PO.CL02.01 · 临床研究
累积烟草暴露对拉丁美洲人肺癌基因组特征的影响
Effects of cumulative tobacco exposure on lung cancer genomic profiles in Latin Americans
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
动机：烟草暴露是非小细胞肺癌（NSCLC）肿瘤基因组图谱的一个主要决定因素。肺癌中两个临床上最相关的可靶向基因EGFR和KRAS表现出相反的模式，吸烟者中KRAS改变的患病率较高，而从不吸烟者中EGFR改变较高。然而，基因组变化随累积烟草暴露的动态和演变过程受到的关注有限。在此，我们研究了肿瘤基因组特征如何随吸烟强度、持续时间和戒烟后时间（TSC）而变化。我们的研究聚焦于代表性不足的拉丁美洲患者群体，该群体需要更多研究以更好地表征肿瘤异质性。
方法：研究人群来自"智利、巴西和秘鲁肺癌患者分子诊断技术的表征与验证"研究方案。参与者招募于2015年7月至2018年10月期间，跨越37个不同中心。分析了原发性或转移性NSCLC标本，并使用Oncomine Focus Assay（OFA）生成基因组特征。共有1,864名参与者产生了通过质控（QC）的基因组特征。在入组时评估了感兴趣的协变量。使用综合吸烟指数（CSI）量化累积烟草暴露，包括吸烟强度（每日吸烟支数）、持续时间和TSC。此外，将吸烟状态（当前吸烟者与从不吸烟者）作为TSC的函数重新编码，以识别主要基因组改变（GA）最可能发生的时间段。使用描述性统计、广义线性模型和广义相加模型来评估CSI与各基因GA患病率之间的关联。所有模型均对潜在混杂因素进行了校正，包括国家、年龄、性别、NSCLC亚型、癌症分期和癌症病史。
结果与结论：共有1100名患者具有完整的基因组和烟草暴露信息。在当前吸烟者中，吸烟强度和持续时间的中位数分别为每日20支和48年，而既往吸烟者为每日30支和47年。90%的既往吸烟者在诊断前至少10年已停止使用烟草，TSC中位数为1年。CSI分析确定了14个与基因组改变状态显著相关的基因，包括EGFR、PIK3CA、ALK、MTOR、ERBB3和RET。较高的CSI值（第4四分位数）显示ALK（16.2%对8.7%）、RET（12.8%对6.9%）和MTOR（15%对6.9%）的基因组改变频率约为最低CSI四分位数的两倍。中等范围的CSI值显示EGFR（12.6%对31%）和PIK3CA（6.9%对14.5%）改变患病率最低。总体而言，这些发现支持CSI在完善暴露-基因型关联方面的价值，以及在多样化人群中改进风险分层工作的必要性。
查看英文原文 English abstract
Motivation: Tobacco exposure is a major determinant of tumor genomic landscapes in non-small cell lung cancer (NSCLC). Two of the most clinically relevant actionable genes in lung cancer, EGFR and KRAS, show opposite patterns, with smokers exhibiting a higher prevalence of alterations in KRAS and never-smokers in EGFR. Yet, the dynamic and evolution of genomic changes as a function of cumulative tobacco exposure has received limited attention. Here, we examine how tumor genomic profiles vary according to smoking intensity, duration, and time since cessation (TSC). Our study focuses on an underrepresented population of Latin American patients, where additional research is needed to better characterize tumor heterogeneity.
Methodology: The population was obtained from the protocol Characterization and Validation of Molecular Diagnostic Technologies for Lung Cancer Patients from Chile, Brazil, and Peru . Participant recruitment was between July 2015 and October 2018 across 37 different centers. Primary or metastatic NSCLC specimens were analyzed, and genomic profiles were generated with the Oncomine Focus Assay (OFA). A total of 1,864 participants yielded QC-approved genomic profiles. Covariates of interest were assessed at enrollment. Cumulative tobacco exposure, including smoking intensity (cigarettes per day), duration, and TSC, was quantified using the Comprehensive Smoking Index (CSI). In addition, smoking status (current vs. never) was recoded as a function of TSC in order to identify the time period during which major genomic alterations (GA) are most likely to occur. Descriptive statistics, generalized linear models, and generalized additive models were used to evaluate the association between CSI and the prevalence of GA across genes. All models were adjusted for potential confounders, including country, age, sex, NSCLC subtype, cancer stage and history of cancer.
Results and Conclusions: A total of 1100 patients had complete genomic and tobacco exposure information. Among current smokers, median smoking intensity and duration were 20 cigarettes per day and 48 years, respectively, compared with 30 cigarettes per day and 47 years among former smokers. Ninety percent of former smokers had ceased tobacco use at least 10 years prior to diagnosis, with a median TSC of 1 year. CSI analysis identified 14 genes significantly associated with genomic alteration status, including EGFR, PIK3CA, ALK, MTOR, ERBB3, and RET. Higher CSI values (4th quartile) showed approximately double the frequency of genomic alterations compared with the lowest CSI quartile for ALK (16.2% vs. 8.7%), RET (12.8% vs. 6.9%), and MTOR (15% vs. 6.9%). Mid-range CSI values exhibited the lowest prevalence of alterations in EGFR (12.6% vs. 31%) and PIK3CA (6.9% vs. 14.5%). Overall, these findings support the value of CSI in refining exposure-genotype associations and the need for improves risk stratification efforts in diverse populations.
利益披露 Disclosure
J. Garrido, None.