Background: Demographic variables such as age and sex have long been associated with risk of cancer incidence, therapeutic response, and mortality. In NENs, specifically, studies have shown differences in overall survival based on age at diagnosis and sex. However, studies investigating the molecular determinants associated with age and gender have been lacking. To delineate the mechanisms of age, gender, and outcomes, we queried a large real-world dataset of NENs originating from the GI-tract and pancreas and characterized their molecular and immune profiles.
Methods: 1935 cases (GI: n=1431, Pancreas: n=504) of NENs were analyzed using Next Generation Sequencing or Whole Exome Sequencing of DNA, and 1211/1935 cases (GI: n=917, Pancreas: n=294) underwent Whole Transcriptome Sequencing at Caris Life Sciences (Phoenix, AZ). To study the age-associated effect on the molecular and immune landscapes, we applied two age cutoffs: below 50 and 70 years of age at the time of tissue collection, respectively. Significance was determined using chi-square, Fisher-Exact or Mann-Whitney U, and p-values were adjusted for multiple comparisons (q<0.05).
Results: In GI-NEN, TP53, RB1 mutations and high tumor mutation burden (TMB_H; >=10 Mut/Mb) were more prevalent and KRAS mutations were less prevalent with increasing age. Interestingly, in pancreatic NENs (P-NENs), KRAS mutations were more prevalent and TMB_H were less prevalent with increasing age. Mutations specific to the sites of origin such as APC (GI) and MUTYH (pancreas) were negatively associated with age while SMAD4 (pancreas) was positively associated with age. While no differences in immune checkpoint gene (ICG) expression were associated with age, immune cell estimates of M1 macrophages (anti-tumorigenic) in GI-NENs were higher in patients above 70 and M2 macrophages (pro-tumorigenic) were higher in patients below 50 (p<0.05, q>0.05). For the analysis with gender, mutations in p53 were more prevalent among males with GI-NEN while dMMR/MSI-H were more prevalent in females with P-NENs. No significant differences in ICG expression and immune cell estimates were associated with gender.
Conclusions: Our study queries one of the largest datasets of GI and P-NENs to date. We observe distinct molecular profiles associated with age and gender in both GI- and P-NENs as well as a distinct immune profile associated with age in GI-NENs. While these results are only hypothesis generating, they are suggestive of how patient demographics may be utilized for rational therapy design.External Link