Lohinai Zoltan, Megyesfalvi Zsolt, Suda Kenichi, Harko Tunde, Ren Shengxiang, Moldvay Judit, Laszlo Viktoria, Rivard Christopher, Dome Balazs, Hirsch Fred R
Department of Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, Hungary.
Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary.
Transl Lung Cancer Res. 2019 Dec;8(6):938-950. doi: 10.21037/tlcr.2019.11.30.
Recent preclinical data suggest that neuroendocrine (NE) subtype of small cell lung cancer (SCLC) has strong therapeutic relevance. NE high tumors are associated with immune desert and NE low tumors are considered to have an immune oasis phenotype. Our aim was to investigate the NE phenotypes of surgically resected SCLC tumors according to inter-tumor heterogeneity.
Expression analysis for 2,560 genes was performed in 32 surgically resected SCLC patients' primary tumors and corresponding lymph node (LN) metastases. To analyze tumor heterogeneity, we examined the differences in the gene expression of primary tumors versus LN metastases. We performed cluster analysis and heat map to divide patients into NE high and low subtypes by using the top NE-associated genes described in preclinical studies.
We found 6% (n=154) genes with significant differences and only 13.1% (n=336) of all genes in the panel had a strong correlation between the primary tumor and LN metastases. Cluster analysis clearly distinguished SCLC NE high versus low subtypes both in primary tumor (20 12, respectively) and LNs (23 9, respectively). As for inter-tumor heterogeneity, in case of five patients, a change in the NE pattern was observed. Specifically, we found significant downregulation of the NE-associated genes (P=0.004), (P=0.029) and (P=0.035) in their LN metastases compared to their primary tumor.
Our data confirm the results of preclinical studies and clearly distinguish NE low and high differentiation clusters in SCLC. Moreover, they highlight the gene expression discordance between primary tumors and corresponding LN metastases suggesting that the NE pattern of metastatic LNs might not reflect that of the primary tumor. Altogether, by shedding light on the diversity of SCLC, the current study might help to improve patient selection and treatment in this devastating disease.
Small cell lung cancer (SCLC); neuroendocrine tumor; lymph node metastasis; tumor heterogeneity; RNA sequencing.
近期临床前数据表明，小细胞肺癌（SCLC）的神经内分泌（NE）亚型具有重要的治疗意义。NE高表达肿瘤与免疫荒漠相关，而NE低表达肿瘤被认为具有免疫绿洲表型。我们的目的是根据肿瘤间异质性研究手术切除的SCLC肿瘤的NE表型。
对32例手术切除的SCLC患者的原发性肿瘤及相应的淋巴结（LN）转移灶进行了2560个基因的表达分析。为分析肿瘤异质性，我们检测了原发性肿瘤与LN转移灶基因表达的差异。我们进行聚类分析和热图分析，以使用临床前研究中描述的顶级NE相关基因将患者分为NE高表达和低表达亚型。
我们发现6%（n = 154）的基因存在显著差异，且在所有基因中，只有13.1%（n = 336）的基因在原发性肿瘤和LN转移灶之间具有强相关性。聚类分析在原发性肿瘤（分别为20例和12例）和LN（分别为23例和9例）中均能清晰区分SCLC的NE高表达和低表达亚型。至于肿瘤间异质性，在5例患者中观察到NE模式的变化。具体而言，我们发现与原发性肿瘤相比，其LN转移灶中NE相关基因 （P = 0.004）、 （P = 0.029）和 （P = 0.035）显著下调。
我们的数据证实了临床前研究的结果，并在SCLC中清晰区分了NE低分化和高分化簇。此外，它们突出了原发性肿瘤与相应LN转移灶之间的基因表达不一致性，表明转移性LN的NE模式可能无法反映原发性肿瘤的NE模式。总之，通过揭示SCLC的多样性，本研究可能有助于改善这种毁灭性疾病的患者选择和治疗。
小细胞肺癌（SCLC）；神经内分泌肿瘤；淋巴结转移；肿瘤异质性；RNA测序
