In contrast, immune checkpoint molecule VISTA, nuclear/proliferation marker Histone-H3, and activated MEK1 (part of the RAF/MEK/ERK pathway known to be involved in inflammation and linked to granuloma formation when inhibited)25,26 each had significantly increased expression in earlier/active stage CS (p = 0.007, p = 0.013, and p = 0.017 respectively). This evidence concerns the gene MAP2K1 and Cowden syndrome 1.