Microsatellite instability in gastric cancer is associated with better prognosis in only stage II cancers

Beghelli, Stefania; Manzoni, Giovanni De; Barbi, Stefano; Tomezzoli, Anna; Roviello, Franco; Gregorio, Carmela Di; Vindigni, Carla; Bortesi, Laura; Parisi, Alice; Saragoni, Luca; Scarpa, Aldo; Moore, Patrick S.

doi:10.1016/j.surg.2005.08.021

Cited by 129 publications

(135 citation statements)

References 33 publications

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“…Several reports, together with our results, have demonstrated that microsatellite-unstable gastric carcinomas are significantly associated with the elderly [2,[4][5][6], women [3,5], and antral location [2,4,5,9]. These characteristics are similar to those of medullary-type, poorly differentiated adenocarcinoma of the colorectum, which is a representative MSI-positive carcinoma showing predominant occurrence in older age, women, and the proximal colon [26].…”

Section: Discussionsupporting

confidence: 80%

“…In contrast, our results indicated worse prognosis in microsatellite-unstable carcinomas in stage II, which may be the result of histological differences among the cases examined. The reports in which microsatellite-unstable carcinoma had an association with intestinal-type histology preferably showed better prognosis [3,5]. Thus, it is still controversial whether microsatellite-unstable carcinoma has better prognosis, even though the tumor has a lower incidence of lymph node metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…MSI has been observed in 8-39 % of gastric carcinomas [1][2][3][4][5][6]. Microsatellite-unstable gastric carcinomas have the following clinicopathological features: older age, expanding growth pattern, antral location, intestinal-type histology, a lower incidence of lymph node metastasis, and favorable prognosis.…”

Section: Introductionmentioning

confidence: 99%

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Frequent microsatellite instability in papillary and solid-type, poorly differentiated adenocarcinomas of the stomach

et al. 2012

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Background Microsatellite instability (MSI) has been observed in 8-39 % of sporadic gastric cancers. However, despite numerous reports indicating a significant relationship between intestinal-type histology and MSI, detailed correlation between histological subtypes and MSI remains obscure. The purpose of the present study is to clarify the relationship between histological subtype and microsatellite status in gastric carcinomas. Methods Microsatellite status was examined for 464 consecutive gastric carcinomas from 420 patients as well as histological subtypes and other clinicopathological findings.Results MSI was observed in 82 carcinomas (17.7 %), and the greatest proportions were observed in solid-type, poorly differentiated adenocarcinoma (43.0 %) and papillary adenocarcinoma (32.5 %), both being significantly higher than those of other subtypes. The proportion increased with advancing age (0 % at 51-64 years, 8.5 % at 65-74 years, 18.4 % at 75-84 years, 35.3 % at 85-96 years). Compared with microsatellite-stable carcinomas, microsatellite-unstable carcinomas were significantly related with older age, female gender, antral location, and predominant papillary adenocarcinoma and solid-type, poorly differentiated adenocarcinoma. Poorly differentiated type carcinoma was significantly less frequent than differentiated type in microsatellite-unstable cancer at the early stage, whereas no significant difference existed at the advanced stage. Conclusions These results suggest that there are specific histological subtypes with highly frequent MSI and that gastric carcinoma with MSI originates from differentiatedtype carcinomas, indicating histological diversity during tumor growth.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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Frequent microsatellite instability in papillary and solid-type, poorly differentiated adenocarcinomas of the stomach

et al. 2012

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“…[40][41][42] The reported incidence is higher in western studies 43 and associated with older age, female gender, larger tumor size, intestinal differentiation, and lower rate of nodal involvement. 40,44 In the Asian Cancer Research Group, the microsatellite-instable subtype was predominantly associated with antral location, early stage, and intestinal phenotype as well. 7 We confirmed the association with intestinal differentiation as established by MUC2 positivity (rather than the Lauren intestinal morphotype) and lower frequency of nodal metastasis.…”

Section: Discussionmentioning

confidence: 99%

A protein and mRNA expression-based classification of gastric cancer

et al. 2016

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The overall survival of gastric carcinoma patients remains poor despite improved control over known risk factors and surveillance. This highlights the need for new classifications, driven towards identification of potential therapeutic targets. Using sophisticated molecular technologies and analysis, three groups recently provided genetic and epigenetic molecular classifications of gastric cancer (The Cancer Genome Atlas, 'Singapore-Duke' study, and Asian Cancer Research Group). Suggested by these classifications, here, we examined the expression of 14 biomarkers in a cohort of 146 gastric adenocarcinomas and performed unsupervised hierarchical clustering analysis using less expensive and widely available immunohistochemistry and in situ hybridization. Ultimately, we identified five groups of gastric cancers based on Epstein-Barr virus (EBV) positivity, microsatellite instability, aberrant E-cadherin, and p53 expression; the remaining cases constituted a group characterized by normal p53 expression. In addition, the five categories correspond to the reported molecular subgroups by virtue of clinicopathologic features. Furthermore, evaluation between these clusters and survival using the Cox proportional hazards model showed a trend for superior survival in the EBV and microsatellite-instable related adenocarcinomas. In conclusion, we offer as a proposal a simplified algorithm that is able to reproduce the recently proposed molecular subgroups of gastric adenocarcinoma, using immunohistochemical and in situ hybridization techniques. Gastric carcinoma is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. Despite better control over known risk factors and development of new chemotherapeutic and targeted agents, in the United States, the 5-year overall survival for gastric cancer patients is only 29%. 1 With regard to patient stratification, although several morphologic classifications have been developed, one broadly used system is the Lauren classification, which divides gastric adenocarcinoma into intestinal and diffuse types. 2 The simple two-tiered classification gives a general understanding of the histogenesis and biology of gastric cancer, and has been particularly helpful in evaluating the epidemiologic data. Another widely used system is the WHO classification, which is based on more precise histologic patterns. It is an all-inclusive system, which recognizes all the rare subtypes that were not identified in the Lauren classification. 3 Nevertheless, its clinical utility is doubtful as there is little difference in outcomes between the distinct histological subgroups.Following the successful Trastuzumab for Gastric Cancer (ToGA) trial, the only validated predictive biomarker for personalized therapy of gastric cancer is limited to human epidermal growth factor receptor (Her2) protein expression. 4 Recently, anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody (ramucirumab) has been FDA approved, and anti-epidermal growth factor receptor (EGFR) an...

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“…However, this finding has been observed earlier for the mismatch repair gene hMLH1, which also has a tumour suppressor function. Inactivation of this gene leads to microsatellite instability of the tumour and patients with microsatellite instable tumours have a better prognosis compared with patients with microsatellite stable tumours (Ribic et al, 2003;Parc et al, 2004;Beghelli et al, 2006). Therefore, tumours without MAL methylation might have a different biology overall, which could relate to poorer clinical outcome, rather than the outcome being dependent on MAL itself.…”

Section: Discussionmentioning

confidence: 99%

MAL promoter hypermethylation as a novel prognostic marker in gastric cancer

et al. 2008

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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 ¼ 0.03) and multivariate analysis (P ¼ 0.03) and with downregulation of expression (P ¼ 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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Microsatellite instability in gastric cancer is associated with better prognosis in only stage II cancers

Cited by 129 publications

References 33 publications

Frequent microsatellite instability in papillary and solid-type, poorly differentiated adenocarcinomas of the stomach

Frequent microsatellite instability in papillary and solid-type, poorly differentiated adenocarcinomas of the stomach

A protein and mRNA expression-based classification of gastric cancer

MAL promoter hypermethylation as a novel prognostic marker in gastric cancer

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