Genetic classification of intestinal-type and diffuse-type gastric cancers based on chromosomal loss and microsatellite instability

Kim, Kyoung‐Mee; Kwon, Mee-Sun; Hong, Seung‐Jin; Min, Ki-Oak; Seo, Eun-Joo; Lee, Kyo‐Young; Choi, Sae Kyung; Rhyu, Mun-Gan

doi:10.1007/s00428-003-0840-0

Cited by 58 publications

(89 citation statements)

References 26 publications

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“…34 Kim et al demonstrated that MSIpositive gastric cancer cases were significantly correlated with intestinal type, late onset and early stage disease. 35 In this current study, we have shown that the presence of RAB32 methylation correlates in statistically significant fashion with mixed or intestinal type cancer and hMLH1 methylation. There was a nonstatistically significant trend towards RAB32 methylation association with nonproximal location.…”

Section: Clinicopathologic Differences Among Subtypes Of Gastric Cancersupporting

confidence: 50%

RAB32 hypermethylation and microsatellite instability in gastric and endometrial adenocarcinomas

Shibata

Mori

Cai

et al. 2006

Intl Journal of Cancer

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The recently described gene, RAB32, is a ras proto-oncogene family member that encodes an A-kinase-anchoring protein. RAB32 has been found to be frequently hypermethylated in microsatellite instability-high (MSI-H) colon cancers. We sought to determine the prevalence of RAB32 hypermethylation in gastric and endometrial adenocarcinomas, the 2 other major tumor types in which MSI-H is common. Moreover, we delineated the association of RAB32 hypermethylation with microsatellite instability (MSI) and hMLH1 hypermethylation. MSI status and hypermethylation of the RAB32 and hMLH1 genes were studied in paired primary normal and tumor tissues from 48 patients with gastric cancer. An additional 80 endometrial cancer patients were studied for RAB32 methylation and MSI status. Thirteen (27%) of 48 gastric cancers demonstrated evidence of RAB32 hypermethylation. MSI status was determined in 46 of the tumors, with 7 (100%) of 7 MSI-H tumors, 1 (33%) of 3 MSI-low (MSI-L) tumors and 4 (11%) of 36 microsatellite-stable (MSS) tumors found to harbor RAB32 hypermethylation. RAB32 methylation was significantly associated with intestinal type histology and concomitant hMLH1 hypermethylation in gastric cancer. In contrast, RAB32 methylation occurred in only 1 of 80 endometrial cancers, including 20 MSI-H, 8 MSI-L and 52 MSS tumors. Hypermethylation of hMLH1 was noted in 16 (20%) of 80 endometrial tumors. We conclude that although RAB32 methylation is rare in endometrial cancers, it is strongly associated with hMLH1 hypermethylation and MSI in gastric adenocarcinomas. Given its similar involvement in colon cancer, RAB32 inactivation may represent a component of the oncogenic pathway of microsatellite-unstable gastrointestinal adenocarcinomas. ' 2006 Wiley-Liss, Inc.Key words: RAB32; methylation; microsatellite instability; gastric cancer; endometrial cancer Hypermethylation of promoter region CpG islands is well recognized as an important mechanism of transcriptional repression and loss of gene function. 1 As a key example, hypermethylation of hMLH1 is strongly associated with sporadic cases of microsatellite instability-high (MSI-H) cancers. There is growing evidence to suggest that concurrent hypermethylation of multiple additional genes may represent an important component in the development and progression of colorectal cancers. [2][3][4][5][6][7][8] This propensity for methylation in such tumors has served as an interesting feature to exploit in the search for novel methylation targets.We have recently applied a global expression profiling-based technique to identify potential novel methylation targets in MSI-H colorectal cancers. One of the genes discovered to have significant differential methylation in microsatellite-unstable cancers was RAB32, a mitochondrial ras family member that encodes an A-kinase anchoring protein. RAB32 was found to be methylated exclusively in MSI-H colon cancers, with no evidence of methylation in either non-MSI-H tumors or normal adjacent mucosal tissue. 9 RAB32 has the ability to anchor the cyclic ...

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Section: Clinicopathologic Differences Among Subtypes Of Gastric Cancersupporting

confidence: 50%

RAB32 hypermethylation and microsatellite instability in gastric and endometrial adenocarcinomas

Shibata

Mori

Cai

et al. 2006

Intl Journal of Cancer

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“…6,7 However, the present study and other studies 5,13,14 did not confirm this reported correlation. Reports on the clinicopathological significance of LOH at 3p14, 13,47 4p15, 8,13 9p21 13 and 13q22 13,14 are very rare, and no positive correlation has been found except for one study stating that 13q los was weakly correlated with advanced tumor (P ¼ 0.049).…”

Section: Resultscontrasting

confidence: 98%

“…Several studies have reported that 17p13 loss was correlated with gastric wall invasion, 5,40 but other studies have failed to find a significant association. 8,13 Allelic losses at 3p14, 4p15, 5q21-22, 9p21, 13q22 and 18q21 did not show a significant association with aggressive behaviors such as stage (depth of invasion), lymphatic or vessel invasion, and lymph node metastasis in the present study, suggesting that putative or candidate tumor suppressor genes at these chromosomal regions may be involved in carcinogenesis of intestinal-and solid-type gastric carcinoma. It is well known that tumor suppressor genes FHIT, APC, p16, DCC and DPC4 have been mapped to 3p14, 5q21-22, 9p21 and 18q21, respectively.…”

Section: Resultscontrasting

confidence: 67%

“…3,4 To date, several studies have attempted to investigate the relationship between various clinicopathological characteristics or outcomes and LOH status in gastric carcinoma. [5][6][7][8][9][10][11][12][13][14][15] However, these studies substantially disagree among themselves with regard to the frequency of LOH, and the relationships between LOH and various clinicopathological factors or outcomes remain controversial. Some of these studies have focused on the relationship between clinicopathological factors and the extent of chromosomal loss (fractional allelic loss (FAL)).…”

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confidence: 99%

“…Some of these studies have focused on the relationship between clinicopathological factors and the extent of chromosomal loss (fractional allelic loss (FAL)). 9,10,13,14 Most studies investigating the relationship between single chromosomal loss and clinicopathological variables have only evaluated tumor stage (depth of invasion). 5,6,8,11 Therefore, the clinicopathological significance of LOH, especially single chromosomal region loss, with respect to the initiation and progression of gastric carcinoma remains poorly understood.…”

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confidence: 99%

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Clinicopathological significance of loss of heterozygosity in intestinal- and solid-type gastric carcinomas: a comprehensive study using the crypt isolation technique

et al. 2006

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The clinicopathological significance of loss of heterozygosity (LOH) in gastric carcinoma remains poorly understood. We and other researchers have previously demonstrated that LOH is fairly common in intestinaland solid-type gastric carcinomas, but rare in diffuse-type tumors. In this study, we investigated the relationship between clinicopathological variables and LOH status in intestinal-and solid-type gastric carcinomas. The crypt isolation technique was utilized to analyze LOH at 1p36, 3p14, 4p15, 5q21-22, 8p11-12, 9p21, 13q22, 17p13.1 18q21 and 22q13.31 in 113 intestinal-and solid-type gastric carcinomas using a polymerase chain reaction assay. Immunostaining with D2-40 and Elastica van Gieson staining were used to detect lymphatic invasion and vessel invasion, respectively. High LOH rates (49-71%) were observed in all chromosomal regions tested. 1p36 loss was significantly associated with advanced tumors and lymph node metastasis. 8p11-12 loss was significantly associated with lymph node metastasis, lymphatic invasion, and vessel invasion. 17p13.1 (TP53) loss was significantly associated with vessel invasion. 22q13.31 loss was significantly associated with advanced tumors, lymph node metastasis, lymphatic invasion, vessel invasion and late TNM stage. No significant associations were observed between LOH at other chromosomal regions and aggressive behaviors. In addition, significantly higher LOH rates at 1p36, 9p21, 18q21 and 22q13.31 were observed in cardiac tumors compared with noncardiac tumors. These results suggest that in intestinal-and solid-type gastric carcinomas, LOH on 3p14, 4p15, 5q21-22, 9p21, 13q22 and 18q21 is associated with carcinogenesis, while LOH on 1p36, 8p11-12, 17p31.1 and 22q13.31 is associated with tumor progression.

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DNA methylation of genes linked with retinoid signaling in gastric carcinoma

Shutoh¹,

Oue²,

Aung³

et al. 2005

Cancer

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BACKGROUNDHypermethylation of CpG islands has been associated with silencing of various tumor suppressor genes, and the retinoid acid receptor β (RARβ), cellular retinol‐binding protein 1 (CRBP1), and tazarotene‐induced gene 1 (TIG1) genes have been associated with retinoic acid signaling. To the authors' knowledge, little is known regarding the involvement of these three genes in gastric carcinoma (GC). In this study, the authors investigated the methylation status of these genes and analyzed the role of their DNA methylation in GC.METHODSDNA methylation of 3 retinoic acid‐associated genes was analyzed in 42 samples of GC from 42 patients and in 8 GC cell lines by methylation‐specific polymerase chain reaction (PCR) analysis. The mRNA expression levels for these three genes were measured by quantitative reverse transcription‐PCR.RESULTSIn 7 of 8 GC cell lines, the CRBP1 gene was hypermethylated, and CRBP1 transcription was inactive. In 6 of 8 GC cell lines, the TIG1 gene was hypermethylated, and TIG1 transcription was inactive. Treatment with demethylating agent 5‐aza‐2′‐deoxycytidine restored both CRBP1 and TIG1 transcription. DNA methylation of the RARβ, CRBP1, and TIG1 genes was detected in 15 of 42 GC samples (36%), 14 of 42 GC samples (33%), and 4 of 42 GC samples (10%), respectively, and in 6 of 30 samples (20%), 0 of 30 samples (0%), and 1 of 30 samples (3%) of corresponding nonneoplastic mucosa. None of the 10 normal gastric mucosa samples from young, healthy individuals demonstrated hypermethylation of any of these genes. DNA methylation of each gene was associated significantly with low mRNA expression of the respective gene. Twenty‐four of 42 GC samples (57%) demonstrated hypermethylation of at least 1 of the 3 genes. However, no significant, concordant hypermethylation of these genes was observed.CONCLUSIONSThe results suggested that gastric carcinogenesis involves transcriptional inactivation by aberrant DNA methylation of genes related to retinoid signaling. Cancer 2005. © 2005 American Cancer Society.

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Genetic classification of intestinal-type and diffuse-type gastric cancers based on chromosomal loss and microsatellite instability

Cited by 58 publications

References 26 publications

RAB32 hypermethylation and microsatellite instability in gastric and endometrial adenocarcinomas

RAB32 hypermethylation and microsatellite instability in gastric and endometrial adenocarcinomas

Clinicopathological significance of loss of heterozygosity in intestinal- and solid-type gastric carcinomas: a comprehensive study using the crypt isolation technique

DNA methylation of genes linked with retinoid signaling in gastric carcinoma

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