Low Microsatellite Instability Is Associated With Poor Prognosis in Stage C Colon Cancer

2005 ◽  
Vol 23 (10) ◽  
pp. 2318-2324 ◽  
Author(s):  
Maija R.J. Kohonen-Corish ◽  
Joseph J. Daniel ◽  
Charles Chan ◽  
Betty P.C. Lin ◽  
Sun Young Kwun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Protein Expression ◽  
Microsatellite Instability ◽  
Dna Methyltransferase ◽  
Prognostic Significance ◽  
Promoter Hypermethylation ◽  
Prognostic Indicator ◽  
Study Cohort ◽  
Distinct Subgroup

Purpose The significance of low microsatellite instability (MSI-L) in colorectal cancer is poorly understood. No clear biologic distinction has been found between MSI-L and microsatellite stable (MSS) colorectal cancer, and these two phenotypes are usually combined when analyzed against the well-defined high MSI (MSI-H) phenotype. Evidence is emerging that an O6-methylguanine DNA methyltransferase (MGMT) gene defect is associated with MSI-L. Therefore, to further define this phenotype, we undertook a detailed analysis of the prognostic significance of MSI-L and loss of MGMT expression in colon cancer. Patients and Methods The study cohort was 183 patients with clinicopathologic stage C colon cancer who had not received adjuvant therapy. We analyzed MSI status, MGMT, and mismatch repair protein expression, as well as MGMT and p16 promoter hypermethylation. Results We showed that MSI-L defines a group of patients with poorer survival (P = .026) than MSS patients, and that MSI-L was an independent prognostic indicator (P = .005) in stage C colon cancer. Loss of MGMT protein expression was associated with the MSI-L phenotype but was not a prognostic factor for overall survival in colon cancer. p16 methylation was significantly less frequent in MSI-L than in MSI-H and MSS tumors and was not associated with survival. Conclusion MSI-L characterizes a distinct subgroup of stage C colon cancer patients, including the MSI-L subset of proximal colon cancer, who have a poorer outcome. Neither the MGMT defect nor p16 methylation are likely to contribute to the worse prognosis of the MSI-L phenotype.

Role of MSI and DCC status to predict response to FOLFOX in metastatic colorectal cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21056-21056
Author(s):  
M. Bennamoun ◽  
O. Schischmanoff ◽  
A. Martin ◽  
P. Mariani ◽  
L. Ah Koon ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Protein Expression ◽  
Microsatellite Instability ◽  
Disease Free Survival ◽  
Current Treatment ◽  
Metastatic Colon Cancer ◽  
Significant Difference ◽  
Microsatellite Stability

21056 Background: Microsatellite instability (MSI) and lack of Deleted Colon Cancer (DCC) protein expression have been observed respectively in ∼15% and 70% of colon cancer cases and are considered as prognostic factors in colorectal cancer (CRC). In adjuvant setting these markers could be considered to decide treatment. We know that MSI colon cancer do not benefit from 5Fluorouracyl (5FU)-based chemotherapy. A current treatment of reference for colon cancer is a combination of 5FU and Oxaliplatin (FOLFOX). Our aim was to determine whether MSI status or DCC expression are predictive markers of FOLFOX efficiency in patients with metastatic CRC. Methods: Tumour specimens were collected from patients with metastatic colon cancer treated with FOLFOX. The FOLFOX regimen was evaluated in first line treatment according to the WHO criteria. The microsatellite instability status was assessed by measurement of the length of five monomorphic mononucleotide markers. DCC protein expression were evaluated by immunohistochemistry. Results: Forty patients (22 men, 18 women), median age 63.5 years (27–83) were treated with FOLFOX. Nine patients had tumours exhibiting high microsatellite instability (microsatellite instability group, MSI group) and 31 patients had tumours exhibiting microsatellite stability (microsatellite stable group, MSS group). In MSS group, we observed 11 partial responses (36%) and only two in MSI group (22%) (not significant difference). Both disease free survival and overall survival were not significantly different for MSI and MSS groups. Determination of DCC status is under investigation. Conclusions: There was no significant difference in chemosensitivity to FOLFOX for MSI and MSS metastatic patients. Therefore FOLFOX regimen could be proposed to metastatic patients irrespective of MSI status. The study of the relationship between DCC expression and response to FOLFOX is ongoing. No significant financial relationships to disclose.

scholarly journals Low Level of Microsatellite Instability Correlates with Poor Clinical Prognosis in Stage II Colorectal Cancer Patients

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Ehsan Nazemalhosseini Mojarad ◽  
Seyed Mohammad Hossein Kashfi ◽  
Hanieh Mirtalebi ◽  
Mohammad Yaghoob Taleghani ◽  
Pedram Azimzadeh ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Prognostic Significance ◽  
Tumor Stage ◽  
Cross Sectional Study ◽  
Stage Ii ◽  
Curative Surgery ◽  
Cross Sectional ◽  
Clinical Prognosis ◽  
Distinct Subgroup

The influence of microsatellite instability (MSI) on the prognosis of colorectal cancer (CRC) requires more investigation. We assessed the role of MSI status in survival of individuals diagnosed with primary colorectal cancer. In this retrospective cross-sectional study the MSI status was determined in 158 formalin-fixed paraffin-embedded tumors and their matched normal tissues from patients who underwent curative surgery. Cox proportional hazard modeling was performed to assess the clinical prognostic significance. In this study we found that MSI-H tumors were predominantly located in the colon versus rectum (p=0.03), associated with poorer differentiation (p=0.003) and TNM stage II/III of tumors (p=0.02). In CRC patients with stage II, MSI-L cases showed significantly poorer survival compared with patients who had MSI-H or MSS tumors (p=0.04). This study indicates that MSI-L tumors correlate with poorer clinical outcome in patients with stage II tumors (p=0.04) or in tumors located in the colon (p=0.02). MSI-L characterizes a distinct subgroup of CRC patients who have a poorer outcome. This study suggests that MSI status in CRC, as a clinical prognostic marker, is dependent on other factors, such as tumor stage and location.

Schisandrin B Attenuates Colitis-Associated Colorectal Cancer through SIRT1 Linked SMURF2 Signaling

2021 ◽  
pp. 1-17
Author(s):  
Zhichen Pu ◽  
Weiwei Zhang ◽  
Minhui Wang ◽  
Maodi Xu ◽  
Haitang Xie ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cell Growth ◽  
Protein Expression ◽  
Hct116 Cell ◽  
Enzyme Linked Immunosorbent Assay ◽  
Schisandrin B ◽  
In Vivo Models

Colon cancer, a common type of malignant tumor, seriously endangers human health. However, due to the relatively slow progress in diagnosis and treatment, the clinical therapeutic technology of colon cancer has not been substantially improved in the past three decades. The present study was designed to investigate the effects and involved mechanisms of schisandrin B in cell growth and metastasis of colon cancer. C57BL/6 mice received AOM and dextran sulfate sodium. Mice in treatment groups were gavaged with 3.75–30 mg/kg/day of schisandrin B. Transwell chamber migration, enzyme-linked immunosorbent assay (ELISA), Western blot analysis, immunoprecipitation (IP) and immunofluorescence were conducted, and HCT116 cell line was employed in this study. Data showed that schisandrin B inhibited tumor number and tumor size in the AOD+DSS-induced colon cancer mouse model. Schisandrin B also inhibited cell proliferation and metastasis of colon cancer cells. We observed that schisandrin B induced SMURF2 protein expression and affected SIRT1 in vitro and in vivo. SMURF2 interacted with SIRT1 protein, and there was a negative correlation between SIRT1 and SMURF2 expressions in human colorectal cancer. The regulation of SMURF2 was involved in the anticancer effects of schisandrin B in both in vitro and in vivo models. In conclusion, the present study revealed that schisandrin B suppressed SIRT1 protein expression, and SIRT1 is negatively correlated with the induction of SMURF2, which inhibited cell growth and metastasis of colon cancer. Schisandrin B could be a leading compound, which will contribute to finding novel potential agents and therapeutic targets for colon cancer.

GCM2 Silencing in Parathyroid Adenoma is associated with Promoter Hypermethylation and Gain of Methylation on Histone 3

2021 ◽  
Author(s):  
Priyanka Singh ◽  
Sanjay Kumar Bhadada ◽  
Divya Dahiya ◽  
Uma Nahar Saikia ◽  
Ashutosh Kumar Arya ◽  
...  
Keyword(s):  
Protein Expression ◽  
Parathyroid Adenoma ◽  
Dna Methyltransferase ◽  
Promoter Hypermethylation ◽  
Epigenetic Alterations ◽  
Protein Levels ◽  
Histone 3 ◽  
Parathyroid Adenomas ◽  
Mrna And Protein Expression

Abstract Purpose Glial cells missing 2 (GCM2), a zinc finger-transcription factor, is essentially required for the development of parathyroid glands. We sought to identify if the epigenetic alterations in the GCM2 transcription are involved in the pathogenesis of sporadic parathyroid adenoma. In addition, we examined the association between promoter methylation and histone modifications with disease indices. Experimental design mRNA and protein expression of GCM2 were analyzed by RT-qPCR and immunohistochemistry in 33 adenomatous and 10 control parathyroid tissues. DNA methylation and histone methylation/acetylation of GCM2 promoter were measured by bisulfite sequencing and ChIP-qPCR. Additionally, we investigated the role of epigenetic modifications on GCM2 and DNA methyltransferase 1 (DNMT1) expression in PTH-C1 cells by treating with 5-aza 2’deoxycytidine (DAC) and BRD4770 and assessed for GCM2 mRNA and DNMT1 protein levels. Results mRNA and protein expression of GCM2 were lower in sporadic adenomatous than in control parathyroid tissues. This reduction correlated with hypermethylation (P<0.001) and higher H3K9me3 levels in GCM2 promoter (P<0.04) in adenomas. In PTH-C1 cells, DAC treatment resulted in increased GCM2 transcription and decreased DNMT1 protein expression, while cells treated with the BRD4770 showed reduced H3K9me3 levels but a non-significant change in GCM2 transcription. Conclusion These findings suggest the concurrent association of promoter hypermethylation and higher H3K9me3 with the repression of GCM2 expression in parathyroid adenomas. Treatment with DAC restored GCM2 expression in PTH-C1 cells. Our results showed a possible epigenetic landscape in the tumorigenesis of parathyroid adenoma and also that DAC may be promising avenues of research for parathyroid adenoma therapeutics.

PD-L1 expression is an unfavourable prognostic indicator in Asian renal cell carcinomas

2020 ◽  
Vol 73 (8) ◽  
pp. 463-469 ◽  
Author(s):  
Joe Yeong ◽  
Zitong Zhao ◽  
Jeffrey Chun Tatt Lim ◽  
Huihua Li ◽  
Aye Aye Thike ◽  
...  
Keyword(s):  
Protein Expression ◽  
Renal Cell ◽  
Death Receptor ◽  
Disease Free Survival ◽  
Prognostic Indicator ◽  
Clinicopathological Features ◽  
Study Cohort ◽  
Entire Cohort ◽  
Asian Patients ◽  
L1 Protein

Background/aimsThe programmed cell death receptor 1 (PD-1) checkpoint inhibitor, nivolumab, has been approved for the treatment of metastatic renal cell carcinoma (RCC). However, the understanding of the expression and distribution of PD ligand 1 (PD-L1) in the tumour immune microenvironment and its prognostic role in an Asian cohort is limited. Our group investigated PD-L1 protein expression in a cohort of Asian patients with RCC of mixed ethnicity, using two commercially available antibody clones.MethodsE1L3N and SP263 anti-PD-L1 clones were used to categorise RCCs of various histological subtypes, diagnosed at our institution between 1995 and 2008, into PD-L1-positive or PD-L1-negative groups, based on a 1% Tumour Proportion Score (TPS) cut-off.ResultsIn total, 267 (83%) clear cell (cc)RCC and 55 (17%) non-ccRCC cases were studied. Overall PD-L1 protein expression rates for the entire cohort were 13% and 8% for the E1L3N and SP263 clones, respectively. Patients bearing PD-L1-positive tumours experienced significantly decreased disease-free survival (DFS; E1L3N: p=0.01; SP263: p=0.03) but not overall survival, compared with those with PD-L1-negative tumours. Multivariate survival analysis further confirmed the results of the E1L3N clone (HR 1.85, 95% CI 1.10 to 3.13, p=0.02), but not SP263, after adjusting for pathological stage, histological subtype and grade. The addition of PD-L1 (E1L3N) TPS to clinicopathological features significantly increased the prognostic value for DFS (∆LRχ2=5.25; p=0.022), compared with clinicopathological features alone.ConclusionsPD-L1 protein expression was associated with an unfavourable prognosis in our study cohort. PD-L1 (E1L3N) expression was an independent prognostic indicator of clinical outcome in all RCCs when using a 1% cut-off.

scholarly journals Cross-platform Data Analysis Reveals a Generic Gene Expression Signature for Microsatellite Instability in Colorectal Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Anna Pačínková ◽  
Vlad Popovici
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Colon Cancer ◽  
Microsatellite Instability ◽  
Gene Expression Signature ◽  
Data Sets ◽  
Rna Seq ◽  
Cancer Data ◽  
Expression Signature ◽  
Endometrial Cancers

The dysfunction of the DNA mismatch repair system results in microsatellite instability (MSI). MSI plays a central role in the development of multiple human cancers. In colon cancer, despite being associated with resistance to 5-fluorouracil treatment, MSI is a favourable prognostic marker. In gastric and endometrial cancers, its prognostic value is not so well established. Nevertheless, recognising the MSI tumours may be important for predicting the therapeutic effect of immune checkpoint inhibitors. Several gene expression signatures were trained on microarray data sets to understand the regulatory mechanisms underlying microsatellite instability in colorectal cancer. A wealth of expression data already exists in the form of microarray data sets. However, the RNA-seq has become a routine for transcriptome analysis. A new MSI gene expression signature presented here is the first to be valid across two different platforms, microarrays and RNA-seq. In the case of colon cancer, its estimated performance was (i) AUC = 0.94, 95% CI = (0.90 – 0.97) on RNA-seq and (ii) AUC = 0.95, 95% CI = (0.92 – 0.97) on microarray. The 25-gene expression signature was also validated in two independent microarray colon cancer data sets. Despite being derived from colorectal cancer, the signature maintained good performance on RNA-seq and microarray gastric cancer data sets (AUC = 0.90, 95% CI = (0.85 – 0.94) and AUC = 0.83, 95% CI = (0.69 – 0.97), respectively). Furthermore, this classifier retained high concordance even when classifying RNA-seq endometrial cancers (AUC = 0.71, 95% CI = (0.62 – 0.81). These results indicate that the new signature was able to remove the platform-specific differences while preserving the underlying biological differences between MSI/MSS phenotypes in colon cancer samples.

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