Hypermethylation of the RUNX3 Gene Promoter in Testicular Yolk Sac Tumor of Infants

Kato, Noriko; Tamura, Gen; Fukase, Masayuki; Shibuya, Hiroyuki; Motoyama, Teiichi

doi:10.1016/s0002-9440(10)63668-1

Cited by 67 publications

(64 citation statements)

References 18 publications

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“…RUNX3 was reported to be frequently methylated in gastric cancers and testicular yolk sac tumors of infant. 26,64 Recently, frequent methylation of RUNX3 was published in CRC cell lines. 47 We clarified the methylation status of primary CRCs, CPs and NME in addition to CRC cell lines.…”

Section: Discussionmentioning

confidence: 99%

Aberrant promoter methylation of multiple genes during multistep pathogenesis of colorectal cancers

Takahashi

Shigematsu

Shivapurkar

et al. 2005

Intl Journal of Cancer

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Aberrant methylation of 5 0 gene promoter regions associated with gene silencing is an epigenetic phenomenon responsible for silencing of tumor suppressor genes in many cancer types. The aims of our study were to study the role of methylation of a large panel of genes during multistage pathogenesis and to correlate our findings with patient age and other clinico-pathological features. We investigated the aberrant promoter methylation profile of 19 genes in 92 colorectal cancers (CRCs) and corresponding nonmalignant epithelia (NME) (n 5 57), and selected 15 genes for studying 26 colorectal adenomas (CAs). On the Basis of our results, the genes could be divided into 3 groups. Group 1 consisted of 13 genes whose methylation was tumor-specific. For 8 of these genes, the methylation frequencies in CAs were similar to those of CRCs, but significantly different from the frequencies in NME. Group 2, consisting of 2 genes demonstrating little or no methylation, were present in any sample type. In Group 3, consisting of 4 genes, relatively frequent methylation was present in both CRCs and NME, and the differences between these specimen types were not significant. Methylation of Group 1 genes were tightly correlated with each other, and these genes demonstrated increased methylation frequencies in CRCs with increasing age. Methylation was not correlated with other clinico-pathological features. In general, methylation frequencies of CAs were intermediate between CRCs and NME. Our study constitutes the most comprehensive methylation profile of CRCs, demonstrates that methylation commences early during CRC pathogenesis and is an age-related phenomenon. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Aberrant promoter methylation of multiple genes during multistep pathogenesis of colorectal cancers

Takahashi

Shigematsu

Shivapurkar

et al. 2005

Intl Journal of Cancer

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“…15 It is important to note that loss of heterozygosity (LOH) at 1p36.1, where the RUNX3 gene locates, was detected in the most hypermethylated cases of testicular yolk sac tumors from infants. 16 Therefore, RUNX3 seems to follow the two-hit model of inactivation of tumor suppressor gene, namely loss of one allele and inactivation of the other by the hypermethylation. Further study on the LOH in various tumor tissues is also needed to better understand the molecular mechanism for the loss of RUNX3 expression.…”

Section: Discussionmentioning

confidence: 99%

Methylation of RUNX3 in various types of human cancers and premalignant stages of gastric carcinoma

Kim¹,

Lee²,

Hwang³

et al. 2004

Laboratory Investigation

197

168

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Accumulating evidence has identified a mechanism potentially responsible for the inactivation of tumor suppressor genes, namely transcriptional silencing by aberrant methylation of CpG islands. A previous study has shown the loss of RUNX3 expression, due to aberrant methylation of its CpG island, in gastric cancer cell lines, suggesting that RUNX3 is a target for epigenetic gene silencing in gastric carcinogenesis. However, there are limited data on the methylation status of RUNX3 in the neoplastic and non-neoplastic tissues in various types of human cancers, including gastric cancer. Here, we report that 60% of gastric cancer cell lines and 64% of primary gastric carcinomas (n ¼ 75) were methylated at the RUNX3 CpG island. RUNX3 methylation was also detected in hepatocellular carcinomas (73%, n ¼ 48), larynx cancers (62%, n ¼ 37), lung cancers (46%, n ¼ 24), breast cancers (25%, n ¼ 25), prostate cancers (23%, n ¼ 44), endometrial cancers (12.5%, n ¼ 24), colon cancers (4.9%, n ¼ 61) and uterine cervical cancers (2.5%, n ¼ 40), showing that RUNX3 methylation is not restricted to gastric cancer. Interestingly, the RUNX3 methylation was especially frequent in tumors from tissues of a foregut derivative, that is, the stomach, liver, larynx and lung. Next, the methylation status of RUNX3 in various nonneoplastic tissues was examined, including the premalignant lesions of gastric carcinomas. The RUNX3 methylation was found in 8.1% of chronic gastritis (n ¼ 99), 28.1% of intestinal metaplasia (n ¼ 32), 27.3% of gastric adenomas (n ¼ 77) and 64% of gastric carcinomas (n ¼ 75), but not in chronic hepatitis B, normal prostate and colon mucosa, even though in cases of chronic hepatitis, the methylation frequency of its neoplastic tissues was very high. In conclusion, RUNX3 methylation is frequently found in human cancers, including gastric cancer, and is mostly cancer specific, with the exception of the stomach, and thus, might be useful as a potential diagnostic biomarker of cancer.

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“…RUNX3 was also identified as one of the five most informative genes of the CpG island methylator phenotype of colorectal cancer (Weisenberger et al, 2006). In addition to gastric and colon cancer, RUNX3 is frequently inactivated in cancers of the lung, bladder, pancreas, liver, prostate, bile duct, breast, larynx, esophagus, and testicular yolk sac by either DNA hypermethylation or mislocalization of the protein in the cytoplasm (Kato et al, 2003;Goel et al, 2004;Kang et al, 2004;Li et al, 2004;Tozawa et al, 2004;Xiao and Liu, 2004;Ito et al, 2005;Kim et al, 2005b;Lau et al, 2006). Among the lung cancers, RUNX3 promoter hypermethylation is preferentially found in lung adenocarcinomas (Sato et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Runx3 is required for the differentiation of lung epithelial cells and suppression of lung cancer

Lee

et al. 2010

Oncogene

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Human lung adenocarcinoma, the most prevalent form of lung cancer, is characterized by many molecular abnormalities. K-ras mutations are associated with the initiation of lung adenocarcinomas, but K-ras-independent mechanisms may also initiate lung tumors. Here, we find that the runt-related transcription factor Runx3 is essential for normal murine lung development and is a tumor suppressor that prevents lung adenocarcinoma. Runx3À/À mice, which die soon after birth, exhibit alveolar hyperplasia. Importantly, Runx3À/À bronchioli exhibit impaired differentiation, as evidenced by the accumulation of epithelial cells containing specific markers for both alveolar (that is SP-B) and bronchiolar (that is CC10) lineages. Runx3À/À epithelial cells also express Bmi1, which supports self-renewal of stem cells. Lung adenomas spontaneously develop in aging Runx3 þ /À mice (B18 months after birth) and invariably exhibit reduced levels of Runx3. As K-ras mutations are very rare in these adenomas, Runx3 þ /À mice provide an animal model for lung tumorigenesis that recapitulates the preneoplastic stage of human lung adenocarcinoma development, which is independent of K-Ras mutation. We conclude that Runx3 is essential for lung epithelial cell differentiation, and that downregulation of Runx3 is causally linked to the preneoplastic stage of lung adenocarcinoma.

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Hypermethylation of the RUNX3 Gene Promoter in Testicular Yolk Sac Tumor of Infants

Cited by 67 publications

References 18 publications

Aberrant promoter methylation of multiple genes during multistep pathogenesis of colorectal cancers

Aberrant promoter methylation of multiple genes during multistep pathogenesis of colorectal cancers

Methylation of RUNX3 in various types of human cancers and premalignant stages of gastric carcinoma

Runx3 is required for the differentiation of lung epithelial cells and suppression of lung cancer

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