Intratumoural heterogeneity of intestinal expression reflects environmental induction and progression-related loss of induction in undifferentiated-type gastric carcinomas

Aims: Gene expression in tumours is regulated by environmental as well as genetic/epigenetic factors. This study assessed the environmental factors in intestinal expression of gastric cancers. Methods and results: We immunohistochemically examined intratumoural heterogeneity in the expression of Cdx2, MUC2, MUC5AC and MUC6 in 39 intramucosal and 49 extramucosally invasive undifferentiated‐type gastric carcinomas (UGCs), consisting of signet ring cell carcinomas showing a layered structure (LS) in the mucosa and dedifferentiated tubular adenocarcinomas without LS and with minor tubular components (TC). The LS retains mucosal vertical polarity with superficial MUC5AC expression. Loss of this polarity was independent of intestinal expression and associated with extramucosal invasion. In LS+ UGCs, intestinal expression was enhanced as the size of mucosal spread increased and was significantly reduced with deeper extramucosal invasion, whereas, in LS−/TC+ UGCs, intestinal expression was frequent and predominant in the mucosa and was insignificantly reduced with deeper extramucosal invasion. Conclusions: In LS+ UGCs, intestinal expression showed dynamic alteration probably by environmental induction and progression‐related loss of induction, whereas it was relatively stable in LS−/TC+ UGCs. Thus, intestinal expression in UGCs is not useful as a marker of tumour progression because it is also affected by environmental factors and genetic lineage.