中国年轻人肺腺癌癌基因及抑癌基因的突变研究

The high prevalence of early-onset lung cancer has attracted increasingattentions. It has its specific characteristics including large percentage of adenocarcinoma and female patients, high malignancy and poor prognosis. However, the mechanism of lung cancer with early onset is still unknown. Epidemiological analyses reveal that genetic changes may be the main factors. Our previous studies primarily focus on the molecular and gene analysis of non-small cell lung cancer. And some of ourresults show that oncogene mutations are frequently found in Chinese NSCLC, especially in adenocarcinoma, which have been published on several renowned journals such as JCO, JTO, Lung Cancer. Based on our previous researches, we hypothesis that both oncogene and tumor suppress gene mutation are possibly prevalent in early-onset lung cancer. Especially,tumor suppress gene mutation may be a more important contributor regarding the early occurrence and high malignancy of the tumor. And the results of our preliminary research analyzing fifteen young patients with adenocarcinoma were consistent with our hypothesis.This study aims to evaluate the gene mutation prevalence including the oncogene and tumor suppress gene in lung cancer with early-onset, to clarify the relation between the gene mutation status and the clinical and pathological variables of patients through the comparison between young lung cancer patients (≤40y)and the others(> 40y), and to testify the function of the newly-found mutated gene on the cytological level by the means of the molecular cloning techniques.

年轻人肺癌（≤40岁）以腺癌为主，遗传因素可能是发病关键环节，但机制未明。本课题组前期发现中国人肺腺癌中存在多个癌基因突变，预实验提示年轻人肺腺癌中存在抑癌基因突变率高、癌基因突变率较低。癌基因/抑癌基因突变与年轻人肺腺癌发病有关，我们提出假说：年轻人肺腺癌的发生过程中不仅存在癌基因的累积突变，抑癌基因的杂合性和纯合性缺失可能也是的重要原因。本项目拟从临床和体外层面进行验证，内容包括：1）应用PCR、FISH等技术，比较年轻人肺腺癌（≤40岁）和其他肺腺癌（>40岁）常见癌基因和抑癌基因突变的差异，分析各种基因突变与年轻人肺腺癌临床病理特征的相关性，并绘制我国年轻人肺腺癌的癌基因和抑癌基因突变谱；本项目为我国年轻人肺腺癌发病机制提供新思路。

研究背景：年轻人肺腺癌患者是否具有独特的临床病理学特征尚不明确。年轻人肺癌常见癌基因及抑癌基因的突变特点也不明确。.研究方法：本项目采用PCR、FISH等技术比较了47例年轻人(≤40岁)肺腺癌和87例其他（＞40岁）肺腺癌癌基因和抑癌基因突变的差异、与临床病理特征的关系，绘制我国年轻人肺腺癌的基因突变谱。.研究结果：本次研究发现47例年轻人肺腺癌中存在26例EGFR突变（55.3%），3例KRAS突变（6.4%），2例ALK融合（4.3%），1例RET融合（2.1%），1例HER2突变（2.1%），1例MET融合（2.1%）和1例AKT突变（2.1%）。同时对抑癌基因TP53和LKB1的突变检测发现了25例TP53突变（53.2%），其中23例的突变形式为P72R（48.9%）；4例LKB1突变（8.5%）。中国年轻人(≤40岁)肺腺癌患者与其他肺腺癌（＞40岁）患者在癌基因突变方面并无差异（P=0.943）；但中国年轻人(≤40岁)肺腺癌患者中抑癌基因TP53的突变率明显高于其他肺腺癌（＞40岁）患者（P=0.001）；而抑癌基因LKB1的突变率两者相似（P=0.590）。另外在临床病理学特点方面的比较发现，年轻人(≤40岁)肺腺癌患者中不吸烟患者的比例高于其他肺腺癌（＞40岁）患者（P=0.001）； 原位腺癌和微浸润腺癌的比例也高于其他肺腺癌（＞40岁）患者（P=0.044）；但在浸润性腺癌中两者的病理分期相似（P=0.245）。.研究结论：中国年轻人肺腺癌具有独特的临床病理学特征。癌基因的突变特点和其他肺腺癌患者并无差异，但抑癌基因TP53的突变率较高。