Comprehensive genomic profiling of neuroendocrine neoplasms of the colorectum

Neuroendocrine tumors (NETs) are classified into G1, G2, and G3, corresponding to low-grade, intermediate-grade, and high-grade tumors, higher grades show greater aggressiveness and poorer outcomes, with molecular mechanisms remaining unclear. This study aimed to investigate gene mutations across G1, G2, and G3 in 24 colorectal neuroendocrine tumors (CRNETs) using whole-exome sequencing to identify somatic single nucleotide polymorphisms (SNPs). The results showed a prominent T>C single nucleotide variant (SNV) in G1 samples, while C>T was prevalent in G2 and G3. The analysis of significant mutated genes revealed that HYDIN (100%) was present in all grades, though mutation sites and frequencies differed. Particularly, tumor-associated HYDIN mutations were exclusive to G3, suggesting it may serve as a candidate biomarker for distinguishing high-grade from lower grades. Important copy number variations (CNVs) were identified in genes such as POP4 (G1), PPARG, MYC, and F10 (G2), as well as VOPP1 and UGT2B17 (G3). The KMT2A gene, associated with potential clinical drug responses, exhibited specific mutation sites across all samples. The study identified seven primary mutation signatures, with signature 6 predominant in G3, and highlighted a link to carcinogenic pathways like RTK-RAS, Notch, WNT, and Hippo, thus providing valuable insights into the pathogenesis of CRNETs.