由Anne-Marie Baird博士撰写，Queensland University of Technology, Australia

Lung cancer is responsible for more cancer-related deaths worldwide than any other cancer type, accounting for approximately 1.37 million deaths annually¹。Data from the recent National Lung Screening Trial (NLST) has demonstrated that screening high-risk smokers with low dose helical CT lead to a reduction in lung cancer mortality by approximately 20% compared with chest radiography²。尽管这些结果是有希望的，但误报率很高²。兄弟们最近的评论等³讨论这些问题，并提供有关“弥合临床差距”的建议，例如使用筛选标记。这些标记可以采用遗传，转录组和表观遗传生物标志物的形式³。

肺癌可以在功能障碍的表观遗传环境中出现，导致原癌基因的激活和肿瘤抑制基因的沉默，通过表观遗传机制的变化，例如组蛋白修饰，DNA甲基化和miRNA调节等表观遗传机制。⁴。表观遗传相关的筛查生物标志物（例如DNA甲基化谱）还可以帮助确定应筛查哪些患者，除了确定哪些可疑结节可能需要手术⁴，因此大大改善了筛选过程。

A number of studies have been carried out in recent years examining the methylation pattern of genes, for example, in lung tissue, serum and sputum. In squamous cell carcinoma, the aberrant methylation of the promoter regions ofP16和/或Mgmt(O⁶-methylguanine-DNA methyltransferase) in sputum was detected in all patients up to three years before a clinical diagnosis of lung cancer⁵。其他几个基因的甲基化，包括：DAPK（与死亡相关的蛋白激酶），RASSF1A（RAS-COSITIATION域家庭成员1A），PAX5α/β（配对框5αβ），GATA4/5（环球蛋白转录因子4/5），SFRP1（像蛋白质1一样分泌毛躁），LAMC2（层粘连蛋白C2），H-辅助蛋白，，，，IGBP3（（insulin-like growth factor receptor 3),BETA3andHLHP（（helix loop helix) have also been studied to determine their use as putative biomarkers^{6，，，，7}。这些基因中的许多是已知的肿瘤抑制基因，并参与细胞凋亡，细胞增殖和基因组稳定性。Belinksy等证明了痰液中这些基因中的6种的甲基化（P16，，，，Mgmt，，，，DAPK, RASSF1A, PAX5β, GATA5）was associated with >50% increased lung cancer risk⁷。

An additional sputum study, conducted in 2012, expanded the panel to include 23 new candidate genes⁸and increased both the sensitivity (75%) and specificity (71-77%) in detecting lung cancer compared with the previous study⁷。This was using a seven-gene panel, which varied slightly depending on patient cohort. New genes in these panels includeddal-1（在肺腺癌中差异表达），PCDH20（prodocadherin-20），JPH3（（Junctophilin-3),kif1a（风化蛋白），Sulf2（细胞外硫酸酶）和CXCL14⁸。Silencing ofCXCL14通过启动子甲基化与肺癌风险显着相关。⁸CXCL14参与炎症和免疫调节过程。

It is widely accepted that inflammatory lung conditions can contribute to an increased lung cancer risk^9,10。DNA甲基化谱也可能有助于确定这些组中哪些患者，例如患有慢性粘液过度分泌（CMH）的患者。布鲁斯等¹¹检查了11个基因，这些基因通常通过CMH患者的痰液中的肺癌中的启动子甲基化而被沉默。这项研究发现，CMH与甲基化基因数量的总体增加包括Sulf2¹¹。In addition, they demonstrated that former male smokers with CMH ‘‘have increased promoter methylation of lung cancer risk genes and may be at risk from lung cancer.’’¹¹An encouraging recent study has refined the number of methylated genes further. Wrangle等¹²have shown that the methylation of one or any of these three genes:CDO1（（cysteine dioxygenase type 1),Hoxa9（（Homeobox protein A9) andTAC1（Protachyinin-1）在肺组织中具有100％的特异性，对非小细胞肺癌（NSCLC）的敏感性为83-99％：这些基因都是与多康布相关的基因¹²。It will be of interest to assess and validate the profile of these genes in other biological samples including sputum.

尽管需要进一步的工作来合并和完善候选DNA甲基化谱，但痰液和组织中的甲基化基因特征在早期肺癌检测中表现出巨大的希望。希望随着这些验证并将其带入临床环境，这些标记可以使患者的早期检测和分期能够提高，从而提高了肺癌患者的生存率和治愈率。最终，采用特定和敏感的“筛选标记”将增加CT筛查并使患有肺癌风险的人受益。

参考：

¹健康Organization. Cancer.事实说明书第297号。2013年1月。

²The National Lung Screening Trial Research Team (2011) Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening.N Engl J Med365：395-409。

³J.F.兄弟，Hijazi K.，Mascaux C.等（（2013) Bridging the clinical gaps: genetic, epigenetic and transcriptomic biomarkers for the early detection of lung cancer in the post-National Lung Cancer Screening Trial era.BMC医学11：168。

⁴Baylin S.B.和琼斯P.A.（2011）探索癌症表观基因组的十年 - 生物学和翻译意义。Nat Rev Cancer11，726-734。

⁵Palmisano W.A., Divine K.K., Saccomanno G.等（（2000) Predicting lung cancer by detecting aberrant promoter methylation in sputum. Cancer Res 60:20:5954-8.

⁶Kim C.E., Tchou-Wong K-M., and Rom W.N. (2011) Sputum-Based Molecular Biomarkers for the Early Detection of Lung Cancer: Limitations and Promise.Cancers (Basel)3（3）: 2975–2989.

⁷Belinsky S.A., Liechty K.C., Gentry F.D.,等（2006）痰中多个基因的启动子高甲基化在高危队列中的肺癌发生率之前。Can Res66;3338。

⁸Leng S.，Do K.，Yingling C.M.，等（2012）在痰中定义基因启动子甲基化特征进行肺癌风险评估。Clin Cancer Res18（12）：3387-95。

⁹Ballaz, S. and Mulshine J.L. (2003) The potential contributions of chronic inflammation to lung carcinogenesis。临床肺癌5（1）:46-62.

¹⁰Lee G.，Walser T.C.和Dubinett S.M.（2009）慢性炎症，慢性阻塞性肺疾病和肺癌。Curr Opin Pulm Med15（4）：303-307。

¹¹Bruse S.，Petersen H.，Weissfeld J.等(2014）Increased methylation of lung cancer-associated genes in sputum DNA of former smokers with chronic mucous hypersecretion.Respir res15:2.

¹²Wrangle J.，Machida E.O.，Danilova L.等(2014）Functional Identification of Cancer-Specific Methylation of CDO1, HOXA9, and TAC1 for the Diagnosis of Lung Cancer.Clin Cancer Res20：1856-1864。