Integrated analysis of cancer-related pathways affected by genetic and epigenetic alterations in gastric cancer

Abstract

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.

Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review

“…Homeostasis of the gastrointestinal epithelium is 87 [47,[69][70][71][72][73][74][75]232] Fzd-3 [78] CTNNB1 [9,[88][89][90][91][92][93]96,97] LRP6 [228] TCF7L2 [98][99][100] PPN [79] CDH17 [80] EZH2 [81] HMGA1, HMGA2 [210,211] YY1 [86] TC1 (C8orf4) [201,202] miR-17-92 [161] mir-10a [168] has-miR-335 [166] hsa-miR-375 [163] Downregulation or function inhibition in gastric cancer Downregulation by hypermethylation Inactivation by miRNAs APC [145,146] APC [175] sFRP1, sFRP2, sFRP4, sFRP5 [78,96,149] AXIN2 [159] WIF-1 [144,149] EZF1 [78] Dkk-1, Dkk-2, Dkk-3 [59,144,148,…”

“…In addition, Yu et al [148] showed by multivariate analysis that Dkk-3 methylation was associated significantly and independently with poor disease survival in gastric cancer, but not in colorectal cancer. Recently, DNA methylation status in 49 gastric cancer samples was analyzed by a bead array with 485512 probes [149] . This study revealed that the Wnt pathway was potentially activated by aberrant methylation of its negative regulators, such as Dkk-3, NKD1, Sox17, WIF-1 and sFRP1.…”

Interaction between Wnt/β-catenin pathway and microRNAs regulates epithelial-mesenchymal transition in gastric cancer (Review)

“…Multiple experiments provided evidence indicating that mutations in exon 3 of CTNNB1 precipitates not only continuous activation of Wnt pathway but also multistep stomach carcinogenesis (67,68). Galectin-3, whose mutation locates at position 191, has been widely recognized equipped to substitute proline to histidine (gal-3H64), followed by increased nuclear accumulation of β-catenin as well as promotion of TCF transcription during gastric cancer evolvement (69).…”

Germline PTPN11 and somatic PIK3CA variant in a boy with megalencephaly-capillary malformation syndrome (MCAP) - pure coincidence?

“…29 A very recent publication even showed that in 4 out of 50 advanced gastric cancers, PIK3CA and PTPN11 were both mutated, leading to activation of the AKT pathway. 30 This seems to be more than just coincidence. It is known that in most cancers, there is not only one gene that is mutated, but a distinct set of genes.…”