Molecular Profiling of Digestive Grade 3 Neuroendocrine Tumors Reveals a Shared Molecular Framework with Lower-Grade...

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Well-differentiated neuroendocrine tumors, grade 3 (NETs G3) are high-grade neoplasms with unclear molecular drivers and therapeutic targets.
• Understanding the molecular landscape of NETs G3 is crucial for developing effective treatments.

Purpose of the Study:

• To define the molecular identity and identify therapeutic vulnerabilities of digestive system NETs G3.
• To compare the genomic and transcriptomic profiles of NETs G3 with lower-grade NETs (G1/G2) and neuroendocrine carcinomas (NECs).

Main Methods:

• Comprehensive genomic profiling and transcriptomic analysis of 40 neuroendocrine neoplasm cases (26 NETs G3, 8 NETs G1/G2, 6 NECs).
• Targeted sequencing for DNA and RNA alterations, and gene expression profiling using an immune-oncology panel.

Main Results:

• NETs G3 exhibit distinct genomic profiles from NECs, retaining alterations in chromatin-regulatory genes and lacking common TP53/RB1 inactivation.
• Transcriptomic analysis revealed NETs G3 partially overlap with NETs G1/G2 but show upregulated extracellular matrix remodeling, metabolic reprogramming, and cytokine signaling.
• Genomic heterogeneity was observed in NETs G3, with frequent large-segment copy-number losses in chromatin-regulatory regions; up to 25% had potentially targetable alterations.
• The tumor immune microenvironment was generally poorly inflamed, though some cases showed microsatellite instability or tumor-infiltrating lymphocytes, suggesting potential immunotherapy response.

Conclusions:

• NETs G3 represent a distinct molecular entity within high-grade neuroendocrine neoplasms.
• The identification of targetable alterations and immune microenvironment features opens avenues for novel therapeutic strategies, including immunotherapy for select cases.