Immunohistochemical and molecular evolutionary features of jejunoileal adenocarcinoma unveiled through comparative...

Jejunoileal adenocarcinoma (JIAC) is a rare type of malignancy, the clinicopathological, genetic, and evolutionary characteristics of which have rarely been reported. In this study, 52 patients with JIAC and 182 patients with colorectal adenocarcinoma (CRAC) were recruited. Immunohistochemical analyses using 34 primary antibodies identified a novel subtype, JIAC with enteroblastic differentiation (JIAED). High MUC1 expression and low Cyclin D1 expression were identified as independent poor prognostic markers. Additionally, compared with mismatch repair deficient (dMMR)-CRAC, MSH2/MSH6 loss was more frequently observed in dMMR-JIAC. These results suggested essential molecular differences between JIAC and CRAC. To better understand these differences, we selected three dMMR-JIACs and eight mismatch repair proficient (pMMR)-JIACs and evaluated molecular evolutionary history by multi-regional whole-exome sequencing. Phylogenetic trees constructed for both pMMR-JIAC and dMMR-JIAC were more consistent with a "long trunk-short branches" structure than were those of CRAC, and the variant allele frequency peaks obtained for JIAC were higher than those of CRAC. Moreover, TP53 and ARID2 were identified as common driver gene mutations in pMMR-JIAC, arising during early tumorigenesis. Our evolutionary analysis revealed that pMMR-CRAC follows the principle of shifting from Darwinian to neutral evolution, generating intratumoral heterogeneity (ITH). In contrast, our findings on pMMR-JIAC and dMMR-JIAC demonstrate that both remain under Darwinian evolution, even in advanced stages, resulting in lower ITH. In summary, we identified a distinct pathohistological subtype of JIAC and highlighted the unique molecular evolutionary dynamics presented in JIAC, potentially lead to the better management and treatment strategies for patients with JIAC in the future.