Purpose: Although primary gastric cancers (PGC) and remnant gastric cancers (RGC) both originate from the same gastrointestinal organ, they have very distinct clinicopathological behaviors. Due to the importance of chronic inflammation in the carcinogenesis of gastric malignancies, we hypothesized that DNA promoter hypermethylation would play a critical role in the carcinogenesis of RGC as well as PGC.Methods: We investigated the genome-wide DNA methylation patterns of PGC and RGC tissues from 48 patients from an academic medical center in Japan using the Infinium HumanMethylation450 BeadChip assay. The results were validated by quantitative methylation-specific PCR (qMSP) in separate, independent cohorts.Results: We found that in our training cohort of 48 patients, genes from the gastric cancer tissues identified by the Infinium HumanMethylation 450 Beadchip clustered into high and low methylation groups on multivariate analysis (p=0.004, OR=12.33). PGCs contributed significantly to the high methylation group suggesting that the DNA promoter methylation status in PGC is higher than that in RGC. Supporting this conclusion was the finding that in a separate qMSP analysis in a test cohort, the gene A had significantly higher DNA promoter methylation in cancer tissues in the validation PGC tissues than in RGC.Conclusion: This study demonstrated that DNA promoter methylation status in PGC is higher than in RGC. This result may reflect the effects of Helicobacter pylori on the induction of DNA methylation in the remnant stomach.Citation Format: Tomoaki Ito, Kiichi Sugimoto, Hajime Orita, Masahiro Maeda, Hiroshi Moro, Toshikazu Ushijima, Hitoshi Katai, Ryo Wada, Kazuhiro Sakamoto, Koichi Sato, Malcolm V. Brock. DNA methylation genome-wide analysis in remnant gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 819.
Abstract Purpose: Although primary gastric cancers (PGC) and remnant gastric cancers (RGC) both originate from the same gastrointestinal organ, they have very distinct clinicopathological behaviors. Due to the importance of chronic inflammation in the carcinogenesis of gastric malignancies, we hypothesized that DNA promoter hypermethylation would play a critical role in the carcinogenesis of RGC as well as PGC. Methods: We investigated the genome-wide DNA methylation patterns of PGC and RGC tissues from 48 patients from an academic medical center in Japan using the Infinium HumanMethylation450 BeadChip assay. The results were validated by quantitative methylation-specific PCR (qMSP) in separate, independent cohorts. Results: We found that in our training cohort of 48 patients, genes from the gastric cancer tissues identified by the Infinium HumanMethylation 450 Beadchip clustered into high and low methylation groups on multivariate analysis (p=0.004, OR=12.33). PGCs contributed significantly to the high methylation group suggesting that the DNA promoter methylation status in PGC is higher than that in RGC. Supporting this conclusion was the finding that in a separate qMSP analysis in a test cohort, the gene A had significantly higher DNA promoter methylation in cancer tissues in the validation PGC tissues than in RGC. Conclusion: This study demonstrated that DNA promoter methylation status in PGC is higher than in RGC. This result may reflect the effects of Helicobacter pylori on the induction of DNA methylation in the remnant stomach. Citation Format: Tomoaki Ito, Kiichi Sugimoto, Hajime Orita, Masahiro Maeda, Hiroshi Moro, Toshikazu Ushijima, Hitoshi Katai, Ryo Wada, Kazuhiro Sakamoto, Koichi Sato, Malcolm V. Brock. DNA methylation genome-wide analysis in remnant gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 819.
Objective Cancer-associated fibroblasts (CAFs), a major component of cancer stroma, can confer aggressive properties to cancer cells by secreting multiple factors. Their phenotypes are stably maintained, but the mechanisms are not fully understood. We aimed to show the critical role of epigenetic changes in CAFs in maintaining their tumour-promoting capacity and to show the validity of the epigenomic approach in identifying therapeutic targets from CAFs to starve cancer cells. Design Twelve pairs of primary gastric CAFs and their corresponding non-CAFs (NCAFs) were established from surgical specimens. Genome-wide DNA methylation and H3K27me3 analyses were conducted by BeadArray 450K and ChIP-on-Chip, respectively. Functions of potential a therapeutic target were analysed by inhibiting it, and prognostic impact was assessed in a database. Results CAFs had diverse and distinct DNA methylation and H3K27me3 patterns compared with NCAFs. Loss of H3K27me3, but not DNA methylation, in CAFs was enriched for genes involved in stem cell niche, cell growth, tissue development and stromal–epithelial interactions, such as WNT5A , GREM1 , NOG and IGF2 . Among these, we revealed that WNT5A, which had been considered to be derived from cancer cells, was highly expressed in cancer stromal fibroblasts, and was associated with poor prognosis. Inhibition of secreted WNT5A from CAFs suppressed cancer cell growth and migration. Conclusions H3K27me3 plays a crucial role in defining tumour-promoting capacities of CAFs, and multiple stem cell niche factors were secreted from CAFs due to loss of H3K27me3. The validity of the epigenetic approach to uncover therapeutic targets for cancer-starving therapy was demonstrated.
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