Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA.
JAMA. 2010 Feb 10;303(6):535-43. doi: 10.1001/jama.2010.80.
Gene expression profiling may be useful in examining differences underlying age- and sex-specific outcomes in non-small cell lung cancer (NSCLC).
To describe clinically relevant differences in the underlying biology of NSCLC based on patient age and sex.
DESIGN, SETTING, AND PATIENTS: Retrospective analysis of 787 patients with predominantly early stage NSCLC performed at Duke University, Durham, North Carolina, from July 2008 to June 2009. Lung tumor samples with corresponding microarray and clinical data were used. All patients were divided into subgroups based on age (< 70 vs > or = 70 years old) or sex. Gene expression signatures representing oncogenic pathway activation and tumor biology/microenvironment status were applied to these samples to obtain patterns of activation/deregulation.
Patterns of oncogenic and molecular signaling pathway activation that are reproducible and correlate with 5-year recurrence-free patient survival.
Low- and high-risk patient clusters/cohorts were identified with the longest and shortest 5-year recurrence-free survival, respectively, within the age and sex NSCLC subgroups. These cohorts of NSCLC demonstrate similar patterns of pathway activation. In patients younger than 70 years, high-risk patients, with the shortest recurrence-free survival, demonstrated increased activation of the Src (25% vs 6%; P<.001) and tumor necrosis factor (76% vs 42%; P<.001) pathways compared with low-risk patients. High-risk patients aged 70 years or older demonstrated increased activation of the wound healing (40% vs 24%; P = .02) and invasiveness (64% vs 20%; P<.001) pathways compared with low-risk patients. In women, high-risk patients demonstrated increased activation of the invasiveness (99% vs 2%; P<.001) and STAT3 (72% vs 35%; P<.001) pathways while high-risk men demonstrated increased activation of the STAT3 (87% vs 18%; P<.001), tumor necrosis factor (90% vs 46%; P<.001), EGFR (13% vs 2%; P = .003), and wound healing (50% vs 22%; P<.001) pathways. Multivariate analyses confirmed the independent clinical relevance of the pathway-based subphenotypes in women (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.34-3.03; P<.001) and patients younger than 70 years (HR, 1.83; 95% CI, 1.24-2.71; P = .003). All observations were reproducible in split sample analyses.
Among a cohort of patients with NSCLC, subgroups defined by oncogenic pathway activation profiles were associated with recurrence-free survival. These findings require validation in independent patient data sets.
基因表达谱分析可能有助于研究非小细胞肺癌（NSCLC）中年龄和性别特异性结果的潜在差异。
描述基于患者年龄和性别的 NSCLC 潜在生物学的临床相关差异。
设计、地点和患者：回顾性分析了 2008 年 7 月至 2009 年 6 月在北卡罗来纳州达勒姆的杜克大学进行的 787 例主要为早期 NSCLC 患者。使用了具有相应微阵列和临床数据的肺肿瘤样本。所有患者均根据年龄（<70 岁与≥70 岁）或性别分为亚组。应用代表致癌途径激活和肿瘤生物学/微环境状态的基因表达特征，对这些样本进行分析，以获得激活/失调模式。
与 5 年无复发生存患者生存相关的可重复且可重现的致癌和分子信号通路激活模式。
在年龄和性别 NSCLC 亚组中，低风险和高风险患者队列/亚组分别确定为具有最长和最短 5 年无复发生存期的患者。这些 NSCLC 队列显示出相似的通路激活模式。在<70 岁的患者中，无复发生存最短的高风险患者，Src（25%比 6%；P<.001）和肿瘤坏死因子（76%比 42%；P<.001）途径的激活增加。年龄≥70 岁的高风险患者，与低风险患者相比，伤口愈合（40%比 24%；P =.02）和侵袭性（64%比 20%；P<.001）途径的激活增加。女性高风险患者表现出侵袭性（99%比 2%；P<.001）和 STAT3（72%比 35%；P<.001）途径的激活增加，而男性高风险患者表现出 STAT3（87%比 18%；P<.001）、肿瘤坏死因子（90%比 46%；P<.001）、EGFR（13%比 2%；P =.003）和伤口愈合（50%比 22%；P<.001）途径的激活增加。多变量分析证实了基于途径的亚表型在女性（危险比[HR]，2.02；95%置信区间[CI]，1.34-3.03；P<.001）和<70 岁患者（HR，1.83；95%CI，1.24-2.71；P =.003）中的独立临床相关性。在独立的样本分析中，所有观察结果都是可重现的。
在非小细胞肺癌患者队列中，根据致癌途径激活谱定义的亚组与无复发生存相关。这些发现需要在独立的患者数据集进行验证。
