Hypermethylation of HPP1 is associated with hMLH1 hypermethylation in gastric adenocarcinomas

David M. Shibata, Fumiaki Sato, Yuriko Mori, Kellie Perry, Jing Yin, Suna Wang, Yan Xu, Andreea Olaru, Florin Selaru, Kevin Spring, Joanne Young, John M. Abraham, Stephen Meltzer

Research output: Contribution to journalArticle

Abstract

The HPP1 gene was initially discovered because of its frequent hypermethylation in hyperplastic colon polyps, but it is also hypermethylated in colorectal adenomas and carcinomas. Expression of the DNA mismatch repair gene hMLH1 is diminished or absent in some hyperplastic polyps, and it has been suggested that HPP1 inactivation is associated with the progression of microsatellite-unstable colorectal tumors. We sought then to determine the prevalence of HPP1 silencing by DNA methylation in gastric adenocarcinomas and to define any association of this event with microsatellite instability (MSI) or hMLH1 hypermethylation. Thirty-two matched normal-gastric adenocarcinoma DNA pairs were studied for MSI status and hypermethylation of HPP1 and hMLH1. Five (100%) of 5 MSI-H tumors, 2 (50%) of 4 MSI-L tumors, and 8 (35%) of 23 MSS tumors demonstrated HPP1 hypermethylation. Eight (25%) of 32 tumors (5 of 5 MSI-H, 2 of 4 MSI-L, and 1 of 23 MSS) showed evidence of hMLH1 hypermethylation. All (8 of 8) of these hMLHI-methylated tumors demonstrated concomitant methylation at the HPP1 locus: there were no cases of hMLH1 methylation occurring in the absence of HPP1 methylation. In gastric adenocarcinoma, hypermethylation frequently targets HPP1. Moreover, hMLH1 hypermethylation occurs predominantly in the setting of HPP1 hypermethylation. HPP1 hypermethylation may represent an early event in mismatch repair-deficient gastric tumorigenesis.

Original languageEnglish (US)
Pages (from-to)5637-5640
Number of pages4
JournalCancer Research
Volume62
Issue number20
StatePublished - Oct 15 2002
Externally publishedYes

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Microsatellite Instability
Stomach
Adenocarcinoma
Methylation
DNA Mismatch Repair
Neoplasms
Polyps
Colorectal Neoplasms
DNA Methylation
Adenoma
Microsatellite Repeats
Genes
Colon
Carcinogenesis
DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Hypermethylation of HPP1 is associated with hMLH1 hypermethylation in gastric adenocarcinomas. / Shibata, David M.; Sato, Fumiaki; Mori, Yuriko; Perry, Kellie; Yin, Jing; Wang, Suna; Xu, Yan; Olaru, Andreea; Selaru, Florin; Spring, Kevin; Young, Joanne; Abraham, John M.; Meltzer, Stephen.

In: Cancer Research, Vol. 62, No. 20, 15.10.2002, p. 5637-5640.

Research output: Contribution to journalArticle

Shibata, DM, Sato, F, Mori, Y, Perry, K, Yin, J, Wang, S, Xu, Y, Olaru, A, Selaru, F, Spring, K, Young, J, Abraham, JM & Meltzer, S 2002, 'Hypermethylation of HPP1 is associated with hMLH1 hypermethylation in gastric adenocarcinomas', Cancer Research, vol. 62, no. 20, pp. 5637-5640.
Shibata DM, Sato F, Mori Y, Perry K, Yin J, Wang S et al. Hypermethylation of HPP1 is associated with hMLH1 hypermethylation in gastric adenocarcinomas. Cancer Research. 2002 Oct 15;62(20):5637-5640.
Shibata, David M. ; Sato, Fumiaki ; Mori, Yuriko ; Perry, Kellie ; Yin, Jing ; Wang, Suna ; Xu, Yan ; Olaru, Andreea ; Selaru, Florin ; Spring, Kevin ; Young, Joanne ; Abraham, John M. ; Meltzer, Stephen. / Hypermethylation of HPP1 is associated with hMLH1 hypermethylation in gastric adenocarcinomas. In: Cancer Research. 2002 ; Vol. 62, No. 20. pp. 5637-5640.
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abstract = "The HPP1 gene was initially discovered because of its frequent hypermethylation in hyperplastic colon polyps, but it is also hypermethylated in colorectal adenomas and carcinomas. Expression of the DNA mismatch repair gene hMLH1 is diminished or absent in some hyperplastic polyps, and it has been suggested that HPP1 inactivation is associated with the progression of microsatellite-unstable colorectal tumors. We sought then to determine the prevalence of HPP1 silencing by DNA methylation in gastric adenocarcinomas and to define any association of this event with microsatellite instability (MSI) or hMLH1 hypermethylation. Thirty-two matched normal-gastric adenocarcinoma DNA pairs were studied for MSI status and hypermethylation of HPP1 and hMLH1. Five (100{\%}) of 5 MSI-H tumors, 2 (50{\%}) of 4 MSI-L tumors, and 8 (35{\%}) of 23 MSS tumors demonstrated HPP1 hypermethylation. Eight (25{\%}) of 32 tumors (5 of 5 MSI-H, 2 of 4 MSI-L, and 1 of 23 MSS) showed evidence of hMLH1 hypermethylation. All (8 of 8) of these hMLHI-methylated tumors demonstrated concomitant methylation at the HPP1 locus: there were no cases of hMLH1 methylation occurring in the absence of HPP1 methylation. In gastric adenocarcinoma, hypermethylation frequently targets HPP1. Moreover, hMLH1 hypermethylation occurs predominantly in the setting of HPP1 hypermethylation. HPP1 hypermethylation may represent an early event in mismatch repair-deficient gastric tumorigenesis.",
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AU - Sato, Fumiaki

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AU - Perry, Kellie

AU - Yin, Jing

AU - Wang, Suna

AU - Xu, Yan

AU - Olaru, Andreea

AU - Selaru, Florin

AU - Spring, Kevin

AU - Young, Joanne

AU - Abraham, John M.

AU - Meltzer, Stephen

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