Gastric cancer with high-level microsatellite instability: target gene mutations, clinicopathologic features, and long-term survival

Falchetti, Mario; Saieva, Calogero; Lupi, Ramona; Masala, Giovanna; Rizzolo, Piera; Zanna, Ines; Ceccarelli, Ketty; Sera, Francesco; Mariani-Costantini, Renato; Nesi, Gabriella; Palli, Domenico; Ottini, Laura

doi:10.1016/j.humpath.2007.10.024

Cited by 114 publications

(109 citation statements)

References 28 publications

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“…In gastric cancers, the incidence of MSI-H varies from 8.2-37%, which was decided by the number of cases investigated. Patients with gastric cancer and MSI-H tend to be older, female, distal located, with a well-differentiated adenocarcinoma type and in lower tumor stages (6,(16)(17)(18)(19)(20)(21)(22). The association between MSI-H and gastric cancer prognosis remains ambiguous.…”

Section: Introductionmentioning

confidence: 99%

Microsatellite instability and survival in gastric cancer: A systematic review and meta-analysis

Zhu

Wang

et al. 2015

Molecular and Clinical Oncology

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Abstract. Microsatellite instability (MSI) is associated with the prognosis in several cancers and is used for determination of the chemotherapy regimen in stage II colon cancer in the National Comprehensive Cancer Network guideline. However, the association between MSI and the prognosis of gastric cancer remains unclear. PubMed database was searched until January 2014 using MeSH terms and key words to identify the studies evaluating MSI and prognosis of gastric cancer and the references were manually searched. The main outcome was the overall survival rate and the subordinate outcome was the association between high-frequency MSI (MSI-H) and clinicopathological characteristics. Eight studies met the inclusion criteria and the majority of data were collected retrospectively. There were 1,976 patients, 431 of which were MSI-H patients, with a range of 11.68-33.82%. Four studies used the National Cancer Institute panel to define MSI-H, the other four had microsatellite markers ranging 2-11. Significant associations were found in three studies and the overall summary estimate was hazard ratio, 0.63 (95% confidence interval, 0.52-0.77), with no evidence of inter-study heterogeneity (I 2 =0.0%). MSI-H patients were identified to have a tendency to have less lymph node (LN) metastasis, superficial tumor invasion and to be intestinal type. In conclusion, MSI-H gastric cancers have an improved prognosis, accompanied with reduced risk of LN metastasis, tumor invasion and mortality.

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Section: Introductionmentioning

confidence: 99%

Microsatellite instability and survival in gastric cancer: A systematic review and meta-analysis

Zhu

Wang

et al. 2015

Molecular and Clinical Oncology

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“…Between 2005 and2008, an MSI status examination was performed in 1,990 gastric cancer patients who had undergone curative gastrectomy for gastric adenocarcinoma. MSI was analyzed by PCR amplification with fluorescent dye-labeled primers of mononucleotide markers (BAT25 and BAT26) and dinucleotide markers (D5S346, D2S123 and D17S250) specific to the microsatellite loci.…”

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confidence: 99%

Microsatellite instability in sporadic gastric cancer: its prognostic role and guidance for 5‐FU based chemotherapy after R0 resection

Kim

Cheong

et al. 2011

Intl Journal of Cancer

133

135

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This study investigated whether MSI status can be used as a prognostic biomarker and whether it is helpful for predicting which patients will benefit from 5-FU based adjuvant chemotherapy. Between 2005 and2008, an MSI status examination was performed in 1,990 gastric cancer patients who had undergone curative gastrectomy for gastric adenocarcinoma. MSI was analyzed by PCR amplification with fluorescent dye-labeled primers of mononucleotide markers (BAT25 and BAT26) and dinucleotide markers (D5S346, D2S123 and D17S250) specific to the microsatellite loci. Patients with MSI-H tumors accounted for 8.5% (n 5 170) of the total study population. They tended to be older and female and to have distal tumor location, lower tumor stage, intestinal type of Lauren classification and differentiated histological type. The disease-free survival curves showed no significant differences between MSS/MSI-L and MSI-H patients at each stage of I, II, III and IV. In gastric cancer patients with stage II and III, 5-FU-based adjuvant chemotherapy showed better disease-free survival in the MSS/MSI-L group, but showed no benefits in the MSI-H group. By multivariate analysis, patients with MSS/MSI-L tumors benefited from 5-FU-based adjuvant chemotherapy in terms of tumor disease-free survival. MSI status in gastric cancer is not itself a prognostic indicator. However, it appears to be a possible guidance for the use of 5-FU-based chemotherapy in stage II and III gastric cancers after R0 resection.Microsatellite instability (MSI) is characterized by novel sized alleles detected in microsatellite sequences found in the DNA of carcinoma tissue that is not present in normal constitutional DNA. Although MSI has been reported along with several types of cancers, it is thought to be an important mechanism of hereditary nonpolyposis colorectal cancer (HNPCC), which occurs by germline mutations in one of the DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6 and PMS2. The clinicopathological characteristics of MSIþ colorectal cancers have been widely studied: proximal location, reduced lymph node metastasis and better overall survival rate.1 Recently, several studies analyzed the relationship between MSI and benefits from adjuvant 5-Fluorouracil (5-FU)-based chemotherapy in colon cancer.2,3 These studies reflect that MSI status has an important role in clinical practices for deciding tumor characteristics, predicting prognosis and planning adjuvant treatment.In gastric cancer, the role of MSI remains to be proven, and it is difficult to judge its value in clinical application. Many studies have also attempted to elucidate the clinical significances of MSI in gastric cancer, suggesting that gastric cancers with a high frequency of MSI are associated with specific clinicopathological characteristics: intestinal type differentiation, reduced lymph node metastasis and better survival rates. However, these findings are not consistent and each study yields controversial results. Some studies reported that the MSI-H phenotype was associated with be...

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“…Even though the data consistently support the possible correlation between the degree of the MSI and clinical outcome (2,23,24), there is no consistent consensus regarding the MSI genotypes. Thus, widely variable results on the frequency and definition of MSI in GC have been reported depending on the type and number of MS markers used (2).…”

Section: Discussionmentioning

confidence: 83%

“…The highest frequency of MSI was simultaneously noted at the D17S261 and D18S34 (44.1%, 15/34) loci; this is superior to the NCI panels of MS markers. The DCC gene at the D18S34 locus is thought to be one of the prime target genes on 18q, and its hyper-methylation or reduced expression in GC has been described in previous studies (23)(24)(25), indicating that the D18S34 locus is critically involved in initiating gastric carcinogenesis and may be a valuable MS marker for GC screening.…”

Section: Discussionmentioning

confidence: 84%

Assessment of the beneficial loci and prognostic implications of microsatellite instability in gastric carcinoma

Kang

Koo

2011

Mol Med Report

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Abstract. Microsatellite instability (MSI) is a hyper-mutable phenotype caused by the loss of DNA mismatch repair activity, and plays a crucial role in gastric carcinogenesis. To clarify the role of genetic instability in relation to clinicopathological variables, and to identify predictive MSI markers that facilitate the early detection and improve the classification of gastric carcinomas (GCs), 13 microsatellite (MS) loci, including the National Cancer Institute (NCI) panel of MS markers (D2S123, D5S346, D17S250, BAT25 and BAT26) and 8 dinucleotide repeats (D3S1260, D5S107, D5S409, D17S261, D17S520, D17S855, D18S34 and D18S61) were studied in GC patients. MSI was found in 88.2% (30/34) of GC cases and the number of high-frequency MSI (MSI-H, 23.5%, 8/34), low-frequency MSI (64.7%, 22/34), and stable MSI (11.8%, 4/34), was calculated. Among the MS loci analyzed, D18S34 and D17S261 (15/34, 44.1%) exhibited the highest frequency of MSI, followed by D2S123 (14/34, 41.2%), D5S107, D5S346, D5S409 and D18S61 (12/34, 35.3%) (MSI>35%). MSI-H was particularly prevalent in older patients and was mainly found in the antrum and poorly differentiated tumors. Furthermore, MSI-H was significantly associated with lymph node involvement cases in females. One notable finding in this analysis was that the markers, D17S250 and D17S520, exhibited a significantly higher percentage of MSI in advanced gastric carcinomas than in early gastric carcinomas (P=0.046 and 0.046, respectively), and the D17S520 and BAT26 loci represented significant different correlations between the tumor stages (P=0.038 and 0.042, respectively). This study indicates that the novel markers, D18S34 and D17S261, perform more favorably than the NCI panel for the detection of MSI, and the D17S520 locus presents a potential target for predicting the clinical impact of GC. These novel MS loci may prove to be beneficial and independent tools for the construction of a comprehensive genetic classification for GC cases.

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Gastric cancer with high-level microsatellite instability: target gene mutations, clinicopathologic features, and long-term survival

Cited by 114 publications

References 28 publications

Microsatellite instability and survival in gastric cancer: A systematic review and meta-analysis

Microsatellite instability and survival in gastric cancer: A systematic review and meta-analysis

Microsatellite instability in sporadic gastric cancer: its prognostic role and guidance for 5‐FU based chemotherapy after R0 resection

Assessment of the beneficial loci and prognostic implications of microsatellite instability in gastric carcinoma

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