Diminished ANK3 contributes to cell survival by inhibiting detachment-induced apoptosis. TP53BP1 that interacts with p53 and MFN1 that encodes a mitochondrial membrane protein are considered to have tumor suppressor gene (TSG) functions. HACD4 involving fatty acid synthesis and TCPL10 with transcription regulation functions are considered TSGs. Many genes involved in DNA methylations such as LCMT2, RNMT, TRMT6, METTL8 and METTL16 are often perturbed in cancer. The aim of our study was to find whether these genes were mutated in colorectal cancer (CRC). In a genome database, we observed that each of these genes harbored mononucleotide repeats in the coding sequences, which could be mutated in cancers with high microsatellite instability (MSI-H). For this, we studied 124 CRCs for the frameshift mutations of these genes and their intratumoral heterogeneity (ITH). ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 harbored 11 (13.9%), 3 (3.8%), 0 (0%), 5 (6.3%), 1 (1.3%), 2 (2.5%), 4 (5.1%), 3 (3.8%), 2 (2.5%) and 2 (2.5%) of 79 CRCs with MSI-H, respectively. However, we found no such mutations in microsatellite stable (MSS) cancers in the nucleotide repeats. There were ITH of the frameshift mutations of ANK3, MFN1 and TP53BP1 in 1 (6.3%), 1 (6.3%) and 1 (6.3%) cases, respectively. Our data exhibit that cancer-related genes ANK3, HACD4, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 harbor mutational ITH as well as the frameshift mutations in CRC with MSI-H. Also, the results suggest that frameshift mutations of these genes might play a role in tumorigenesis through their inactivation in CRC.

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MYH11 functions as a contractile protein, converting chemical energy into mechanical energy through adenosine triphosphate hydrolysis. In cancers, an oncogenic fusion CBFB/MYH11 and frameshift mutations have been reported. Truncating mutants of MYH11 exhibited increased ATPase and motor activity, suggesting their roles in energy balance and movement of cancer cells. MYH11 gene has a mononucleotide repeat (C8) in the coding sequences that could be a mutational target in the cancers exhibiting microsatellite instability (MSI). We analyzed the C8 repeat in 79 gastric cancers (GCs) and 124 colorectal cancers (CRCs) including 113 high MSI (MSI-H) and 90 microsatellite stable/low MSI cases. We detected MYH11 frameshift mutations in 4 (11.8%) GCs and 17 (21.5%) CRCs with MSI-H (21/113, 18.6%), but not in microsatellite stable/low MSI cancers (0/90) (P<0.001). We also analyzed intratumoral heterogeneity (ITH) of the MYH11 frameshift mutations and found that 10 of 16 CRCs (62.5%) harbored the regional ITH. Our results show that MYH11 gene harbors somatic frameshift mutations mostly associated with mutational ITH, which together may be features of MSI-H GCs and CRCs. Practically, the data suggest that multiregional analysis is needed for a better evaluation of mutation status in MSI-H tumors to overcome ITH.