Candidate Tumor Suppressor Gene EAF2 is Mutated in Colorectal and Gastric Cancers

[摘要] Fusion of ELL-associated factor 2 (EAF2) with ELL is related to myeloid leukemia development [1]. Loss of expression and deletion of EAF2 is common in prostate cancer and EAF2 expression blocks prostate cancer growth, suggesting that EAF2 might have tumor suppressor gene (TSG) functions [2]. However, the roles of EAF2 in colorectal (CRC) and gastric (GC) cancers are not known. About one third of CRC and GC have defects in mismatch repair that can cause microsatellite instability (MSI). TSGs are often observed to have mutations at monocleotide repeats in high MSI (MSI-H) GC and CRC [3]. We hypothesize that EAF2 gene might harbor frameshift mutations at its A8 repeat that would result in inhibition of the EAF functions and play a role in tumor development. For this, we studied the A8 repeat in 79 high MSI (MSI-H) CRCs, 45 microsatellite stable/low MSI (MSS/MSI-L) CRCs, 34 MSI-H GCs and 45 MSS/MSI-L GCs by single-strand conformation polymorphism (SSCP) assay. After SSCP, Sanger DNA sequencings were done in the cancers with mobility shifts in the SSCP to confirm the mutations [4]. We found a type of somatic frameshift mutation in seven CRCs (7/79, 8.9%) and one GC (1/34, 3.0%) with MSI-H phenotype, but there was none in those with MSS/MSI-L (CRCs (0/45) and GCs (0/45)) (Fisher’s exact test, p = 0.001). The mutation was a deletion (c.334delA (p.Thr112GlnfsX30) in the coding region. We also attempted to find whether there was intratumor heterogeneity (ITH) in the EAF2 frameshift mutation, which is known to play a role in cancer evolution as well as treatment resistance in cancer. We studied 16 cases of CRCs with 4–7 tissue fragments per CRC. Three of the 16 CRCs (18.8%) showed the deletion mutation (c.334delA) in different tissue regions (Table 1), indicating ITH of the EAF2 mutation existed in CRC.