非小细胞肺癌驱动基因突变谱及其临床病理 特征相关性的研究进展

Research Progress on Driver Gene Mutation Profiles in Non-Small Cell Lung Cancer and Their Association with Clinicopathological Characteristics

摘要: 非小细胞肺癌(non-small cell lung cancer, NSCLC)是肺癌最主要病理亚型，肿瘤发生演进与多种驱动基因异常密切相关。伴随分子病理检测、二代测序(next-generation sequencing, NGS)技术普及，表皮生长因子受体(EGFR)、间变性淋巴瘤激酶(ALK)、KRAS、ROS1、BRAF、HER2、MET、RET等驱动基因已成为NSCLC精准诊疗核心靶点。不同驱动基因突变的人群发生率、分子分布模式及临床预后价值存在显著差异，且与患者性别、年龄、吸烟史、组织病理类型、临床分期、远处转移状态等临床病理指标高度关联。EGFR突变多见于女性、无吸烟史肺腺癌患者；ALK融合高发于年轻腺癌人群；KRAS突变则集中于男性、长期吸烟患者。多基因联合检测的广泛应用，使驱动基因共突变、治疗后异时性突变、靶向耐药相关基因变异逐渐成为研究热点。目前国内尚缺乏整合全国多地域、含少数民族队列数据，系统阐释中国人群NSCLC驱动基因谱与临床病理特征的综述。本文系统梳理NSCLC高频、低频驱动基因突变分布特征，归纳突变与临床病理指标的关联规律，总结共突变、肿瘤时空异质性特点，综述各靶点靶向治疗方案与耐药机制，同时分层阐述国内分子检测实施策略，旨在为NSCLC分子分型、个体化精准治疗提供循证参考。

Abstract: Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer cases, and its initiation and progression are tightly regulated by multiple driver gene alterations. With the advancement of molecular pathological detection and next-generation sequencing (NGS), driver genes including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), KRAS, ROS1, BRAF, HER2, MET and RET have become pivotal targets for precision diagnosis and treatment of NSCLC. The incidence, distribution pattern and clinical significance of distinct driver gene variants vary among NSCLC patients, and these variants are significantly correlated with clinicopathological factors such as gender, age, smoking history, histological subtype, clinical stage and metastatic status. EGFR mutations are predominant in female, never-smoking patients with lung adenocarcinoma; ALK rearrangements are more prevalent in younger patients; while KRAS mutations mainly occur in male and heavy-smoking populations. The popularization of multigene panel testing has attracted increasing attention to driver gene co-mutations, metachronous genetic alterations and resistance-related variants. Nevertheless, systematic reviews integrating driver gene profiles and matched clinicopathological data based on Chinese multi-regional cohorts (including ethnic minority populations) remain scarce. This review summarizes the mutational landscape of common driver genes in NSCLC, elaborates their correlations with clinicopathological features, characterizes co-mutation patterns and tumor heterogeneity, updates targeted therapeutic regimens and underlying drug resistance mechanisms, and proposes hierarchical molecular testing strategies adapted to domestic medical conditions, so as to provide evidence-based references for molecular subtyping and individualized management of NSCLC.