Age- and sex-based differences in the genomic profiles of patients with gastrointestinal and pancreatic neuroendocrine neoplasms.

Age and sex are known to influence outcomes in neuroendocrine neoplasms (NENs), yet their molecular determinants remain poorly defined. We queried a real-world dataset of gastrointestinal (GI) tract and pancreatic (P) NENs and characterized their clinical, molecular, and immune profiles. One thousand nine hundred thirty-five cases (GI: n = 1431, P: n = 504) of NENs were analyzed using Next Generation or Whole Exome Sequencing of DNA, and 1211/1935 cases (GI: n = 917, P: n = 294) underwent Whole Transcriptome Sequencing. We compared the molecular and immune profile with respect to age and sex. Older age at diagnosis was associated with worse survival in both GI- and P-NENs. In patients with GI-NENs, there was decreased survival in males compared to females. In GI-NENs, TP53, RB1, FAT1, and KMT2D mutations, as well as immune checkpoint gene (ICG) expressions of LAG3, CD80, and HAVCR2 and M1 macrophages increased with increasing age while APC mutations and M2 macrophages decreased with increasing age. In P-NENs, TP53, RB1, KRAS, and SMAD4 mutations and CD4+ T cells increased with increasing age while MUTYH and NTHL1 mutations and M2 macrophages decreased with increasing age. In GI-NENs, TP53, FBXW7, and TERT (promoter) mutations and genomic loss of heterozygosity (gLOH) were increased in males. In P-NENs, PIK3CA mutations and dMMR/MSI-H were increased in females. Our study queries one of the largest datasets of GI- and P-NENs to date and highlights distinct age- and sex-specific molecular and immune profiles. Given the exploratory nature of these analyses and borderline significance, these results remain hypothesis-generating, providing an initial framework for future validation studies.