Gastric cancers of the microsatellite mutator phenotype display characteristic genetic and clinical features☆, ☆☆

Yamamoto, Hiroyuki; Pérez-Piteira, J; Yoshida, Teruhiko; Terada, Masaaki; Itoh, Fumio; Imai, Kohzoh; Perucho, Manuel

doi:10.1016/s0016-5085(99)70499-3

Cited by 171 publications

(156 citation statements)

References 34 publications

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“…Thus, the paradoxically better clinical course in Bax-mutated tumors is well in line with the known overall better prognosis of patients with MMR-deficient tumors. 25,26 Figure 1c confirms that Bax mutation was associated with lower Bax expression in the tumors (MannWhitney U-test: P¼0.0079). Apart from defining the impact of Bax mutation on Bax expression, we were interested in the role of p53, a transcriptional activator of the Bax gene and upstream activator of mitochondrial apoptosis.…”

Section: Bax Expression and Mutationsupporting

confidence: 62%

Combined p53/Bax mutation results in extremely poor prognosis in gastric carcinoma with low microsatellite instability

et al. 2003

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Gastric cancer is highly refractory to DNA-damaging therapies. We therefore studied both gene mutation and protein expression of p53 and Bax in a cohort of 116 patients with gastric cancer who underwent R0-resection with a curative intent. Bax mutation was independent from severe microsatellite instability (MSI), that is, global mismatch repair deficiency as determined by analysis of BAT-25/BAT-26 microsatellite markers. Thus, Bax-frameshift mutation is a feature of tumors with low MSI. In contrast and as expected, no p53 mutations were observed in the microsatellite instable tumors. p53 Mutation or p53 overexpression did not have an impact on disease prognosis. p53-Inactivation was, however, associated with an extremely poor prognosis in the subgroup of patients with Bax-mutated tumors. Thus, we show for the first time that the combined mutation of p53 and Bax, two key regulators of the mitochondrial apoptosis pathway, results in an extremely aggressive tumor biology and poor clinical prognosis.

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Section: Bax Expression and Mutationsupporting

confidence: 62%

Combined p53/Bax mutation results in extremely poor prognosis in gastric carcinoma with low microsatellite instability

et al. 2003

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“…This finding is in line with other studies which state p53 gene alterations appeared to be rarely accompanied with MSI (Yamamoto et al, 1999).…”

Section: Discussionsupporting

confidence: 93%

Detection of p53 Common Intron Polymorphisms in Patients with Gastritis Lesions from Iran

Sadeghi

Damavand²,

Vahedi³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: p53 alterations have been implicated in the development of many cancers, such as gastric cancer, but there is no evidence of p53 intron alterations in gastritis lesions. The aim of this study was to investigate the p53 intron alterations in gastritis along with p53 and mismatch repair protein expression and microsatellite status. Materials and Methods: PCR-sequencing was conducted for introns 2-7 on DNA extracted from 97 paired samples of gastritis lesions and normal adjacent tissue. Abnormal accumulation of p53 and mismatch repair proteins was investigated using immunohistochemistry. In addition, microsatellite status was evaluated with reference to five mononucleotide markers. Results: Gastritis cases included 41 males and 56 females in the age range of 15-83 years, 87.6% being H.pylori positive. IVS2+38, IVS3ins16 and IVS7+72 were the most polymorphic sites. Their minor allele frequency values were as follows: 0.38, 0.21 and 0.06, respectively. Samples with GG genotype at IVS2+38 and CT at IVS7+72 had no insertion. Moreover, most of the stable samples (91.9 %) had a G allele at IVS2+38. All of the samples were IHC negative for p53 protein, microsatellite stable and expressed mismatch repair proteins. p53 alterations were prominent in the H. Pylori+ group, but without statistical significance. Conclusions: According to our results, some p53 polymorphisms such as IVS2+38, IVS3ins16 and IVS7+72, because of their correlations together or with microsatellite status may contribute to gastritis development. However, so far effects on p53 expression and function remain unclear. Therefore, a comprehensive survey is needed to delineate their biological significance.

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“…Furthermore, we have noticed that patients with tumours showing demethylation of both MAGE-A1 and -A3 tend to have a worse prognosis, although this difference was not statistically significant. In contrast, hypermethylation of the hMLH1 gene promoter is a marker of a better prognosis (Yamamoto et al, 1999). No correlation has been observed between demethylation of the MAGE genes and hypermethylation of hMLH1 or p16 (data not shown).…”

Section: Discussionmentioning

confidence: 86%

Demethylation of MAGE promoters during gastric cancer progression

et al. 2004

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Melanoma antigen (MAGE)-encoding genes are expressed in various tumour types via demethylation of their promoter CpG islands, which are silent in all non-neoplastic tissues except for the testis and placenta. The clinicopathological significance of demethylation of MAGE genes in gastric carcinoma is not known. We investigated the promoter methylation status of MAGE-A1 and -A3 in 10 gastric cancer cell lines and in surgical specimens from 84 gastric cancer patients by methylation-specific PCR (MSP). Expression of MAGE-A1 and -A3 in the 10 gastric cancer cell lines was also investigated by RT -PCR. Any correlation between the methylation status of the MAGE promoters and clinicopathological characteristics of the gastric cancer patients was then assessed. Eight of the 10 gastric cancer cell lines showed demethylation of both MAGE-A1 and -A3, and the remaining two cell lines did either of MAGE-A1 or -A3. Expression of MAGE-A1 and -A3 was confirmed in seven and nine of the 10 gastric cancer cell lines, respectively. The MAGE-A1 and -A3 promoters were demethylated in 29% (25 out of 84) and 66% (56 out of 84) of the gastric tumour specimens, respectively. Demethylation of both MAGE-A1 and -A3 promoters (n ¼ 22) was found more frequently in gastric cancer patients in advanced clinical stages (P ¼ 0.0035), and these patients also exhibited a higher incidence of lymph node metastasis (P ¼ 0.0007) compared to those patients without demethylation (n ¼ 25). Furthermore, demethylation patients tended to have a worse prognosis, although this difference was not statistically significant (P ¼ 0.183). Demethylation of MAGE-A1 and -A3 occurs during progressive stages of gastric cancer, and may be associated with aggressive biological behaviour of gastric cancer.

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Gastric cancers of the microsatellite mutator phenotype display characteristic genetic and clinical features☆, ☆☆

Cited by 171 publications

References 34 publications

Combined p53/Bax mutation results in extremely poor prognosis in gastric carcinoma with low microsatellite instability

Combined p53/Bax mutation results in extremely poor prognosis in gastric carcinoma with low microsatellite instability

Detection of p53 Common Intron Polymorphisms in Patients with Gastritis Lesions from Iran

Demethylation of MAGE promoters during gastric cancer progression

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