增加风险，这突出了基因-环境相互作用在该疾病病因学中的重要性。
