Distinct promoter hypermethylation of p16INK4a, CDH1, and RAR‐beta in intestinal, diffuse–adherent, and diffuse–scattered type gastric carcinomas

Oue, Naohide; Motoshita, Junichi; Yokozaki, Hiroshi; Hayashi, Ken; Tahara, Eiichi; Taniyama, Kiyomi; Matsusaki, Keisuke; Yasui, Wataru

doi:10.1002/path.1170

Cited by 77 publications

(60 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These tendencies were reported previously for CDH1 25) and for p16 INK4a and RAR-β. 20) Considering that gastric carcinoma with the CIMP occurred preferentially in intestinal-and diffuse-adherent-type gastric carcinomas, gastric carcinomas with CIMP may not always involve hypermethylation of the CDH1 and RAR-β genes. Though hypermethylation of the CDH1 and RAR-β genes was observed more frequently in diffuse-scattered-type gastric carcinomas, among the combined group of 66 intestinal-and diffuse-adherent-type gastric carcinomas, 27 showed CDH1 hypermethylation and 28 showed RAR-β hypermethylation.…”

Section: Discussionmentioning

confidence: 98%

“…19) The status of hypermethylation of CpG islands in the promoter of CDH1 gene, CpG islands overlapping exon 1 of p16 INK4a gene, and a non-CpG island in exon 1 of the RAR-β gene was determined previously in 45 of the 103 gastric carcinoma samples. 20) Because written informed consent was not available, for strict privacy protection, all samples were disidentified before analyzing DNA methylation status. This procedure is in accordance with Ethical Guidelines for Human Genome/Gene Research enacted by the Japanese Government.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

DNA methylation of multiple genes in gastric carcinoma: Association with histological type and CpG island methylator phenotype

et al. 2003

Self Cite

View full text Add to dashboard Cite

Hypermethylation of CpG islands is associated with silencing of various tumor suppressor genes. Recent studies on colorectal and gastric cancer have identified a CpG island methylator phenotype (CIMP), which involves the targeting of multiple genes by promoter hypermethylation. For determination of association between DNA methylation pattern or histological type and CIMP status in gastric carcinoma, CpG islands in the promoters of hMLH1 and CDH1 genes, CpG islands overlapping exon 1 of MGMT and p16INK4a genes, and a non-CpG island in exon 1 of the RAR-β β β β gene were studied. The presence of the CIMP was determined by monitoring five methylated in tumor (MINT) loci in 103 gastric carcinomas. Among the 103 gastric carcinomas, DNA hypermethylation was detected in the following frequencies: 14 (14%) for hMLH1, 26 (25%) for MGMT, 26 (25%) for p16 INK4a , 54 (52%) for CDH1, and 53 (52%) for RAR-β β β β. Forty-two (41%) of 103 gastric carcinomas were positive for the CIMP. CIMP and hypermethylation of p16INK4a gene were found more frequently in intestinal and diffuse-adherent types than in diffuse-scattered type (P = = = =0.013 and 0.017, respectively). In contrast, hypermethylation of the CDH1 and RAR-β β β β genes was more common in the diffusescattered type than in the other types (P = = = =0.008 and 0.007, respectively). In intestinal-and diffuse-adherent-type gastric carcinomas, we found significant associations between the presence of the CIMP and hypermethylation of several genes: hMLH1 (P = = = =0.006), p16 INK4a(P = = = =0.018), CDH1 (P = = = =0.024), and RAR-β β β β (P = = = =0.044). Our overall results suggest that in some intestinal-and diffuse-adherent-type gastric carcinomas, DNA hypermethylation affects non-specific gene promoters concordantly, at least in part, whereas in diffuse-scattered-type gastric carcinoma, DNA hypermethylation affects specific genes such as CDH1 and RAR-β β β β. lterations in DNA methylation patterns, such as hypermethylation of CpG islands, are common changes in human cancers. Hypermethylation of CpG islands in promoters is associated with silencing of various tumor suppressor genes.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

DNA methylation of multiple genes in gastric carcinoma: Association with histological type and CpG island methylator phenotype

et al. 2003

Self Cite

View full text Add to dashboard Cite

show abstract

“…12 In diffuse type GC, the survival rate was not statistically different between patients with olfactomedin 4-positive GC and those with olfactomedin 4-negative GC. In diffuse type GC, E-cadherin is frequently inactivated by DNA hypermethylation, 23 suggesting that olfactomedin 4 expression may not affect the ability of cancer cell invasion and metastasis in diffuse type GC. The detailed mechanisms of inhibition of cell migration should be investigated.…”

Section: Discussionmentioning

confidence: 99%

Serum olfactomedin 4 (GW112, hGC‐1) in combination with Reg IV is a highly sensitive biomarker for gastric cancer patients

Oue

Sentani

Noguchi

et al. 2009

Intl Journal of Cancer

Self Cite

104

View full text Add to dashboard Cite

Gastric cancer (GC) is 1 of the most common human cancers. Early detection remains the most promising approach to improving long‐term survival of patients with GC. We previously performed Serial Analysis of Gene Expression (SAGE) on 4 primary GCs and identified several GC‐specific genes including Reg IV. Of these genes, olfactomedin 4 (OLFM4, also known as GW112 or hGC‐1) is a candidate gene for cancer‐specific expression. In this study, we examined the expression of olfactomedin 4 in human GC by immunohistochemistry. We also assessed serum olfactomedin 4 levels in GC patients by enzyme‐linked immunosorbent assay. 94 (56%) of 167 GC cases were positive for olfactomedin 4 by immunostaining. Olfactomedin 4 staining was observed more frequently in stage I/II cases than in stage III/IV cases. The serum olfactomedin 4 concentration in presurgical GC patients (n = 123, mean ± SE, 36.3 ± 3.5 ng/mL) was significantly higher than that in healthy individuals (n = 76, 16.6 ± 1.6 ng/mL). In patients with stage I GC, the sensitivity of serum olfactomedin 4 (25%) and Reg IV (35%) was superior to that of CA19‐9 (5%) or CEA (3%). Furthermore, in patients with stage I GC, the combination of olfactomedin 4 and Reg IV elevated the diagnostic sensitivity to 52%. These results suggest that serum olfactomedin 4 is a useful marker for GC and its measurement alone or in combination with Reg IV has utility in the early detection of GC. © 2009 UICC

show abstract

“…p53 mutations have been found frequently in colorectal and gastric cancers without DNA methylation. (23,24) However, the association between genetic and epigenetic alterations has not been investigated in PCa.In the present study, we investigated the relationship between RIZ1 methylation status and p53 mutation status in 47 PCa tissues. To determine whether transcriptional silencing of the RIZ1 gene is caused by DNA hypermethylation, we compared the methylation status with expression of RIZ1 mRNA in PCa cell lines.…”

mentioning

confidence: 99%

DNA methylation of the RIZ1 gene is associated with nuclear accumulation of p53 in prostate cancer

et al. 2006

Self Cite

View full text Add to dashboard Cite

The retinoblastoma protein-interacting zinc finger gene, RIZ1, is thought to be a tumor suppressor gene. RIZ1 is inactivated by mutation, deletion and DNA methylation in several human cancers. In the present study, the relationship between DNA methylation of RIZ1 and mutation of p53 was investigated in prostate cancer (PCa). In total, 47 cases of node-negative PCa (stages I-III) were analyzed. DNA methylation of the RIZ1 gene was detected in 20 (42.6%) of the 47 PCa tissues by methylation-specific polymerase chain reaction. DNA methylation of the RIZ1 gene was not associated with clinicopathological features. DNA methylation of RIZ1 tended to be present more frequently in PCa specimens with a high Gleason score (16/30, 53.3%) than in those with a low Gleason score (4/17, 23.5%); however, this tendency was not statistically significant (P = 0.0675). Nuclear accumulation of p53 was observed in four (8.5%) of 47 PCa specimens by immunostaining. All four PCa specimens with nuclear accumulation of p53 were stage III disease and showed DNA methylation of RIZ1. However, of the remaining 43 cancers without nuclear accumulation of p53, DNA methylation of RIZ1 was observed in only 16 (37.2%) specimens (P = 0.0272). Of the three PCa cell lines, only the PC3 cell line showed loss of RIZ1 mRNA due to DNA methylation, and this loss was rectified by treatment with a demethylating agent, 5-Aza-2′ ′ ′ ′-deoxycytidine. These results suggest that transcriptional inactivation of RIZ1 by aberrant DNA methylation may contribute to prostate carcinogenesis. Genetic alterations are likely associated with epigenetic alterations in PCa. (Cancer Sci 2007; 98: 32-36) P rostate cancer (PCa) is one of the most common cancers and the second leading cause of cancer death in men in the USA.(1) An understanding of the genetic and epigenetic pathways involved in the pathogenesis of PCa is essential for development of improved diagnostic and treatment modalities. A variety of genetic and epigenetic alterations are associated with PCa. (2,3) Epigenetic changes, such as DNA methylation of CpG islands, are detected commonly in human cancers. Hypermethylation of CpG islands is associated with silencing of many genes, especially defective tumor-related genes, and has been proposed as an alternative way to inactivate tumor-related genes in human cancers.(4,5) Identification of methylated genes may be useful in the diagnosis and treatment of PCa and may provide insight into prostate carcinogenesis. Prior studies have shown that DNA hypermethylation is a crucial mechanism in transcriptional silencing of tumor-related genes in PCa. (6,7) The retinoblastoma protein-interacting zinc finger gene, RIZ1, was isolated with a functional screen for retinoblastoma (Rb)-binding proteins.(8) Domain analysis suggested that RIZ1 is a histone methyltransferase (HMT) specific for the lysine 9 residue of histone H3, an activity known to be linked with transcriptional repression.(9) RIZ1 is considered to be a tumor suppressor gene because it can induce G 2 -M arrest and apo...

show abstract

Distinct promoter hypermethylation of p16^INK4a, CDH1, and RAR‐beta in intestinal, diffuse–adherent, and diffuse–scattered type gastric carcinomas

Cited by 77 publications

References 23 publications

DNA methylation of multiple genes in gastric carcinoma: Association with histological type and CpG island methylator phenotype

DNA methylation of multiple genes in gastric carcinoma: Association with histological type and CpG island methylator phenotype

Serum olfactomedin 4 (GW112, hGC‐1) in combination with Reg IV is a highly sensitive biomarker for gastric cancer patients

DNA methylation of the RIZ1 gene is associated with nuclear accumulation of p53 in prostate cancer

Contact Info

Product

Resources

About