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研究者报告，阿法1抗胰蛋白酶缺失（AATD）会显著增加罹患肺癌风险；根据发表于5月26日内科学志的新研究数据，相较于非带原者，AATD带原者发生肺癌的风险可能高出了70%。
主要作者明尼苏达州罗彻斯特梅约诊所流行病学教授Ping Yang医师向Medscape肿瘤学表示，过去的研究已经显示慢性肺阻塞疾病（COPD）是肺癌的一个独立危险因子，但是阿法1抗胰蛋白酶缺失带原者更容易罹患早发性肺气肿。
AATD是美国人常见的一种基因疾病，特别是那些遗传自欧洲血统的人们；在基因同核子人们身上可能不会察觉自己是带原者，且一般并不会有AATD相关的疾病发生；然而，相较于一般大众，AATD带原者可能更容易受到吸烟烟雾的致癌原攻击，特别是当阿法1抗胰蛋白酶浓度被生理压力降低，或是他们已经有某些肺组织的损伤。
作者表示，肺癌的发生是一个复杂且牵涉到许多宿主内在与外在因素的多阶段进程，烟草烟雾里面的有毒物质会破坏细胞的DNA，并刺激肺部的发炎反应；相对的，宿主的作用机转可以去活化烟草烟雾里的有毒物质、去除或是修复受损的DNA，并透过改变肺组织适应这些刺激物；肺癌的机转围绕在这些因素的相互作用之中。
在这项研究中，Yang博士与其同事评估AATD、COPD与吸烟之间的相互作用对肺癌生成的关系，同时评估这些因素对一般大众肺癌风险的相对影响；他们检验1997年到2003年之间在梅约诊所接受肺癌治疗病患、797位未接受治疗与健康的控制组、以及902位肺癌患者后裔的AAT对偶基因。
他们的分析显示，COPD病患罹患肺癌的风险是无COPD病患的6倍，且端看吸烟的程度，吸烟病患的风险比非吸烟者高2~9倍；环境二手烟（ETS）并不会显著增加肺癌风险，但检验吸烟程度发现，吸烟程度越高，有罹癌机率越高的趋势；吸烟程度分级包括从未吸烟且没有ETS、从未吸烟但有ETS、轻度、中度与重度吸烟者。
【相较于未接受治疗的控制组】
肺癌患者中AATD整体带原机率为13.4%，未接受治疗控制组则是7.8%；带原者发生肺癌的风险比非带原者高70%，有吸烟或无吸烟且有COPD病史分别增加肺癌风险2.5至5.9倍，对于从未吸烟者的影响最大。
在带原者之间，发生肺癌的风险与吸烟史并无绝对关系，在校正包括未确认COPD等影响因子后，带原者罹患肺癌的风险是非带原者的2.2倍；轻度吸烟的带原者罹患肺癌风险是非带原者的2.3倍。
【相较于肺癌病患的后代】
当肺癌患者与他们未罹癌的后代比较时，肺癌患者与未接受治疗控制组有相似的结果：AATD带原者罹患癌症的风险是后代控制组的2倍；研究者预估AATD带原者可能占了参与该研究病患的11%~12%肺癌病例。
作者表示，世界卫生组织估计，目前至少有1千万美国人以及全球1亿2千万人口是AATD带原者，这些结果代表AATD对罹患肺癌风险的显著影响，同时凸显了找出可能容易受致癌原影响的人们将有潜在的好处。
Yang医师相信，那些AATD高危险群病患，例如有肺癌家族遗传史或是早发性肺气肿的人们应该接受基因筛检；然而，目前的检验是根据蛋白质以及临床诊断；这些技术应用在筛检上并不可行，仍需要研发DNA为主的检验，这比较适合用在筛检用途。
她表示，最终，这些资讯将可以提供罹患肺癌的AATD带原者更具专一性的治疗，且这正在研发中。
这项研究由国家卫生研究院赞助。研究者表示无相关资金上的往来。
Alpha1-Antitrypsin Deficiency Significantly Increases Risk for Lung Cancer
By Roxanne Nelson
Medscape Medical News
Alpha1-antitrypsin deficiency (AATD) can greatly increase the risk for lung cancer, researchers report. AATD carriers might have a risk of developing lung cancer that is 70% higher than that for noncarriers, according to new data published in the May 26 issue of Archives of Internal Medicine.
Previous studies have shown that chronic obstructive pulmonary disease (COPD) is an independent risk factor for lung cancer. "COPD in general is associated with an increased risk of lung cancer, but alpha-1 antitrypsin deficiency carriers are more prone to early-onset emphysema," lead author Ping Yang, MD, PhD, professor of epidemiology at the Mayo Clinic, in Rochester, Minnesota, told Medscape Oncology.
AATD is one of the most common genetic conditions affecting people in the United States, particularly those of European descent. Among homozygous people, it can lead to early-onset of emphysema; heterozygous people might be unaware of their status as carriers and generally do not experience AATD-related diseases. However, carriers of AATD might be more vulnerable to the carcinogenic effects of tobacco smoke than the general population, especially when their levels of alpha1-antirypsin are compromised by physiologic stress or if they already have some degree of lung-tissue damage.
The authors note that the development of lung cancer is a complex and multistage process that involves numerous factors that are intrinsic and extrinsic to the host. Noxious substances in tobacco smoke can damage the DNA of cells and also stimulate an inflammatory response in the lung. Conversely, host mechanisms can inactivate harmful substances in tobacco smoke, remove or repair damaged DNA, and adapt the stimulants by structural changes in the lung tissue. The underlying mechanism of lung cancer encompasses an intricate interplay of these factors.
In this study, Dr. Yang and colleagues evaluated the interplay of AATD, COPD, and cigarette smoking in lung cancer development and estimated the relative contributions of such factors to lung cancer risk in the general population. They tested AAT allele types in 1443 patients with lung cancer treated at the Mayo Clinic from 1997 to 2003, 797 unrelated and healthy controls, and 902 full siblings of the lung cancer patients.
Their analysis showed that the risk for lung cancer in people with COPD was more than 6 times the risk in people without COPD and, depending on the intensity of tobacco use, the risk for smokers was 2 to 9 times higher than the risk for nonsmokers. Environmental tobacco smoke (ETS) did not significantly increase the risk for lung cancer, but a trend test of 5-level cigarette-smoking-exposure intensity was significant; it included never smokers with no ETS, never smokers with ETS, and light, moderate, and heavy smokers.
Comparison With Unrelated Controls
The overall carrier rate of AATD among the lung cancer patients was 13.4%; for the unrelated control group it was 7.8%. The risk for lung cancer was 70% higher in carriers than in noncarriers. A history of COPD increased lung cancer risk 2.5- to 5.9-fold among smokers and nonsmokers, with the greatest influence in never smokers
Among carriers, the risk of developing lung cancer was similar regardless of smoking history. The risk for lung cancer in carriers was 2.2 times the risk in noncarriers, after adjustment for confounders that included a history of unspecified COPD. Carriers who were light smokers had a risk for lung cancer that was more than 2 times greater than the risk for noncarriers; carriers who were moderate to heavy smokers had a risk 2.3 times greater than noncarriers.
Comparison With Siblings
When lung cancer patients were compared with their cancer-free siblings, the results were similar to those seen in the comparison between patients and unrelated controls: the AATD carriers had twice the risk of developing lung cancer as the sibling controls. The researchers estimated that AATD carrier status might account for 11% to 12% of the lung cancer in patients who participated in this study.
The authors note that according to estimates from the World Health Organization, there are at least 10?million Americans and 120?million people worldwide who are AATD carriers. These results indicate a potentially significant impact of AATD on the risk for lung cancer, and highlight the potential benefit of identifying people who might have an increased vulnerability to carcinogens.
Dr. Yang believes that people who appear to be at a higher risk for AATD, such as those with a family history of lung cancer or early-onset emphysema, should be screened. "However, the current test is protein based and meant for clinical diagnosis," she said. "It is not feasible to use it for screening purposes. A DNA-based test, which still needs to be developed, is more suitable for the purpose of screening."
Eventually, this information could lead to more targeted therapy for lung cancer patients who are AATD carriers, and that is under investigation, she added.
The study was supported by grants from the National Institutes of Health. The researchers have disclosed no relevant financial relationships.
Arch Intern Med. 2008;168:1097-1103