Microsatellite instability in mismatch repair and tumor suppressor genes and their expression profiling provide important targets for the development of biomarkers in gastric cancer

Verma, Renu; Agarwal, Anil; Sakhuja, Puja; Sharma, Prakash C.

doi:10.1016/j.gene.2019.05.051

Cited by 18 publications

(9 citation statements)

References 38 publications

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“…One of our earlier reports on gastric cancer also suggested MSH6 gene as an important target for microsatellite instability. This study reinforces the role of MSH6 in the occurrence of gastric cancer [26]. Correlation between different clinical features and loss of MMR protein expression in GC has been analyzed.…”

Section: Discussionsupporting

confidence: 79%

Implication of expression of MMR proteins and clinicopathological characteristics in gastric cancer

et al. 2020

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Introduction Microsatellite instability (MSI), referred to as variations at microsatellite loci, at mismatch repair (MMR) genes leads to the formation of an aberrant MMR system that fails to rectify errors occurring during DNA replication. MMR deficiency can be assessed by immunohistochemical analysis of the expression of mismatch repair proteins in the target tissues. Methods We investigated the expression of four key MMR proteins (MLH1, MSH2, MSH6, and PMS2) in formalin-fixed paraffin-embedded (FFPE) tumor and normal tissues obtained from thirty gastric cancer (GC) patients. The association of clinicopathological features with MMR status was also analyzed. Results A total of 12 (40%) GC patients exhibited loss of expression of MMR proteins, including loss of MLH1 and PMS2 in 3 cases and loss of MSH2 and MSH6 in 4 cases. Univariate analysis showed an association of loss of MMR protein expression with moderately differentiated GC. However, there was no statistically significant association between loss of MMR protein expression with gender, tumor location, depth of invasion, lymph node metastasis, WHO classification, lympho-vascular invasion, and infection with H. pylori. Conclusion Our results implicate the role of mismatch repair proteins in gastric tumorigenesis. The MMR protein status is an important aspect of tumorigenesis and can be prescribed for the screening of GC.

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Section: Discussionsupporting

confidence: 79%

Implication of expression of MMR proteins and clinicopathological characteristics in gastric cancer

et al. 2020

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“…25 Reduced expression of TGFBR2 is associated with a high frequency of MSI at this gene (approximately 52%) in GC. 26 Like the other subtypes of GC, genes associated with increased susceptibility to altered TGF-β signaling were common in the genomically stable and the chromosomal instability types. In the genomically stable tumors, 37% had mutations in CDH1 ; in the chromosomal instability tumors, 71% had mutations in TP53 .…”

Section: Transforming Growth Factor–β/smad Signaling In Diseases Of T...mentioning

confidence: 99%

TGF-β Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer

2021

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Genetic alterations affecting transforming growth factor-b (TGF-b) signaling are exceptionally common in diseases and cancers of the gastrointestinal system. As a regulator of tissue renewal, TGF-b signaling and the downstream SMAD-dependent transcriptional events play complex roles in the transition from a noncancerous disease state to cancer in the gastrointestinal tract, liver, and pancreas. Furthermore, this pathway also regulates the stromal cells and the immune system, which may contribute to evasion of the tumors from immune-mediated elimination. Here, we review the involvement of the TGF-b pathway mediated by the transcriptional regulators SMADs in disease progression to cancer in the digestive system. The review integrates human genomic studies with animal models that provide clues toward understanding and managing the complexity of the pathway in disease and cancer.

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“…These different subtypes exhibit unique molecular features that could potentially be used to guide therapeutic decisions, and have been shown to have prognostic signi cance; for example, Epstein-Barr virus (EBV) infection has been associated with improved prognosis. Since the molecular classi cation of GC has potential prognostic and therapeutic implications, it may be used identify biomarkers and therapeutic targets for each subtype, particularly through strati cation according to EBV infection and microsatellite instability (MSI) [4][5][6][7][8]. Currently, the expression of programmed death-ligand 1 (PD-L1) in tumor cells is a validated predictive marker for the tumor response to anti programmed cell death-1 protein (anti-PD-1) or PD-L1 immunotherapy in different malignancies, including GC [9].…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological features of Epstein-Barr virus infection, microsatellite instability, tumor mutation burden and PD-L1 status in Chinese patients with gastric cancer

Zhang

Li³

2020

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Objectives: Gastric cancer (GC) is the 4th most common type of cancer worldwide. Different GC subtypes exhibit unique molecular features that may potentially guide therapeutic decisions. The aim of the present study was to investigate Epstein-Barr virus (EBV) infection, microsatellite instability (MSI) status, the expression of programmed death-ligand 1 (PD-L1) and gene mutations in patients with surgically-treated GC. Methods: The data of 2,504 GC patients, who underwent potentially curative gastrectomy with lymphadenectomy at Peking University Cancer Hospital between 2013 and 2018, were reviewed from a prospectively collected medical database. We also analyzed the clinicopathological factors associated with the immunohistochemistry (IHC) profiles of these patients, and genetic alterations were analyzed using next generation sequencing (NGS). Results: Mismatch repair-deficient (d-MMR) GC patients were found to have a higher probability of expressing PD-L1 (p<0.001, PD-L1 cutoff value = 1%). In addition, 4 and 6.9% of the 2,504 gastric cancer patients were EBV-positive and d-MMR, respectively. The number of MLH1/PMS2-negative cases was 126 (6%), and the number of MSH2/MSH6-negative cases was 14 (0.9%). d-MMR status was associated with a diffuse/mixed group (p<0.05), but not with tumor differentiation. Furthermore, MSI and d-MMR GC status (detected by NGS and IHC, respectively) were consistently high, and the rate of MSI was higher in patients with d-MMR GC. A number of genes associated with DNA damage repair were detected in GC patients with MSI, including POLE, ETV6, BRCA and RNF43. In patients with a high tumor mutation burden, the most significantly mutated genes were LRP1B (79.07%), ARID1A (74.42%), RNF43 (69.77%), ZFHX3 (65.12%), TP53 (58.14%), GANS (51.16%), BRCA2 (51.16%), PIK3CA (51.16%), NOTCH1 (51.16%), SMARCA4 (48.84%), ATR (46.51%), POLE (41.86%) and ATM (39.53%). Conclusions: Using IHC and NGS, MSI status, protein expression, TMB and genetic alterations were identified in patients with GC, which provides a theoretical basis for the future clinical treatment of GC.

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Microsatellite instability in mismatch repair and tumor suppressor genes and their expression profiling provide important targets for the development of biomarkers in gastric cancer

Cited by 18 publications

References 38 publications

Implication of expression of MMR proteins and clinicopathological characteristics in gastric cancer

Implication of expression of MMR proteins and clinicopathological characteristics in gastric cancer

TGF-β Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer

Clinicopathological features of Epstein-Barr virus infection, microsatellite instability, tumor mutation burden and PD-L1 status in Chinese patients with gastric cancer

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