Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
Department of Pathology and Translational Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
Cancer Res Treat. 2024 Apr;56(2):442-454. doi: 10.4143/crt.2023.764. Epub 2023 Nov 14.
Pulmonary sarcomatoid carcinoma (PSC) is a rare aggressive subtype of non-small cell lung cancer (NSCLC) with limited therapeutic strategies. We attempted to elucidate the evolutionary trajectories of PSC using multiregional and longitudinal tumor samples.
A total of 31 patients were enrolled in this study and 11 longitudinal samples were available from them. Using whole exome sequencing data, we analyzed the mutational signatures in both carcinomatous and sarcomatous areas in primary tumors of the 31 patients and longitudinal samples obtained from 11 patients. Furthermore, digital droplet polymerase chain reaction (ddPCR), and programmed death-ligand 1 (PD-L1) immunohistochemistry using the Ventana SP263 assay were performed.
TP53 was identified as the most frequently altered gene in the primary (74%) and metastatic (73%) samples. MET exon 14 skipping mutations, confirmed by ddPCR, and TP53 mutations were mutually exclusive; whereas, MET exon 14 skipping mutations frequently co-occurred with MDM2 amplification. Metastatic tumors showed dissimilar genetic profiles from either primary component. During metastasis, the signatures of APOBEC decreased in metastatic lesions compared with that in primary lesions. PSC showed higher MET and KEAP1 mutations and stronger PD-L1 protein expression compared with that recorded in other NSCLCs.
Decreased APOBEC signatures and subclonal diversity were detected during malignant progression in PSC. Frequent MET mutations and strong PD-L1 expression distinguished PSC from other NSCLCs. The aggressiveness and therapeutic difficulties of PSC were possibly attributable to profound intratumoral and intertumoral genetic diversity. Next-generation sequencing could suggest the appropriate treatment strategy for PSC.
肺肉瘤样癌（PSC）是一种罕见的侵袭性非小细胞肺癌（NSCLC）亚型，治疗策略有限。我们试图通过多区域和纵向肿瘤样本阐明 PSC 的进化轨迹。
本研究共纳入 31 例患者，其中 11 例有纵向样本。我们使用全外显子组测序数据，分析了 31 例患者的原发性肿瘤和 11 例患者的纵向样本中癌性和肉瘤性区域的突变特征。此外，还进行了数字液滴聚合酶链反应（ddPCR）和程序性死亡配体 1（PD-L1）免疫组织化学检测，使用的是 Ventana SP263 检测法。
TP53 是原发性（74%）和转移性（73%）样本中最常改变的基因。通过 ddPCR 证实的 MET 外显子 14 跳跃突变与 TP53 突变互斥；而 MET 外显子 14 跳跃突变常与 MDM2 扩增同时发生。转移性肿瘤的遗传谱与原发性肿瘤成分不同。在转移过程中，与原发性肿瘤相比，转移性肿瘤中的 APOBEC 特征降低。PSC 与其他 NSCLC 相比，MET 和 KEAP1 突变率更高，PD-L1 蛋白表达更强。
在 PSC 的恶性进展过程中，检测到 APOBEC 特征降低和亚克隆多样性降低。频繁的 MET 突变和强烈的 PD-L1 表达将 PSC 与其他 NSCLC 区分开来。PSC 的侵袭性和治疗困难可能归因于肿瘤内和肿瘤间遗传多样性的深刻变化。下一代测序可以为 PSC 提供合适的治疗策略。
