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. 2020 Nov-Dec;34(6):3375-3385.
doi: 10.21873/invivo.12176.

Genomic Profiling and Clinicopathological Characteristics of Neuroendocrine Tumors of the Lung in East Asian Patients

Moonsik Kim  1 , Yeon Seung Chung  1 , Kyoung A Kim  1 , Hyo Sup Shim  2
Affiliations

Genomic Profiling and Clinicopathological Characteristics of Neuroendocrine Tumors of the Lung in East Asian Patients

Moonsik Kim et al. In Vivo. 2020 Nov-Dec.

Abstract

Background/aim: In recent years, the genomic landscape of neuroendocrine tumors (NETs) of the lung has been investigated. However, more data are necessary to elucidate the heterogeneous nature of NETs, especially in East Asian patients.

Patients and methods: A total of 64 patients who underwent surgical resection for lung NETs [26 typical or atypical carcinoid tumors, 21 large-cell neuroendocrine carcinomas (LCNECs), and 19 small-cell lung carcinomas (SCLCs)] were enrolled, and samples from 46 patients were subjected to targeted next-generation sequencing.

Results: Co-mutations of tumor protein p53 (TP53) and RB transcriptional corepressor 1 (RB1) were detected in 15%, 42%, and 93% of carcinoid tumors, LCNECs, and SCLCs, respectively. Oncogenic or targetable genetic alterations identified in this study included mutations of KRAS proto-oncogene (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), ALK receptor tyrosine kinase (ALK), mitogen-activated protein kinase kinase 1 (MAP2K1), and isocitrate dehydrogenase 1 (IDH1), as well as amplifications of erb-b2 receptor tyrosine kinase 2 (ERBB2), fibroblast growth factor receptor 1 (FGFR1), CD274 molecule (CD274), and MYCN proto-oncogene (MYCN). These alterations were more frequently found in high-grade NETs than in carcinoid tumors (33.3% vs. 7.7%). Programmed cell death-ligand 1 expression was strongly associated with the LCNEC subtype among NETs (p=0.002).

Conclusion: The mutational status of TP53 and RB1 was significantly associated with NET subtypes in East Asian patients. Targeted therapy or immunotherapy may serve as a treatment option in a subset of patients with high-grade NETs.

Keywords: Neuroendocrine tumor; PD-L1; RB1; TP53; lung; next-generation sequencing.

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Conflict of interest statement

The Authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Representative photos of lung neuroendocrine tumors according to subtype. A: typical carcinoid tumor, B: atypical carcinoid tumor, C: large-cell neuroendocrine carcinoma, and D: small-cell lung carcinoma (original magnifications: A: ×100; B-D: ×200)
Figure 2
Figure 2. Survival curves according to the lung neuroendocrine tumor subtype. A: overall survival (p=0.005), B: recurrence-free survival (p=0.004)
Figure 3
Figure 3. OncoPrint heatmap for genetic alterations in lung neuroendocrine tumors according to subtype. Please refer to Table I for gene designations. AC: Atypical carcinoid tumor; LCNEC: large-cell neuroendocrine carcinoma; SCLC: small-cell lung carcinoma; TC: typical carcinoid tumor
Figure 4
Figure 4. A case of large-cell neuroendocrine carcinoma (LCNEC) harboring amplifications of erb-b2 receptor tyrosine kinase 2 (ERBB2 or HER2) (A and B) and CD274 (C). A: HER2 immunohistochemical staining demonstrates diffuse membranous positivity. B: ERBB2 silver in-situ hybridization illustrates the amplification of the ERBB2 gene. C: A case of LCNEC with a CD274 amplification with a 100% tumor proportion score in programmed cell death-ligand 1 (PD-L1) immunohistochemical staining
Figure 5
Figure 5. Overall survival according to the large-cell neuroendocrine carcinoma molecular subtype (p=0.703)
See this image and copyright information in PMC

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