Yoda Yukie, Takeshima Hideyuki, Niwa Tohru, Kim Jeong Goo, Ando Takayuki, Kushima Ryoji, Sugiyama Toshiro, Katai Hitoshi, Noshiro Hirokazu, Ushijima Toshikazu
Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
Gastric Cancer. 2015 Jan;18(1):65-76. doi: 10.1007/s10120-014-0348-0. Epub 2014 Feb 9.
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).
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.
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.
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.
癌症相关通路中的遗传和表观遗传改变特征被认为有助于选择可能对特定药物有反应的患者，包括分子靶向药物和表观遗传药物。在本研究中，我们旨在描述胃癌（GC）中的此类特征。
通过台式下一代测序仪分析55个癌症相关基因的遗传改变。通过具有485,512个探针的微珠阵列分析DNA甲基化状态。
WNT通路在2例GC中因CTNNB1突变而激活，在49例GC中可能因DKK3、NKD1和SFRP1等负调控因子的异常甲基化而激活。AKT/mTOR通路在4例GC中因PIK3CA和PTPN11突变而激活。MAPK通路在11例GC中因ERBB2、FLT3和KRAS的突变及基因扩增而激活。细胞周期调控在13例GC中受CDKN2A和CHFR异常甲基化影响。错配修复在1例GC中受MLH1突变影响，在2例GC中受MLH1异常甲基化影响。p53通路在19例GC中因TP53突变而失活，在38例GC中可能因其下游基因的异常甲基化而失活。细胞黏附在2例GC中受CDH1突变影响。
癌症相关通路中的基因受表观遗传改变影响比受遗传改变影响更频繁。遗传和表观遗传改变特征有望有助于选择可能从特定药物中获益的患者。
