Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors
Copyright policy )Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors
AbstractPulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: “type I LCNECs” with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and “type II LCNECs” enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1high/DLL3high/NOTCHlow, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1low/DLL3low/NOTCHhigh, and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors.
- Peter MacCallum Cancer Centre Australia
- Institut Albert Bonniot France
- University of Zurich Switzerland
- Grenoble Alpes University France
- University of Milan Italy
Lung Neoplasms, Science, Oncology and Carcinogenesis, DNA Mutational Analysis, 610, In Vitro Techniques, Fluorescence, Article, Rare Diseases, Carcinoma, Non-Small-Cell Lung, Genetics, Humans, Non-Small-Cell Lung, Lung, In Situ Hybridization, In Situ Hybridization, Fluorescence, Cancer, Biomedical and Clinical Sciences, Lung Cancer, Human Genome, Carcinoma, Q, High-Throughput Nucleotide Sequencing, Genomics, Immunohistochemistry, Small Cell Lung Carcinoma, Carcinoma, Neuroendocrine, Neuroendocrine Tumors, Neuroendocrine, Technology Platforms, Biotechnology
Lung Neoplasms, Science, Oncology and Carcinogenesis, DNA Mutational Analysis, 610, In Vitro Techniques, Fluorescence, Article, Rare Diseases, Carcinoma, Non-Small-Cell Lung, Genetics, Humans, Non-Small-Cell Lung, Lung, In Situ Hybridization, In Situ Hybridization, Fluorescence, Cancer, Biomedical and Clinical Sciences, Lung Cancer, Human Genome, Carcinoma, Q, High-Throughput Nucleotide Sequencing, Genomics, Immunohistochemistry, Small Cell Lung Carcinoma, Carcinoma, Neuroendocrine, Neuroendocrine Tumors, Neuroendocrine, Technology Platforms, Biotechnology
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