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

Arai, Tomio; Sakurai, Urara; Sawabe, Motoji; Honma, Naoko; Aida, Junko; Ushio, Yasuko; Kanazawa, Nobuo; Kuroiwa, Koichi; Takubo, Kaiyo

doi:10.1007/s10120-012-0226-6

Cited by 62 publications

(54 citation statements)

References 23 publications

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“…Many other publications linked MSI to the intestinal type15,16,25,32,35 and could not show MSI in poorly cohesive carcinomas. Another study performed in Japan40 did not find an association with the tumor phenotype.…”

Section: Discussionmentioning

confidence: 92%

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Clinicopathologic Characteristics of Microsatellite Instable Gastric Carcinomas Revisited: Urgent Need for Standardization

Mathiak

Warneke

Behrens

et al. 2017

Applied Immunohistochemistry &Amp; Molecular Morphology

121

104

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Microsatellite instable gastric cancer (MSI-GC) is a specific molecular subtype of GC. We studied the phenotypes, genotypes, and clinicopathologic characteristics of MSI-GC in a white GC cohort and compared our findings with an extended literature review. The study cohort consisted of 482 patients. Specimens were available from 452 cases and were used for immunostaining (MLH1, PMS2, MSH2, MSH6) and molecular biological analyses (BAT-25, BAT-26, NR-21, NR-24, NR-27; Epstein-Barr virus in situ hybridization). Thirty-four (7.5%) GCs were MSI. Loss of MLH1 and/or PMS2 was found in 30 (88%) MSI-GC, 3 (9%) showed loss of MSH2 and/or MSH6. One (3%) MSI-GC was identified only by molecular biological testing. A single case was heterogeneous and contained microsatellite-stable and instable tumor areas. Twenty-one (62%) MSI-GCs showed unusual histologic features. MSI-GC was not found in diffuse-type or Epstein-Barr virus-positive GC. MSI-GC was significantly more prevalent in elderly patients, distal stomach, and was associated with a significantly lower number of lymph node metastases and a significantly better overall and tumor-specific survival. MSI-GC constitutes a small but relevant subgroup of GC with distinct clinicopathologic characteristics. Our literature review illustrates the shortcomings of missing standardized testing algorithms with prevalences of MSI-GC ranging from 0% to 44.5%. Future studies should test the hypothesis that patients with MSI-GCs may not need adjuvant/perioperative chemotherapy. However, this will require a standardized, quality-controlled diagnostic algorithm of MSI for GC.

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Section: Discussionmentioning

confidence: 92%

“…Only 2 groups previously used our 5 markers 24,37. Others used only 1 or 2 markers15,29,36,40 mixed microsatellite markers established for colon cancer with other microsatellite markers, or even used a panel of 40 different markers33 (Table 2). Different marker panels probably lead to different test results.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic Characteristics of Microsatellite Instable Gastric Carcinomas Revisited: Urgent Need for Standardization

Mathiak

Warneke

Behrens

et al. 2017

Applied Immunohistochemistry &Amp; Molecular Morphology

121

104

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“…Microsatellite-instable gastric adenocarcinomas have been recognized previously as a distinct group based on clinicopathologic 37 and molecular findings. 6,38 However, aberrant E-cadherin or p53 expression may be seen in this subgroup, with hypermethylation of CDH1 27 and abnormalities in TP53 (most frequently as a result of loss of heterozygosity).…”

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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“…Previous studies have shown that most MSI-high tumors are of the intestinal histotype, located in the distal portion of the stomach, and occur more frequently in older women [27]. In particular, MSI-high tumors show distinct histological features, such as mucinous, serrated, and medullary patterns, in advanced cancers [27].…”

Section: Discussionmentioning

confidence: 99%

Genetic differences stratified by PCR-based microsatellite analysis in gastric intramucosal neoplasia

et al. 2016

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Background Although genetic alterations in patients with advanced gastric cancer have been extensively studied, those in patients with intramucosal neoplasia (IMN) are still poorly understood. Methods We evaluated genetic differences in 158 IMNs, including 51 low-grade dysplasias, 58 high-grade dysplasias (HGDs), 30 intramucosal cancers (IMCs), and 19 mixed tumors (composed of IMC and HGD within the same tumor), using PCR-based microsatellite analysis [allelic imbalance (AI) and microsatellite instability (MSI)]. We classified the DNA methylation status as a hypermethylated epigenome, a moderately methylated epigenome, or a hypomethylated epigenome. In addition, p53 overexpression, b-catenin nuclear localization, and mucin expression were also examined. Results From cluster analysis, the IMNs examined were categorized into four subgroups as follows. Tumors in subgroup 1 were characterized by MSI-high status, a hypermethylated epigenome, and loss or reduction of expression of MLH-1. Tumors in subgroup 2 showed a mixed pattern consisting of AI and MSI. In contrast, tumors in subgroup 3, which showed accumulation of multiple AIs, were closely associated with HGD, IMC, or mixed tumor and exhibited nuclear expression of b-catenin. Tumors in subgroup 4, which were generally low-grade dysplasias, exhibited a low frequency of AIs and no MSI. Although the mucin phenotype was not correlated with any subgroup, expression of mucin was associated with some subgroups. Overexpression of p53 was common in all subgroups. Conclusion The approach described herein was useful for studying genetic differences in IMNs. In addition, we suggest that stratification of genetic differences may help to identify genetic molecular profiles in IMNs.

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

Cited by 62 publications

References 23 publications

Clinicopathologic Characteristics of Microsatellite Instable Gastric Carcinomas Revisited: Urgent Need for Standardization

Clinicopathologic Characteristics of Microsatellite Instable Gastric Carcinomas Revisited: Urgent Need for Standardization

A protein and mRNA expression-based classification of gastric cancer

Genetic differences stratified by PCR-based microsatellite analysis in gastric intramucosal neoplasia

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