文章：

晚期非小细胞肺癌的分子病理学：生物标志物与治疗决策

Molecular Pathology of Advanced NSCLC: Biomarkers and Therapeutic Decisions

原文发布日期：9 January 2026

DOI: 10.3390/cancers18020216

类型: Article

开放获取: 是

英文摘要：

Background:Advances in molecular pathology have transformed NSCLC (Non-Small Cell Lung Cancer) diagnosis, prognosis, and treatment by enabling precise tumor characterization and targeted therapeutic strategies. We review key genomic alterations in NSCLC, includingEGFR(epidermal growth factor receptor) mutations,ALK(anaplastic lymphoma kinase) andROS1(ROS proto-oncogene 1) rearrangements,BRAF(B-Raf proto-oncogene serine/threonine kinase) mutations,MET(mesenchymal–epithelial transition factor) alterations,KRAS(Kirsten rat sarcoma) mutations,HER2(human epidermal growth factor receptor 2) alterations and emergingNTRK(neurotrophic receptor tyrosine kinase) fusions andAXL-related pathways.Methods:A total of 48 patients with NSCLC was analyzed, including 22 women and 26 men (mean age 70 years, range 44–86). Tumor specimens were classified histologically as adenocarcinomas (n= 81%) or squamous cell carcinomas (n= 19%). Smoking history, PD-L1 (programmed death-ligand 1) expression, and genetic alterations were assessed. NGS (Next-generation sequencing) identified genomic variants, which were classified according to ACMG (American College of Medical Genetics and Genomics) guidelines.Results:The cohort consisted of 29 former smokers, 13 current smokers, and 5 non-smokers (12%), with a mean smoking burden of 33 pack years. PD-L1 TPS (tumor proportion score) was ≥50% in 10 patients, ≥1–<50% in 22, and <1% in 15 patients. In total, 120 genomic variants were detected (allele frequency ≥ 5%). Of these, 52 (43%) were classified as likely pathogenic or pathogenic, 48 (40%) as variants of unknown significance, and 20 (17%) as benign or likely benign. The most frequently altered genes wereTP53(tumor protein p53) (31%),KRASandEGFR(15% each), andSTK11(serine/threonine kinase 11) (12%). Adenocarcinomas accounted for 89% of all alterations, withTP53(21%) andKRAS(15%) being most common, while squamous cell carcinomas predominantly harboredTP53(38%) andMET(15%) mutations. In patients with PD-L1 TPS ≥ 50%,KRASmutations were enriched (50%), particularlyKRASG12C and G12D, with frequent co-occurrence ofTP53mutations (20%). No pathogenic EGFR mutations were detected in this subgroup.Conclusions:Comprehensive genomic profiling in NSCLC revealed a high prevalence of clinically relevant mutations, withTP53,KRASandEGFRas the dominant drivers. The strong association ofKRASmutations with high PD-L1 expression, irrespective of smoking history, highlights the interplay between genetic and immunological pathways in NSCLC. These findings support the routine implementation of broad molecular testing to guide precision oncology approaches in both adenocarcinoma and squamous cell carcinoma patients.

摘要翻译： 

背景：分子病理学进展通过实现精确的肿瘤表征和靶向治疗策略，改变了非小细胞肺癌（NSCLC）的诊断、预后和治疗。本文综述了NSCLC中的关键基因组改变，包括EGFR（表皮生长因子受体）突变，ALK（间变性淋巴瘤激酶）和ROS1（ROS原癌基因1）重排，BRAF（B-Raf原癌基因丝氨酸/苏氨酸激酶）突变，MET（间质-上皮细胞转化因子）改变，KRAS（Kirsten大鼠肉瘤病毒癌基因同源物）突变，HER2（人表皮生长因子受体2）改变，以及新兴的NTRK（神经营养受体酪氨酸激酶）融合和AXL相关通路。

方法：共分析了48例NSCLC患者，包括22例女性和26例男性（平均年龄70岁，范围44–86岁）。肿瘤标本按组织学分类为腺癌（81%）或鳞状细胞癌（19%）。评估了吸烟史、PD-L1（程序性死亡配体1）表达和遗传学改变。通过下一代测序（NGS）鉴定了基因组变异，并依据美国医学遗传学与基因组学学会（ACMG）指南进行分类。

结果：该队列包括29例既往吸烟者、13例当前吸烟者和5例非吸烟者（12%），平均吸烟负荷为33包年。PD-L1肿瘤比例评分（TPS）≥50%者10例，≥1%但<50%者22例，<1%者15例。共检测到120个基因组变异（等位基因频率≥5%）。其中，52个（43%）被归类为可能致病性或致病性变异，48个（40%）为意义未明变异，20个（17%）为良性或可能良性变异。最常见的变异基因是TP53（31%），KRAS和EGFR（各占15%），以及STK11（12%）。腺癌占所有变异的89%，其中最常见的是TP53（21%）和KRAS（15%），而鳞状细胞癌则主要携带TP53（38%）和MET（15%）突变。在PD-L1 TPS≥50%的患者中，KRAS突变富集（50%），特别是KRAS G12C和G12D突变，并常与TP53突变（20%）共存。在该亚组中未检测到致病性EGFR突变。

结论：NSCLC的综合基因组分析揭示了临床相关突变的高发生率，其中TP53、KRAS和EGFR是主要的驱动因素。无论吸烟史如何，KRAS突变与高PD-L1表达的强相关性，凸显了NSCLC中遗传学通路与免疫学通路之间的相互作用。这些发现支持在腺癌和鳞状细胞癌患者中常规实施广泛的分子检测，以指导精准肿瘤学治疗策略。

原文链接：

Molecular Pathology of Advanced NSCLC: Biomarkers and Therapeutic Decisions