【背景】多原发性肺癌（Multiple primary lung cancer, MPLC）是一种在同一或不同肺叶中同时或先后出现多个肿瘤结节的肺癌类型。随着低剂量螺旋CT筛查的广泛应用，MPLC的检出率显著提高，尤其在早期阶段的病例中更为常见。然而，对于拥有五个或更多原发性病灶的超级多原发性肺癌（super MPLC），其基因特征及分子机制尚未得到充分研究。这类患者常表现出多个独立病灶的同步存在，并且由于病灶数量多，容易被误诊为肺部感染或转移性肺癌。理解super MPLC的基因特征对于制定个性化治疗方案、降低疾病负担以及更好地理解肿瘤演化具有重要意义。

【方法】本研究通过对来自18名super MPLC患者的130个病灶样本进行全外显子组测序（Whole Exome Sequencing, WES），系统分析了super MPLC的基因组突变特征。所有患者均为I期肺腺癌患者（其中17人为IA期），且病灶数量均为五个及以上。研究通过比较super MPLC与少病灶MPLC及单病灶肺癌的基因特征，重点探讨了与MAPK和PI3K-Akt信号通路相关的突变特征。此外，本研究还分析了BRAF和EGFR基因突变的频率及其在不同病灶之间的分布模式。

【结果】研究结果显示super MPLC中的BRAF突变频率较高，达到31.5%，高于少病灶MPLC（11.0%）和单病灶肺癌患者；相反，EGFR突变的频率较低，仅为13.8%。随着病灶数量的增加，BRAF突变逐渐成为主导突变，尤其是BRAF的II类突变占比更高，而EGFR突变减少，这类独特的突变模式可能是super MPLC患者靶向治疗获益有限的一个原因。研究还显示，super MPLC的突变主要富集在MAPK和PI3K-Akt信号通路中，这与病灶较少的MPLC和早期单病灶肺癌存在显著差异。

【结论】本研究系统地揭示了super MPLC的独特基因组特征，并发现其突变模式与少病灶MPLC和单病灶肺癌存在差异。EGFR和BRAF Class I突变在super MPLC中的低频率，可能限制了现有EGFR-TKI和BRAF抑制剂等靶向治疗的应用。研究还表明，手术仍是super MPLC的重要治疗手段，而多学科团队的协作对于提高诊断准确性和治疗效果至关重要。

[Background] Multiple primary lung cancer (MPLC) is a type of lung cancer characterized by the presence of multiple tumor nodules occurring either simultaneously or sequentially in the same or different lobes of the lungs. With the widespread application of low-dose spiral CT screening, the detection rate of MPLC has significantly increased, particularly in early-stage cases. However, the genomic features and molecular mechanisms of super multiple primary lung cancer (super MPLC)—defined as having five or more primary lesions—remain poorly understood. These patients often present with multiple synchronous, independent lesions and are prone to misdiagnosis as pulmonary infections or metastatic lung cancer due to the large number of lesions. Understanding the genetic characteristics of super MPLC is essential for developing personalized treatment strategies, reducing disease burden, and improving our understanding of tumor evolution.

[Methods] This study performed whole-exome sequencing (WES) on 130 tumor samples from 18 patients diagnosed with super MPLC, all of whom had stage I lung adenocarcinoma (17 at stage IA) with five or more lesions. The study systematically analyzed the genomic mutation characteristics of super MPLC and compared them with those of MPLC with fewer lesions and single-lesion lung cancer. Special focus was given to mutations related to the MAPK and PI3K-Akt signaling pathways. Additionally, the frequency and distribution patterns of BRAF and EGFR mutations across different lesions were analyzed.

[Results] The study revealed that BRAF mutations were more frequent in super MPLC, reaching 31.5%, which is higher than that in MPLC with fewer lesions (11.0%) and in single-lesion lung cancer patients. In contrast, the frequency of EGFR mutations was relatively low, at only 13.8%. As the number of lesions increased, BRAF mutations gradually became the dominant driver, with a higher proportion of class II BRAF mutations, while EGFR mutations decreased. This distinct mutational pattern may partly explain the limited benefit of targeted therapy in super MPLC patients. Additionally, mutations in super MPLC were mainly enriched in the MAPK and PI3K-Akt signaling pathways, showing significant differences compared to MPLC with fewer lesions and early-stage single-lesion lung cancer.

[Conclusion] This study systematically reveals the distinct genomic features of super MPLC and highlights differences in mutation patterns compared with MPLC with fewer lesions and single-lesion lung cancer. The low frequency of EGFR and BRAF Class I mutations in super MPLC may limit the effectiveness of existing targeted therapies such as EGFR-TKIs and BRAF inhibitors. The findings also support that surgery remains a key treatment approach for super MPLC, and multidisciplinary team (MDT) collaboration is critical to ensuring accurate diagnosis and effective treatment.