Comprehensive genomic profiling of combined small cell lung cancer

Abstract

Background: Combined small cell lung cancer (CSCLC) is an uncommon and heterogeneous subtype of small cell lung cancer (SCLC). However, there is limited data concerning the different molecular changes and clinical features in CSCLC compared to pure SCLC.

Methods: The clinical and pathological characteristics of pure SCLC and CSCLC patients were analyzed. Immunohistochemistry and microdissection were performed to isolate the CSCLC components. Further molecular analysis was carried out by next-generation sequencing (NGS) in 12 CSCLC and 30 pure SCLC.

Results: There were no significant differences in clinical features between CSCLC and pure SCLC. Overall survival (OS) of CSCLC patients was worse than pure SCLC (P=0.005). NGS results indicated that TP53 and RB1 were the most frequently mutated genes in both CSCLC (83.33% and 66.67%) and pure SCLC (80.00% and 63.33%) groups. However, less than 10% common mutations were found in both CSCLC and pure SCLC. When analyzing the data of SCLC and non-small cell lung cancer (NSCLC) components of CSCLC, more than 50% common mutations, and identical genes with mutations were detected. Moreover, there were also common biological processes and signaling pathways identified in CSCLC and pure SCLC, in addition to SCLC and NSCLC components.

Conclusions: There were no significant differences in terms of clinical features between CSCLC and pure SCLC. However, the prognosis for CSCLC was worse than pure SCLC. NGS analysis suggested that CSCLC components might derive from the same pluripotent single clone with common initial molecular alterations and subsequent acquisitions of other genetic mutations.

Keywords: Combined small cell lung cancer (CSCLC); comprehensive genomic profiling; small cell lung cancer (SCLC); targeted gene sequencing.

Figure 1

The overall survival of pure small cell lung cancer (SCLC) was better than combined small cell lung cancer (CSCLC) (P=0.005).

Figure 2

Representative images of specific markers and the boundary of the different components of combined small cell lung cancer (CSCLC). The left panel shows the staining of small cell lung cancer (SCLC) and adenocarcinoma (AD), while the right panel shows the staining of SCLC and squamous cell carcinoma (SCC).

Figure 3

Summary of gene mutations in combined small cell lung cancer (CSCLC) and pure small cell lung cancer (SCLC). The distribution patterns of single nucleotide variants (top) and copy number variations (bottom) in our study assessed by next-generation sequencing (NGS). Histology and tumor mutation burden (TMB) values of each patient are depicted at the top. H1 in the sample identity (ID) (bottom) represents the component of SCLC; H2 in the sample ID represents the component of non-small cell lung cancer (NSCLC).

Figure 4

The biological process and the pathways of the mutated genes in different components predicted by the Database for Annotation, Visualization and Integrated Discovery (DAVID). (A,B) Images of the biological processes of the mutated genes in the combined small cell lung cancer (CSCLC) and pure small cell lung cancer (SCLC). (C,D) Images of signaling pathways involved in the mutated genes in combined small cell lung cancer (CSCLC) and pure SCLC.

Figure 5

The biological process and the pathways of the mutated genes in different components predicted by the Database for Annotation, Visualization and Integrated Discovery (DAVID). (A,B) Images of the biological processes of the mutated genes in the non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) components of combined small cell lung cancer (CSCLC). (C,D) Images of the signaling pathways of the mutated genes in NSCLC and SCLC components of CSCLC.