Background The profiles of genetic and epigenetic alterations in cancer-related pathways are considered to be useful for selection of patients likely to respond to specific drugs, including molecular-targeted and epigenetic drugs. In this study, we aimed to characterize such profiles in gastric cancers (GCs).Methods Genetic alterations of 55 cancer-related genes were analyzed by a benchtop next-generation sequencer. DNA methylation statuses were analyzed by a bead array with 485,512 probes. Results The WNT pathway was activated by mutations of CTNNB1 in 2 GCs and potentially by aberrant methylation of its negative regulators, such as DKK3, NKD1, and SFRP1, in 49 GCs. The AKT/mTOR pathway was activated by mutations of PIK3CA and PTPN11 in 4 GCs. The MAPK pathway was activated by mutations and gene amplifications of ERBB2, FLT3, and KRAS in 11 GCs. Cell-cycle regulation was affected by aberrant methylation of CDKN2A and CHFR in 13 GCs. Mismatch repair was affected by a mutation of MLH1 in 1 GC and by aberrant methylation of MLH1 in 2 GCs. The p53 pathway was inactivated by mutations of TP53 in 19 GCs and potentially by aberrant methylation of its downstream genes in 38 GCs. Cell adhesion was affected by mutations of CDH1 in 2 GCs. Conclusions Genes involved in cancer-related pathways were more frequently affected by epigenetic alterations than by genetic alterations. The profiles of genetic and epigenetic alterations are expected to be useful for selection of the patients who are likely to benefit from specific drugs.

A PTMC≤7 mm is less likely to have aggressive features, including central lymph node metastasis, capsule invasion, extrathyroidal extension, and lymphovascular invasion, than a PTMC>7 mm. Because the aggressiveness of PTMC was found mainly in the patients with tumors >7 mm, we think that a cutoff value of 7 mm may be considered the threshold of aggressiveness of PTMCs.

Recent development of personal sequencers for extensive mutation analysis and bead array technology for comprehensive DNA methylation analysis have made it possible to obtain integrated pictures of genetic and epigenetic alterations on the same set of cancer samples. Here, we aimed to establish such pictures of gastric cancers (GCs). Comprehensive methylation analysis of 30 GCs revealed that the number of aberrantly methylated genes was highly variable among individual GCs. Extensive mutation analysis of 55 known cancer-related genes revealed that 19 of the 30 GCs had 24 somatic mutations of eight different genes (CDH1, CTNNB1, ERBB2, KRAS, MLH1, PIK3CA, SMARCB1, and TP53). Integration of information on the genetic and epigenetic alterations revealed that the GCs with the CpG island methylator phenotype (CIMP) tended to have mutations of oncogenes, CTNNB1, ERBB2, KRAS, and PIK3CA. This is one of the first studies in which both genetic and epigenetic alterations were extensively analyzed in the same set of samples. It was also demonstrated for the first time in GCs that the CIMP was associated with oncogene mutations.

Bilaterality is found more frequently when the tumor is large. Multifocality also can help predict the possibility of bilaterality. Therefore, total thyroidectomy may be necessary for patients with a multifocal or large tumor. It should be noted that the presence of a contralateral cancer is missed in 4.7 and 5.5 % of patients with preoperatively diagnosed unilateral PTC and PTMC, respectively.