香煙留給你的絕對不止衣服和指甲上的嗆人氣味。一項新的研究找到了有力證據(jù)，表明煙草的使用能夠在化學上改變和影響那些已知可以增加罹患癌癥風險的基因的活性。這項研究或許能夠為研究人員提供新的工具，用以評估吸煙人群的癌癥風險。

　　脫氧核糖核酸（DNA）并不是命中注定的。能夠影響基因功能的化合物可以與我們的遺傳物質結合，從而開啟或關閉某些基因。這些所謂的后天修飾能夠影響各種各樣的特征，例如肥胖和性取向?？茖W家甚至已經(jīng)確定了吸煙人群基因的特定表觀遺傳模式。然而，由于沒有發(fā)現(xiàn)修改后的基因與癌癥任何直接聯(lián)系，因此科學家并不清楚這些化學變化是否增加了罹患癌癥的風險。

　　在發(fā)表于《人類分子遺傳學》雜志上的這項最新研究中，研究人員分析了來自374名個體的血細胞后生特征，這些人都參與了一項歐洲癌癥與營養(yǎng)前瞻性調查（EPIC）。正如人們所知道的那樣，EPIC是一項目的在于搞清飲食、生活習慣和環(huán)境因素與癌癥及其他慢性疾病發(fā)病率之間聯(lián)系的大型研究。其中有一半受試者在第一次加入這項研究的5到7年后患上了結腸癌或乳腺癌，而另一半受試者則依然保持健康。

　　由英國倫敦帝國學院的人類遺傳學家James Flanagan率領的這一研究團隊，在那些作為“煙民”的研究受試者中發(fā)現(xiàn)了一種獨特的“后生足跡”。與那些從未吸煙的人相比，這些人在其DNA的20個不同區(qū)域中具有更少的被稱為甲基組的化學標記，后者是后生變化的一種常見類型。當研究人員將這項分析延伸到暴露在煙草煙霧下的一組單獨病人和小鼠后，他們將后天修飾的范圍縮小到之前被認為與癌癥有微弱聯(lián)系的4個基因的幾個位點上。Flanagan 指出，所有這些變化都會增加這幾種基因的活性。他說，尚不清楚為什么增加這些基因的活性能夠導致癌癥，但未曾患癌癥的人通常不攜帶這些修飾。

　　美國愛荷華大學的行為遺傳學家Robert Philibert指出，這項研究第一次在一種癌癥基因的后天修飾與罹患這種疾病的風險之間建立了一種密切的聯(lián)系。海德爾堡德國癌癥研究中心的流行病學家Lutz Breitling強調：“據(jù)我所知，之前還沒有一項全基因組的表觀遺傳學研究進行過這樣的嘗試——從最初的發(fā)現(xiàn)到重復實驗證據(jù)。”

　　這項研究可能為評估吸煙人群的癌癥風險開辟了一條新的道路。Flanagan表示：“之前有關吸煙的研究經(jīng)常會要求人們填寫問卷表……這里存在著明顯的缺點和誤差。”他說，新的研究使醫(yī)生們只需簡單對人們的DNA進行后生分析便將量化一個人的患癌風險成為了可能。

　　Epigenome-wide association study in the European Prospective Investigation into Cancer and Nutrition (EPIC-Turin) identifies novel genetic loci associated with smoking

　　Natalie S. Shenker1, Silvia Polidoro2, Karin van Veldhoven2,3,Carlotta Sacerdote2, Fulvio Ricceri2, Mark A. Birrell4, Maria G. Belvisi4,Robert Brown1, Paolo Vineis2,3 and James M. Flanagan1,*

　　A single cytosine–guanine dinucleotide (CpG) site within coagulation factor II (thrombin) receptor-like 3 (F2RL3) was recently found to be hypomethylated in pe**heral blood genomic DNA from smokers compared with former and non-smokers. We performed two epigenome-wide association studies (EWAS) nested in a prospective healthy cohort using the Illumina 450K Methylation Beadchip. The two populations consisted of matched pairs of healthy individuals (n = 374), of which half went on to develop breast or colon cancer. The association was analysed between methylation and smoking status, as well as cancer risk. In addition to the same locus in F2RL3, we report several loci that are hypomethylated in smokers compared with former and non-smokers, including an intragenic region of the aryl hydrocarbon receptor repressor gene (AHRR; cg05575921, P = 2.31 × 10??15; effect size = 14–17%), an intergenic CpG island on 2q37.1 (cg21566642, P = 3.73 × 10??13; effect size = 12%) and a further intergenic region at 6p21.33 (cg06126421, P = 4.96 × 10??11, effect size = 7–8%). Bisulphite pyrosequencing validated six loci in a further independent population of healthy individuals (n = 180). Methylation levels in AHRR were also significantly decreased (P < 0.001) and expression increased (P = 0.0047) in the lung tissue of current smokers compared with non-smokers. This was further validated in a mouse model of smoke exposure. We observed an association with breast cancer risk for the 2q37.1 locus (P = 0.003, adjusted for the smoking status), but not for the other loci associated with smoking. These data show that smoking has a direct effect on the epigenome in lung tissue, which is also detectable in pe**heral blood DNA and may contribute to cancer risk.