Molecular landscape of metastatic bronchial neuroendocrine tumors

Metastatic bronchial neuroendocrine tumors (MBNET) are rare and poorly characterized. Understanding their molecular landscape is crucial. This pilot study aimed to identify key genetic and epigenetic alterations in MBNET using large scale genomic analyses to uncover potential therapeutic targets.

and Methods: Ten patients diagnosed with MBNET and treated at Institut Curie between 2016 and 2021 were included after giving consent. Targeted DNA sequencing, RNAseq and methylation profiling were conducted on formalin-fixed paraffin-embedded (FFPE) and frozen metastatic tissues. Data were analyzed using bioinformatics pipelines to assess genetic mutations, transcriptional alterations and methylation patterns.

Mutations in epigenetic regulators genes, including MEN1 (20%), ARID1A (20%), KMT2B (10%) and KMT2C (10%) were identified, along with additional mutations in MGA (30%) and EIF1AX (20%). Transcriptomic analysis revealed significant differential expression of neuroendocrine-related genes (SSTR1, SSTR2, CHGA, and CHGB) in epigenetic regulator mutated tumors, showing an association with neuroendocrine phenotype regulation. Gene set enrichment analysis highlighted upregulation in neuroactive ligand-receptor interaction and cytokine signaling pathways. Methylation analysis showed a distinct clustering of MEN1-mutated tumors, with differential methylation in various cancer genes, including IKBKE, WNT3A, MYOD1, DNMT3A and ZNRF3.

Our pilot study highlights an association between epigenetic alterations and molecular features of MBNET, with potential therapeutic implications that warrant further investigation. The higher expression of somatostatin receptors and neuroendocrine markers observed in tumors harboring epigenetic alterations provides a potential rationale for further investigation of targeted therapies. Further research is needed to explore the role of epigenetic modifications in MBNET progression and treatment response.