Purpose

The aim of this study is to investigate the genetic heterogeneity (carcinomatous vs. sarcomatous components) and predictive biomarkers in patients with pulmonary sarcomatoid carcinoma (PSC).

Methods

Genetic alterations and biomarkers of immunotherapy were performed in a discovery set (n = 6) of PSC. Next-generation sequencing (NGS) on a pan-cancer gene panel was applied to detect the genetic alterations in each component, and the respective mutation profiling and tumor mutation burden (TMB) were compared as well. Immunohistochemistry (IHC) assay with SP263 antibody was used to detect the protein expression of programmed death-ligand 1 (PD-L1) in each component.

Results

Comparative genetic analysis revealed that the separate carcinomatous and sarcomatous components shared strikingly common mutations. TP53 (4/6, 66.7%) was the most common genetic alteration in 6 PSC patients. MET exon 14 skipping was detected in one case, accounting for 16.7%. An EZR-ROS1 fusion (EZR: intron10-ROS1: intron32) was identified in one case. The TMB of the two components was similar. Nevertheless, significantly higher PD-L1 expression was found in carcinomatous components compared to sarcomatous components. MDM2 amplification was detected in 2/6 (33.3%) of cases and STK11 mutation in 1/6 (16.7%) of cases.

Conclusions

PSC containing carcinomatous and sarcomatous components had a mild heterogeneity; the two components may evolve from common ancestral cells. High PD-L1 expression suggests that immunotherapy could be used as a potential therapy for PSC patients, while patients with negative immune-responsive genes need to be screened out. Altogether, these findings further highlight that the detection of genetic alteration and PD-L1 expression plays an important role in treatment of patients with PSC.

中文翻译：

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肺肉瘤样癌的遗传异质性和预测性生物标志物

目的

这项研究的目的是调查肺肉瘤样癌（PSC）患者的遗传异质性（癌性与肉瘤性成分）和预测性生物标志物。

方法

在 PSC的发现组（n = 6）中进行了免疫疗法的遗传改变和生物标记。运用全癌基因面板上的下一代测序（NGS）来检测每个组分的遗传变化，并分别比较了各自的突变谱和肿瘤突变负担（TMB）。使用SP263抗体的免疫组织化学（IHC）分析来检测每个组件中程序性死亡配体1（PD-L1）的蛋白表达。

结果

比较基因分析表明，癌变和肉瘤分离的成分共有惊人的共同突变。TP53（4/6，66.7％）是6例PSC患者中最常见的遗传改变。MET外显子14跳越1例，占16.7％。一个EZR - ROS1融合（EZR：intron10- ROS1：intron32）在一种情况下被确定。这两个组件的TMB相似。然而，与肉瘤成分相比，在癌性成分中发现PD-L1表达明显更高。在2/6（33.3％）的病例中检测到MDM2扩增，在1/6（16.7％）的病例中检测到STK11突变。

结论

含有癌性和肉瘤成分的PSC具有轻度异质性。这两个成分可能从共同的祖先细胞演化而来。PD-L1高表达提示免疫疗法可以作为PSC患者的潜在疗法，而免疫反应基因阴性的患者则需要筛选。总而言之，这些发现进一步凸显了基因改变和PD-L1表达的检测在PSC患者的治疗中起重要作用。