188bet体育网址研究人员分析癌前病变定义在肺癌早期基因变化

尽管在肺癌治疗显著的进步，早期发现和预防的新途径仍然有限，因为肺癌发展的早期阶段仍不清楚。在最近的一项研究成果发表在癌症研究188bet体育网址, MD Anderson researchers have uncovered gene mutation and expression changes in lung cancer precursor cells to define the earliest events driving tumor progression.

Lung cancer is the leading cause of cancer mortality in the United States, with more than 220,000 new cases and 155,000 deaths expected in 2017, according to the American Cancer Society. Non-small cell lung cancer is the most common type of lung cancer, with lung adenocarcinoma (LUAD) being the most frequent subtype.

由于肺癌的症状往往不出现，直到在疾病晚期阶段，有必要提高早期发现和预防战略，以减少本病的显著影响。了解驱动正常组织向恶性肿瘤的遗传变化的目录，称为“癌前病变地图集”，可以提供洞察新的筛查和干预方法。

Atypical adenomatous hyperplasias (AAHs) are the only known precursors to LUAD, and therefore offer a rare opportunity to characterize the premalignant landscape, explains保罗Scheet博士, associate professor ofEpidemiology和相应的研究报告的作者。

对于目前的研究，通过Scheet和，私自Kadara，博士，谁现在是在贝鲁特的美国大学领导的研究人员对肺癌患者采取的正常组织，AAH和恶性LUAD的匹配样本进行深DNA和RNA测序188bet体育网址。这项研究是在为数不多的必须有进行AAHS这样的表征。

The researchers analyzed 67 normal, AAH and LUAD samples from 22 patients evaluated at Aichi Cancer Center (Nagoya, Japan) and Nagasaki University (Nagasaki, Japan) between 2011 and 2015. All but one of the patients had stage I lung cancers.

Among the AAH samples, 23 percent (5/22) had mutations in the oncogeneBRAF，已知在肺癌发展中的作用。有趣的是，匹配LUAD样品没有表现出BRAFmutations, but rather 4/5 displayed mutations inEGFR, another oncogene. These samples comprised both smokers and non-smokers.

The second-most common mutated oncogene in AAH samples wasKRAS与窝藏突变，所有这些都是曾经吸烟者的样本的18％（4/22）。匹配的恶性组织中其它肿瘤表现出司机的突变，包括TP53。

Notably, theKRAS和BRAFmutations showed mutual exclusivity in the AAH samples analyzed. The researchers discovered additional mutations in a number of additional oncogenes and tumor suppressors across the samples.

“我们的研究结果揭示了潜在的不同途径推动肺癌进展的前兆恶性肿瘤，” Smruthy西瓦库玛，M.S.，新毕业的实习生和研究的主要作者。“这表明可能有AAHS的不同亚组在驱动突变KRAS要么BRAF，各有不同的生物学意义“。

In addition to genetic mutations, the researchers performed RNA sequencing in a subset of samples (based on sample availability and quality) to characterize expression profiles throughout the process of LUAD development.

Genes involved in immune-cell trafficking andWNT/β-catenin signaling were elevated in AAHs, compared to normal lung tissue, whereas inflammatory response andTGFB1通路基因被压抑。此外，研究人员发现套的差异188bet体育网址表达基因AAHS与KRASmutations compared to those withBRAF突变，强调他们不同的途径肿瘤的发展。

LUAD样品显示与增加的细胞增殖相关的基因表达的变化和减少的细胞死亡，包括由经调节的EGFR,MYC和CSF2pathways.

基于对肿瘤发展的免疫反应称为角色，研究人员在他们的样本中免疫功能的已知标记更仔细地看了看，解释Scheet。188bet体育网址

一般地，这些发现表明亲肿瘤免疫途径和抗肿瘤免疫应答的基因抑制的激活AAHS与正常组织相比。LUAD样品显示基因表达的变化暗示降低T细胞活化，包括升高的表达的主要免疫检查点的蛋白质，CTLA-4。

“There is clearly a role for immune dysregulation early in the path of lung cancer development, as indicated by our results,” says Scheet. “This highlights a need to pursue research on immune-based intervention strategies at the earliest stages, before lung cancer has progressed to an aggressive malignancy.”

而限制由小数量的样本，这研究揭示了一些在肺癌发生的前体的最早变化的光。研究人员188bet体育网址希望继续与更多的样本，以更好地表征机制驾驶肿瘤的进展，在确定检测更好的标记或策略在患者个性化的预防与早期疾病的希望调查。