根据由国际肺癌研究协会（IASLC）在阿姆斯特丹举行的第14届世界肺癌大会上公布的研究，从不吸烟者的肺腺癌显示出了比吸烟者更大的基因组不稳定性，这支持了一种理论，即从不吸烟者的肺癌源于不同的路径。
吸烟不是肺癌的唯一诱因
“我们发现了吸烟者和从不吸烟者的肺肿瘤基因组中被不同地改变的几个基因组区域，”设在温哥华的加拿大不列颠哥伦比亚癌症机构研究中心的研究人员、研究组长Kelsie Thu说。“我们还发现，与吸烟者相比，从不吸烟者的很大一部分肺肿瘤DNA有遗传变化。这个关于吸烟者和从不吸烟者具有不同的遗传变化模式的发现提示，这些人群中的肺癌很可能是由不同的分子机制驱动的截然不同的疾病，因此需要不同的疗法。
全世界至多25%的肺癌病例发生在从不吸烟的人中间，而从不吸烟的肺癌病人通常表现出了与吸烟的肺癌病人不同的特征。这些人以女性、亚洲人居多，表皮生长因子受体（EGFR）突变的发生率更高，对表皮生长因子受体（EGFR）具有专一性的药物的响应更好，而且更普遍地被诊断为腺癌。
“吸烟的和从不吸烟的肺癌病人之间有一些已知的差异。然而，迄今发现的差异是临床特征或者仅仅在几个特定基因上的遗传改变，”Thu说。“在我们的研究中，我们希望使用一种无偏见的、全基因组的方法，让我们能够同时调查基因组中的所有基因。这让我们能够发现吸烟者和从不吸烟者的肺肿瘤的全基因组遗传改变的模式。我们的研究是一项比较研究，这意味着我们比较了吸烟者的肺肿瘤和从不吸烟者的肺肿瘤从而发现各自人群特有的遗传（DNA层次）改变。从不吸烟人群特有的这些遗传改变可能在驱动从不吸烟者的肺癌发展方面具有重要作用。”
在这项研究中，科研人员从30位从不吸烟者、14位曾经的吸烟者和39位目前的吸烟者的肺腺癌和相同的非恶性组织中提取了DNA。对这些DNA进行了EGFR 和KRAS突变评估。使用相同的非恶性非组织作为基准，测定了每一个肿瘤的拷贝数谱，从而发现体细胞拷贝数的改变。使用了两个独立的可以公开获取的从不吸烟者和吸烟者的肺腺癌数据集作为验证数据集。
平均起来，与吸烟者相比，从不吸烟者的肺肿瘤显示出了更高的拷贝数改变的频率和更大比例的被改变的基因组。当曾经的吸烟者被排除在外而把从不吸烟者与目前吸烟者进行比较的时候，这种差异更加显著。
生物探索推荐英文原文
Lung tumors in never-smokers show greater genomic instability than those in smokers
Lung adenocarcinomas in people who have never smoked show greater genome instability than those in smokers, supporting the theory that lung cancer in never smokers arises through different pathways, according to research presented at the 14th World Conference on Lung Cancer in Amsterdam, hosted by the International Association for the Study of Lung Cancer (IASLC).
"We identified several genomic regions that were differentially altered in the lung tumor genomes of smokers and never smokers," said principal investigator Kelsie Thu, a researcher at the BC Cancer Agency Research Centre in Vancouver, Canada. "We also found that a greater fraction of lung tumor DNA harbored genetic alterations in never smokers compared to smokers. The discovery that there are different patterns of genetic alterations in smokers and never smokers suggests that lung cancers in these cohorts are likely distinct diseases driven by different molecular mechanisms, and thus, may require different treatments."
Up to 25% of lung cancer cases worldwide occur in people who have never smoked, and never smokers with lung cancer typically exhibit traits different from those of smokers. They are more often women, Asian, have a higher incidence of epidermal growth factor receptor (EGFR) mutations, better responses to EGFR-targeting drugs and are more commonly diagnosed with adenocarcinoma.
"There are a few known differences between lung cancers in smokers and never smokers. However, the differences discovered thus far are clinical features or genetic alterations at only a few specific genes," Thu said. "For our study, we wanted to use an unbiased, whole-genome approach that would allow us to investigate all of the genes in the genome simultaneously. This enables us to identify genome-wide patterns of genetic alterations in lung tumors from smokers and never smokers. Our study was a comparative study, meaning that we compared the lung tumor genomes from smokers to those from never smokers to identify genetic (DNA level) alterations specific to one group or the other. The genetic alterations specific to the never smoker group may have important roles in driving the development of lung cancer in never smokers."
In the study, researchers extracted DNA from lung adenocarcinomas and matched non-malignant tissues for 30 never smokers, 14 former smokers and 39 current smokers. The DNA was assessed for EGFR and KRAS mutations. Copy number profiles were generated for each tumor using matched non-malignant lung tissue as a baseline for the identification of somatic copy number alterations. Two independent, publicly available datasets composed of lung adenocarcinomas from never smokers and smokers were used as validation datasets.
On average, never smokers' lung tumors showed higher frequencies of copy number alterations and greater proportions of altered genomes compared with those of smokers. This difference was more pronounced when former smokers were excluded and never smokers were compared with current smokers only.
