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MAL promoter hypermethylation as a novel prognostic marker in gastric cancer.

Buffart TE, Overmeer RM, Steenbergen RD, Tijssen M, van Grieken NC, Snijders PJ, Grabsch HI, van de Velde CJ, Carvalho B, Meijer GA - Br. J. Cancer (2008)

Bottom Line: T-lymphocyte maturation associated protein, MAL, has been described as a tumour-suppressor gene with diagnostic value in colorectal and oesophageal cancers, and can be inactivated by promoter hypermethylation.Two regions within the MAL promoter (M1 and M2) were analysed.Hypermethylation of M2, but not M1, correlated with significantly better disease-free survival in a univariate (P=0.03) and multivariate analysis (P=0.03) and with downregulation of expression (P=0.01).

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.

ABSTRACT
T-lymphocyte maturation associated protein, MAL, has been described as a tumour-suppressor gene with diagnostic value in colorectal and oesophageal cancers, and can be inactivated by promoter hypermethylation. The aim of this study was to analyse the prevalence of MAL promoter hypermethylation and the association with mRNA expression in gastric cancers and to correlate methylation status to clinicopathological data. Bisulphite-treated DNA isolated from formalin-fixed and paraffin-embedded samples of 202 gastric adenocarcinomas and 22 normal gastric mucosae was subjected to real-time methylation-specific PCR (Q-MSP). Two regions within the MAL promoter (M1 and M2) were analysed. In addition, 17 frozen gastric carcinomas and two gastric cancer cell lines were analysed both by Q-MSP and real-time RT-PCR. Methylation of M1 and M2 occurred in 71 and 80% of the gastric cancers, respectively, but not in normal gastric mucosa tissue. Hypermethylation of M2, but not M1, correlated with significantly better disease-free survival in a univariate (P=0.03) and multivariate analysis (P=0.03) and with downregulation of expression (P=0.01). These results indicate that MAL has a putative tumour-suppressor gene function in gastric cancer, and detection of promoter hypermethylation may be useful as a prognostic marker.

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Box plots of the relative expression values of 17 gastric carcinoma tissue samples methylated and unmethylated for the M1 (A) and M2 (B) promoter regions. Gastric carcinomas methylated for the M2 MAL promoter region show significantly lower expression of the MAL gene compared with unmethylated gastric carcinomas (P=0.01).
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fig3: Box plots of the relative expression values of 17 gastric carcinoma tissue samples methylated and unmethylated for the M1 (A) and M2 (B) promoter regions. Gastric carcinomas methylated for the M2 MAL promoter region show significantly lower expression of the MAL gene compared with unmethylated gastric carcinomas (P=0.01).

Mentions: Reduced expression of MAL relative to the housekeeping gene snRNP U1A was observed in both gastric cancer cell lines compared with primary keratinocytes that did not show MAL promoter hypermethylation. Of the 17 gastric cancer tissue samples tested for MAL mRNA expression, 11 (64.7%) were methylated for M1, 11 (64.7%) for M2 and 9 (52.9%) samples showed methylation of both regions. Gastric carcinomas with M2 promoter methylation showed significantly lower expression of the MAL gene compared with M2 unmethylated gastric cancers (P=0.01) (Figure 3, Table 3). For the M1 region, no significant differences in MAL mRNA expression were found between methylated and unmethylated tumours.


MAL promoter hypermethylation as a novel prognostic marker in gastric cancer.

Buffart TE, Overmeer RM, Steenbergen RD, Tijssen M, van Grieken NC, Snijders PJ, Grabsch HI, van de Velde CJ, Carvalho B, Meijer GA - Br. J. Cancer (2008)

Box plots of the relative expression values of 17 gastric carcinoma tissue samples methylated and unmethylated for the M1 (A) and M2 (B) promoter regions. Gastric carcinomas methylated for the M2 MAL promoter region show significantly lower expression of the MAL gene compared with unmethylated gastric carcinomas (P=0.01).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2600687&req=5

fig3: Box plots of the relative expression values of 17 gastric carcinoma tissue samples methylated and unmethylated for the M1 (A) and M2 (B) promoter regions. Gastric carcinomas methylated for the M2 MAL promoter region show significantly lower expression of the MAL gene compared with unmethylated gastric carcinomas (P=0.01).
Mentions: Reduced expression of MAL relative to the housekeeping gene snRNP U1A was observed in both gastric cancer cell lines compared with primary keratinocytes that did not show MAL promoter hypermethylation. Of the 17 gastric cancer tissue samples tested for MAL mRNA expression, 11 (64.7%) were methylated for M1, 11 (64.7%) for M2 and 9 (52.9%) samples showed methylation of both regions. Gastric carcinomas with M2 promoter methylation showed significantly lower expression of the MAL gene compared with M2 unmethylated gastric cancers (P=0.01) (Figure 3, Table 3). For the M1 region, no significant differences in MAL mRNA expression were found between methylated and unmethylated tumours.

Bottom Line: T-lymphocyte maturation associated protein, MAL, has been described as a tumour-suppressor gene with diagnostic value in colorectal and oesophageal cancers, and can be inactivated by promoter hypermethylation.Two regions within the MAL promoter (M1 and M2) were analysed.Hypermethylation of M2, but not M1, correlated with significantly better disease-free survival in a univariate (P=0.03) and multivariate analysis (P=0.03) and with downregulation of expression (P=0.01).

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.

ABSTRACT
T-lymphocyte maturation associated protein, MAL, has been described as a tumour-suppressor gene with diagnostic value in colorectal and oesophageal cancers, and can be inactivated by promoter hypermethylation. The aim of this study was to analyse the prevalence of MAL promoter hypermethylation and the association with mRNA expression in gastric cancers and to correlate methylation status to clinicopathological data. Bisulphite-treated DNA isolated from formalin-fixed and paraffin-embedded samples of 202 gastric adenocarcinomas and 22 normal gastric mucosae was subjected to real-time methylation-specific PCR (Q-MSP). Two regions within the MAL promoter (M1 and M2) were analysed. In addition, 17 frozen gastric carcinomas and two gastric cancer cell lines were analysed both by Q-MSP and real-time RT-PCR. Methylation of M1 and M2 occurred in 71 and 80% of the gastric cancers, respectively, but not in normal gastric mucosa tissue. Hypermethylation of M2, but not M1, correlated with significantly better disease-free survival in a univariate (P=0.03) and multivariate analysis (P=0.03) and with downregulation of expression (P=0.01). These results indicate that MAL has a putative tumour-suppressor gene function in gastric cancer, and detection of promoter hypermethylation may be useful as a prognostic marker.

Show MeSH
Related in: MedlinePlus