RAC1 and Cowden syndrome 1: Among the up-regulated genes in SPEN there was a significant enrichment for the CS-associated genes (hypergeometric test, 34 genes; P = 5.5 × 10−03), which includes oncogenes (BCL2, CDK6, MDM2, and NR4A3), cytokines and growth factors (AGT, CYR61, FGF1, and IGF1), transcription factors (MECP2, PCGF2, PER2, and TP63), member of RAS superfamily of small GTP-binding proteins (RAC1), and genes involved in the oxidative stress pathway (SOD1) (Figure 2 and Supplementary Table 3).