背景:烟草使用是肺癌(LC)发展的主要危险因素之一。然而,大约10-20%的被诊断患有这种疾病的人从不吸烟者。对于非小细胞肺癌(NSCLC),吸烟者和从不吸烟者之间的临床表现和肿瘤基因组谱均存在明显差异。例如,从不吸烟者的肺腺癌(LUAD)组织学亚型主要存在于欧洲的年轻女性中,北美,和亚洲血统。虽然吸烟者的临床表现和肿瘤基因组谱已被广泛检查,从不吸烟者通常代表性不足,尤其是那些拉丁美洲(LA)背景。在这项工作中,我们表征,第一次,来自智利的吸烟者和不吸烟者LC患者基因组谱的差异.
方法:我们通过吸烟状态对总共10个临床相关基因的基因组改变(GA)频率进行比较,包括体细胞突变和结构变异(融合)。包括八个最常见的LC可操作基因(EGFR,KRAS,ALK,MET,BRAF,RET,ERBB2和ROS1)和两个已建立的除LC以外的恶性肿瘤的驱动基因(PIK3CA和MAP2K1)。研究参与者被分组为吸烟者(当前和以前,根据注册时的自我报告烟草使用情况,n=473)或从不吸烟者(n=200)。
结果:我们的研究结果表明,与吸烟者相比,从不吸烟者的总体GA频率更高(58vs.45.7,p值<0.01)与EGFR基因,KRAS,和PIK3CA显示最高的患病率,而ERBB2,RET,ROS1最低。从不吸烟者在10个基因中的7个基因中表现出更高的频率;然而,吸烟者拥有更复杂的基因组图谱。两组之间最明显的差异是EGFR(15.6vs.21.5,p值:<0.01),PIK3CA(6.8vs9.5)和ALK(3.2vs7.5)支持从不吸烟者,和KRAS(16.3vs.11.5)和MAP2K1(6.6与3.5)有利于吸烟者。这些基因的改变几乎完全由EGFR中的体细胞突变组成,主要由ALK中的融合体组成。仅通过PIK3CA的突变,KRAS和MAP2K1。
结论:我们发现,在来自智利的LUAD患者中,根据吸烟状况,基因组景观存在明显差异。在这些资源有限的环境中,对临床管理有潜在的影响。
BACKGROUND: Tobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10-20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smokers and never-
smokers. For example, the Lung Adenocarcinoma (LUAD) histological subtype in never-smokers is predominately found in young women of European, North American, and Asian descent. While the clinical presentation and tumor genomic profiles of
smokers have been widely examined, never-
smokers are usually underrepresented, especially those of a Latin American (LA) background. In this work, we characterize, for the first time, the difference in the genomic profiles between smokers and never-
smokers LC patients from Chile.
METHODS: We conduct a comparison by smoking status in the frequencies of genomic alterations (GAs) including somatic mutations and structural variants (fusions) in a total of 10 clinically relevant genes, including the eight most common actionable genes for LC (EGFR, KRAS, ALK, MET, BRAF, RET, ERBB2, and ROS1) and two established driver genes for malignancies other than LC (PIK3CA and MAP2K1). Study participants were grouped as either
smokers (current and former, n = 473) or never-
smokers (n = 200) according to self-report tobacco use at enrollment.
RESULTS: Our findings indicate a higher overall GA frequency for never-smokers compared to smokers (58 vs. 45.7, p-value < 0.01) with the genes EGFR, KRAS, and PIK3CA displaying the highest prevalence while ERBB2, RET, and ROS1 the lowest. Never-
smokers present higher frequencies in seven out of the 10 genes; however,
smokers harbor a more complex genomic profile. The clearest differences between groups are seen for EGFR (15.6 vs. 21.5, p-value: < 0.01), PIK3CA (6.8 vs 9.5) and ALK (3.2 vs 7.5) in favor of never-smokers, and KRAS (16.3 vs. 11.5) and MAP2K1 (6.6 vs. 3.5) in favor of smokers. Alterations in these genes are comprised almost exclusively by somatic mutations in EGFR and mainly by fusions in ALK, and only by mutations in PIK3CA, KRAS and MAP2K1.
CONCLUSIONS: We found clear differences in the genomic landscape by smoking status in LUAD patients from Chile, with potential implications for clinical management in these limited-resource settings.