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张晓东, 刘德若. 肺腺癌新分类与表皮生长因子受体基因突变之间的关系. 北京大学学报(医学版), 2018,50(4): 640-644.
ZHANG Xiao-dong, LIU De-ruo. Correlation between the new lung adenocarcinoma classification and epidermal growth factor receptor mutation. Journal of Peking University(Health Sciences), 2018,50(4): 640-644.  
Doi: 10.3969/j.issn.1671-167X.2018.04.012
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肺腺癌新分类与表皮生长因子受体基因突变之间的关系
张晓东1, 刘德若2,△
1.北京大学国际医院胸外科, 北京 102206
2.中日友好医院胸外科, 北京 100029
收稿日期: 2017-11-24
摘要

目的: 探讨肺腺癌新分类与表皮生长因子受体(epidermal growth factor receptor, EGFR)基因突变之间的关系。方法: 共纳入中日友好医院2010年3月至2014年12月经手术肺切除术后且病理证实为浸润性肺腺癌患者94例,对其进行 EGFR基因突变检测;入组患者均按照2011 年国际肺癌研究学会(Intemational Association for the Study of Lung Cancer,IASLC)、美国胸科学会(American Thoracic Society,ATS)和欧洲呼吸学会(European Respiratory Society,ERS)分类方法进行肺腺癌亚型分类,分析肺腺癌新分类与 EGFR基因突变之间的关系;采用SPSS 20.0统计软件卡方检验分析, P<0.05为差异有统计学意义。结果: 入组的94例肺腺癌患者,男、女患者均为47例;年龄24~79岁,中位年龄61岁,60岁及以上48例,60岁以下46例;既往或现在吸烟者34例,不吸烟者60例。根据病理分期,Ⅰ期患者34例,Ⅱ期患者17例,Ⅲ期24例,Ⅳ期19例。 EGFR基因外显子19突变例数22,外显子20突变例数2,外显子21突变例数26,外显子10和21同时突变例数1,入组患者 EGFR基因总突变率为54.3%(51/94),其中腺泡状为主型肺腺癌 EGFR突变例数24例,伏壁状为主型肺腺癌14例,乳头状为主型肺腺癌与实体状为主型肺腺癌均为5例,微乳头状为主型肺腺癌3例,黏液腺癌为0;腺泡状为主型肺腺癌较非腺泡状为主型肺腺癌 EGFR突变率高,但差异无统计学意义(66.7% vs. 46.6%, P=0.057);实体状为主型肺腺癌较非实体状为主型肺腺癌 EGFR突变率低,差异有统计学意义(26.3% vs. 61.3%, P=0.005);黏液腺癌较非黏液腺癌 EGFR基因突变率低,差异有统计学意义(0 vs. 57.3%, P=0.018)。结论: 不同的病理亚型肺腺癌 EGFR突变率存在差异,其中腺泡状为主型肺腺癌较非腺泡状为主型肺腺癌的 EGFR基因突变发生率高,实性为主型肺腺癌较非实性为主肺腺癌 EGFR突变发生率低,黏液腺癌较非黏液腺癌 EGFR基因突变率低。

关键词: 肺腺癌; 表皮生长因子受体; 基因突变
中图分类号:R655.3 文献标志码:A 文章编号:1671-167X(2018)04-0640-05
Correlation between the new lung adenocarcinoma classification and epidermal growth factor receptor mutation
ZHANG Xiao-dong1, LIU De-ruo2,△
1.Department of Thoracic Surgery, Peking University International Hospital, Beijing 102206, China
2.Department of Thoracic Surgery, China-Japan Friendship Hospital, Beijing 100029, China
△ Corresponding author's e-mail, deruoliu@sina.vip.com
Abstract

Objective: To evaluate the association of the histological subtype of lung adenocarcinoma with epidermal growth factor receptor ( EGFR) mutation.Methods: A total of 94 patients with resected lung adenocarcinoma in the Department of Thoracic Surgery of China-Japan Friendship Hospital from Ja-nuary 2010 to December 2014 were enrolled in the study. All specimens were tested for EGFR mutation by a company. In the 94 patients, histological subtypes were classified according to the 2011 International Association for the Study of Lung Cancer and American Thoracic Society and European Respiratory Society classification. We compared the association with the histological subtype of lung adenocarcinoma with EGFR mutation frequency by the χ2 test, with SPSS 20.0.Results: The 94 patients of surgically resected lung adenocarcinomas were included in this analysis,of whom,47 were male and 47 female (male :female= 1 :1) . The median age was 61 (range: 24-79) years, and 48 of the 94 patients were 60 years and above. Regarding the pathological staging, 34 patients were diagnosed as Stage Ⅰ of the disease,17 as Stage Ⅱ,24 as Stage Ⅲ, and 19 as Stage Ⅳ. Among the 51 patients with EGFR mutation, exon 19 mutation was 22, exon 20 mutation was 2, exon 21 mutation was 26, exon 20 and 21 mutation were 1, and the total EGFR mutation rate was 54.3% (51/94). The cases of EGFR gene mutation of acinar predominant lung adenocarcinoma, lepidic predominant lung adenocarcinoma, papillary predominant lung adenocarcinoma, solid predominant lung adenocarcinoma, micropapillary predominant lung adenocarcinoma and mucious adenocarcinoma were 24, 14, 5, 5, 3, and 0, respectively. The rate of EGFR gene mutation of acinar predominant lung adenocarcinoma was higher than that of non-acinar predominant lung adenocarcinom, but there was not statistically significant (66.7% vs. 46.6%, P=0.057). The rate of EGFR gene mutation of solid predominant lung adenocarcinoma was lower than that of non-solid predominant lung adenocarcinom (26.3% vs. 61.3%, P=0.005). The rate of EGFR gene mutation of mucious adenocarcinoma was lower than that of non-mucious adenocarcinom (0 vs. 57.3%, P=0.018).Conclusion: There is heterogeneity of EGFR mutation in lung adenocarcinoma. The presence of lung adenocarcinoma with acinar indicates a higher EGFR mutation rate, while the solid and mucinous component indicates a lower EGFR mutation rate.

Key words: Epidermal growth factor receptor; Lung adenocarcinoma; Mutation

肺癌是当今世界最常见的恶性肿瘤, 男性肺癌的发病率最高, 女性肺癌发病率仅次于乳腺癌[1] 。根据组织学特征和治疗方法的不同, 可以把肺癌分成两大类:非小细胞肺癌(non-small cell lung can-cer, NSCLC) 和小细胞肺癌(small cell lung cancer, SCLC)。NSCLC占肺癌总病例数的75%~85%, 其中腺癌又是主要的类型。2011 年国际肺癌研究学会(Intemational Association for the Study of Lung Cancer, IASLC)、美国胸科学会(American Thoracic Society, ATS)和欧洲呼吸学会(European Respiratory Society, ERS)联合多学科共同发起了关于肺腺癌的国际多学科分类方法[2]。该肺腺癌新分类方法提供了统一的专业术语及诊断标准, 取消了细支气管肺泡癌这一分类, 新增了4 个命名:原位腺癌、微浸润性腺癌、浸润性腺癌和浸润性黏液型腺癌, 其中浸润性腺癌包括伏壁状为主、腺泡状为主、乳头状为主、微乳头状为主、实体状为主、黏液腺癌、胎儿型腺癌、胶样癌和肠型腺癌。

据统计, 肺腺癌患者的总手术切除率仅有25%, 5年生存率低于20%[1], 靶向药物的临床应用一定程度上改善了这一现状。表皮生长因子受体(epidermal growth factor receptor, EGFR)是一种蛋白酪氨酸激酶受体(receptor tyrosine kinase, RTK) [3]。研究证实, 具有EGFR基因突变的肺腺癌患者接受EGFR酪氨酸激酶抑制剂(tyrosine kinase inhibitors, TKIs)的治疗能够明显改善生存期[4, 5]。相对于化疗, EGFR基因突变的肺腺癌患者接受EGFR-TKIs治疗的总生存率(overall survival, OS)和无进展生存率(progress free survival, PFS)明显改善[6, 7]。大量数据已表明, EGFR-TKIs已经成为肺腺癌患者的标准治疗。美国病理学协会、IASLC最近出版了肺癌EGFR突变的分子检测建议, 指出患有晚期肺腺癌的所有患者, 无论性别、种族、是否有吸烟史或其他临床危险因素, 都应该进行EGFR基因检测[8]。

尽管近年来已经发表了一些关于EGFR突变的腺癌亚型的报道, 但是新的肺腺癌病理亚型分类与EGFR突变的关系仍尚未明确, 因此, 本研究通过检测94例肺腺癌患者EGFR的突变情况, 探讨新的肺腺癌分类中不同病理亚型与EGFR突变之间的关系。

1 资料与方法
1.1 研究对象

共纳入中日友好医院2010年3月至2014年12月经手术肺切除术后病理证实为浸润性肺腺癌患者94例。组织学类型根据世界卫生组织(World Health Organization, WHO)(2015年)肺肿瘤组织学分类方法确诊为肺腺癌。病理分期是根据美国癌症联合委员会(American Joint Committee on Cancer, AJCC)提出的癌症分期方法。

1.2 研究方法

所有入组肺腺癌患者均按照2011 年IASLC/ATS/ERS提出的分类方法进行肺腺癌亚型分类。

EGFR基因突变情况由益善生物技术股份有限公司测定, 检测患者EGFR主要突变基因18、19、20及21外显子。

1.3 统计学分析

采用SPSS 20.0软件, 统计分析方法采用卡方检验及Fisher精确概率法分析分类变量, P< 0.05认为差异有统计学意义。

2 结果

纳入的94例肺腺癌患者中, 男、女均为47例; 年龄24~79岁, 中位年龄61岁, 60岁及以上48例, 60岁以下46例。根据吸烟史统计, 既往或现在吸烟者34例, 不吸烟者60例。根据病理分期, Ⅰ 期患者34例, Ⅱ 期患者17例, Ⅲ 期24例, Ⅳ 期19例。EGFR基因外显子19突变例数22, 外显子20突变例数2, 外显子21突变例数26, 外显子10和21突变例数1, 具体见表1。

表1 94例肺腺癌患者临床病理特征 Table 1 Clinicopathological features of 94 cases of lung adenocarcinomas

入组94例肺腺癌患者EGFR基因总突变率为54.3%(51/94), 其中, 腺泡状为主型肺腺癌EGFR突变例数24例, 伏壁状为主型肺腺癌14例, 乳头状为主型肺腺癌与实体状为主型肺腺癌均为5例, 微乳头状为主型肺腺癌3例, 黏液腺癌为0; 腺泡状为主型肺腺癌较非腺泡状为主型肺腺癌EGFR突变率高, 但差异无统计学意义(66.7% vs. 46.6%, P=0.057); 伏壁状为主型肺腺癌与非伏壁状为主型肺腺癌EGFR突变率差异无统计学意义(66.7% vs. 50.7%, P=0.195); 乳头状为主型肺腺癌与非乳头状为主型肺腺癌EGFR突变率差异无统计学意义(55.6% vs. 54.1%, P=1.000); 实体状为主型肺腺癌较非实体状为主型肺腺癌EGFR突变率低(26.3% vs. 61.3%, P=0.005); 微乳头状为主型肺腺癌与非微乳头状为主型肺腺癌EGFR突变率差异无统计学意义(75.0% vs. 53.3%, P=0.735); 黏液腺癌较非黏液腺癌EGFR基因突变率低(0 vs. 57.3%, P=0.018)。不同的病理亚型肺腺癌EGFR突变率存在差异, 其中腺泡状为主型肺腺癌EGFR基因突变率较高, 实体状为主型肺腺癌与黏液腺癌EGFR基因突变率较低, 具体见表2。

表2 94例肺腺癌患者组织学亚型与EGFR基因突变的关系 Table 2 Relationship between EGFR gene mutation and histologic subtypes with and without certain components of 94 lung adenocarcinoma cases
3 讨论

在检测到特定基因突变之前, 肺癌靶向药物已经应用于临床, 研究显示厄洛替尼、吉非替尼等能够明显改善患者病情[9, 10]。厄洛替尼与吉非替尼在临床的应用引起了人们对肺癌EGFR分子特点的探索, 研究发现, 一些基因突变使肺腺癌对吉非替尼的敏感性提高[11], 对这部分吉非替尼治疗敏感的患者进行EGFR基因的突变分析发现腺苷三磷酸依赖性TK区域发生突变[11, 12]。当前, EGFR TKIs已经作为肺腺癌的标准治疗出现在临床。

EGFR基因比较常见的突变区域是外显子19和外显子21突变[13]。据Eberhard等[13]及Paez等[14]的研究, 最常见的EGFR基因突变是外显子21点突变(L858R)和外显子19的缺失(del746-750)。Sakurada等[15]报道, 外显子19和外显子21突变占非小细胞肺癌的EGFR总突变的86%。本研究中, 在EGFR基因突变的外显子中, 外显子19和21的突变率最高, 分别为43.1%(22/51)和52.9%(27/51)。

Sun等[16]表示EGFR突变除与实体状为主腺癌有关外, 还与乳头状、伏壁状为主型和黏液腺癌有关, 而与微乳头状腺癌无关, 其他的研究[17, 18, 19]结果也不完全一致。研究[20, 21]表明, EGFR突变主要在微乳头状腺癌中比较常见, 其次是乳头状、腺泡状和伏壁状为主的腺癌, EGFR突变少见于实体状为主型腺癌。本研究显示, 94例入组肺腺癌患者EGFR基因突变率54.3%(51/94), 腺泡状为主型肺腺癌EGFR突变例数24例, 伏壁状为主型肺腺癌14例, 乳头状为主型肺腺癌与实体状为主型肺腺癌均为5例, 微乳头状为主型肺腺癌3例, 黏液腺癌为0; EGFR基因突变常见于腺泡状为主、伏壁状为主型肺腺癌, 少见于乳头状为主、实体状为主、微乳头状为主及黏液腺癌, 与之前文献报道结果并不完全一致[16, 17, 18, 19, 20, 21]。

Lee等[22]对138例肺切除标本研究分析发现, 微小浸润性肺腺癌、乳头状为主肺腺癌和原位腺癌EGFR基因突变率较高。Kim等[23]通过对小组织活检肺腺癌标本研究发现, EGFR基因突变率最高的是乳头状为主腺癌, 达81.3%, 其次为伏壁状为主(70.4%)、腺泡状为主(58.1%)。Nakamura等[24]的研究发现腺泡状为主肺腺癌EGFR基因突变率高。本研究显示, 腺泡状为主型肺腺癌较非腺泡状为主型肺腺癌EGFR突变率高, 但差异无统计学意义(66.7%vs.46.6%, P=0.057); 实体状为主型肺腺癌较非实体状为主型肺腺癌EGFR突变率低

(26.3% vs. 61.3%, P=0.005); 黏液腺癌较非黏液腺癌EGFR基因突变率低(0 vs. 57.3%, P=0.018)。伏壁状为主型、乳头状为主型、微乳头状为主型肺腺癌EGFR突变率差异无统计学意义(P> 0.05)。本研究结果与其他研究结果[22, 23, 24]不完全一致, 原因可能是本研究样本量较小, 纳入的对象均为浸润性肺腺癌患者, 不包括微小浸润性肺腺癌、原位腺癌的患者。

浸润性肺腺癌是肺腺癌新分类中的主要类型, 腺泡状为主肺腺癌EGFR突变率更高, 而实体状为主型、黏液腺癌等却较低。目前不管哪种肺腺癌的组织学亚型, 都不能完全预测EGFR的突变状态, 肺腺癌组织学亚型与EGFR基因突变是否具有确定关系仍需要我们进一步探索。

(本文编辑:刘淑萍)

The authors have declared that no competing interests exist.

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