scholarly journals Ribonucleotide reductase small subunit M2 serves as a prognostic biomarker and predicts poor survival of colorectal cancers

2013 ◽  
Vol 124 (9) ◽  
pp. 567-579 ◽  
Author(s):  
Xiyong Liu ◽  
Hang Zhang ◽  
Lily Lai ◽  
Xiaochen Wang ◽  
Sofia Loera ◽  
...  
Keyword(s):  
Real Time ◽  
Ribonucleotide Reductase ◽  
Negative Impact ◽  
Medical Center ◽  
Distant Metastases ◽  
Small Subunit ◽  
Colorectal Cancers ◽  
Mismatch Repair Gene ◽  
Poor Survival ◽  
Repair Gene

The overexpression of RRM2 [RR (ribonucleotide reductase) small subunit M2] dramatically enhances the ability of the cancer cell to proliferate and to invade. To investigate further the relevance of RRM2 and CRCs (colorectal cancers), we correlated the expression of RRM2 with the clinical outcome of CRCs. A retrospective outcome study was conducted on CRCs collected from the COH [(City of Hope) National Medical Center, 217 cases] and ZJU (Zhejiang University, 220 cases). IHC (immunohistochemistry) was employed to determine the protein expression level of RRM2, and quantitative real-time PCR was employed to validate. Multivariate logistic analysis indicated that the adjusted ORs (odds ratios) of RRM2-high for distant metastases were 2.06 [95% CI (confidence interval), 1.01–4.30] and 5.89 (95% CI, 1.51–39.13) in the COH and ZJU sets respectively. The Kaplan–Meier analysis displayed that high expression of RRM2 had a negative impact on the OS (overall survival) and PFS (progress-free survival) of CRC in both sets significantly. The multivariate Cox analysis further demonstrated that HRs (hazard ratios) of RRM2-high for OS were 1.88 (95% CI, 1.03–3.36) and 2.06 (95% CI, 1.10–4.00) in the COH and ZJU sets respectively. Stratification analysis demonstrated that the HR of RRM2 dramatically increased to 12.22 (95% CI, 1.62–258.31) in the MMR (mismatch repair) gene-deficient subgroup in the COH set. Meanwhile, a real-time study demonstrated that down-regulation of RRM2 by siRNA (small interfering RNA) could significantly and specifically reduce the cell growth and adhesion ability in HT-29 and HCT-8 cells. Therefore RRM2 is an independent prognostic factor and predicts poor survival of CRCs. It is also a potential predictor for identifying good responders to chemotherapy for CRCs.

scholarly journals Colorectal Carcinogenesis: MSI-H Versus MSI-L

2004 ◽  
Vol 20 (4-5) ◽  
pp. 199-206 ◽  
Author(s):  
Timothy M. Pawlik ◽  
Chandrajit P. Raut ◽  
Miguel A. Rodriguez-Bigas
Keyword(s):  
Colorectal Carcinogenesis ◽  
Colorectal Cancers ◽  
Mismatch Repair Gene ◽  
Clinicopathologic Features ◽  
Colorectal Tumors ◽  
Repair Gene ◽  
Molecular Features ◽  
Need To Evaluate ◽  
Frequent Mutations ◽  
High Level

Microsatellite instability (MSI) is a well-recognized phenomenon that is classically a feature of tumors in the hereditary non-polyposis colorectal syndrome. Ten to 15% of sporadic colorectal cancers, however, will have MSI. Microsatellite unstable tumors can be divided into two distinct MSI phenotypes: MSI-high (MSI-H) and MSI-low (MSI-L). MSI sporadic colorectal cancers with a high level of MSI (MSI-H) form a well defined group with distinct clinicopathologic features characterized by an overall better long-term prognosis. These sporadic MSI-H colorectal tumors most often arise from the epigenetic silencing of the mismatch repair gene MLH1. In contrast, MSI-L colorectal tumors have not been shown to differ in their clinicopathologic features or in most molecular features from microsatellite stable (MSS) tumors. Unlike MSI-H tumors, MSI-L tumors appear to arise through the chromosomal instability carcinogenesis pathway, similar to MSS tumors. Some groups have reported more frequent mutations in K-ras and in the methylation of methylguanine transferase in MSI-L tumors, but others have questioned these findings. Therefore, although the use of the MSI-L category is widespread, there continues to be some debate as to whether a discrete MSI-L group truly exists. Rather, it has been suggested that MSI-L tumors differ quantitatively from MSS tumors but do not differ qualitatively. Future studies will need to evaluate the specific mutations in non-MSI-H tumors in an attempt to sub-classify MSI-L tumors with regard to MSS tumors so that subtle differences between these two sub-groups can be identified.

scholarly journals Genomic and phenotypic diversity of Enterococcus faecalis isolated from endophthalmitis

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0250084
Author(s):  
Gayatri Shankar Chilambi ◽  
Hayley R. Nordstrom ◽  
Daniel R. Evans ◽  
Regis P. Kowalski ◽  
Deepinder K. Dhaliwal ◽  
...  
Keyword(s):  
Enterococcus Faecalis ◽  
Biofilm Formation ◽  
Phenotypic Diversity ◽  
Medical Center ◽  
Phenotypic Variability ◽  
Spontaneous Mutation ◽  
Comparative Genomic ◽  
Mismatch Repair Gene ◽  
Ocular Infection ◽  
Repair Gene

Enterococcus faecalis are hospital-associated opportunistic pathogens and also causative agents of post-operative endophthalmitis. Patients with enterococcal endophthalmitis often have poor visual outcomes, despite appropriate antibiotic therapy. Here we investigated the genomic and phenotypic characteristics of E. faecalis isolates collected from 13 patients treated at the University of Pittsburgh Medical Center Eye Center over 19 years. Comparative genomic analysis indicated that patients were infected with E. faecalis belonging to diverse multi-locus sequence types (STs) and resembled E. faecalis sampled from clinical, commensal, and environmental sources. We identified known E. faecalis virulence factors and antibiotic resistance genes in each genome, including genes conferring resistance to aminoglycosides, erythromycin, and tetracyclines. We assessed all isolates for their cytolysin production, biofilm formation, and antibiotic susceptibility, and observed phenotypic differences between isolates. Fluoroquinolone and cephalosporin susceptibilities were particularly variable between isolates, as were biofilm formation and cytolysin production. In addition, we found evidence of E. faecalis adaptation during recurrent endophthalmitis by identifying genetic variants that arose in sequential isolates sampled over eight months from the same patient. We identified a mutation in the DNA mismatch repair gene mutS that was associated with an increased rate of spontaneous mutation in the final isolate from the patient. Overall this study documents the genomic and phenotypic variability among E. faecalis causing endophthalmitis, as well as possible adaptive mechanisms underlying bacterial persistence during recurrent ocular infection.

scholarly journals The polymorphic variant rs1800734 influences methylation acquisition and allele-specific TFAP4 binding in the MLH1 promoter leading to differential mRNA expression

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Rachael Thomas ◽  
Davide Trapani ◽  
Lily Goodyer-Sait ◽  
Marketa Tomkova ◽  
Ceres Fernandez-Rozadilla ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cancer Risk ◽  
Promoter Methylation ◽  
Detection Methods ◽  
Colorectal Cancers ◽  
Mismatch Repair Gene ◽  
Colon Tissue ◽  
Repair Gene ◽  
Mlh1 Promoter ◽  
Allele Specific

Abstract Expression of the mismatch repair gene MutL homolog 1 (MLH1) is silenced in a clinically important subgroup of sporadic colorectal cancers. These cancers exhibit hypermutability with microsatellite instability (MSI) and differ from microsatellite-stable (MSS) colorectal cancers in both prognosis and response to therapies. Loss of MLH1 is usually due to epigenetic silencing with associated promoter methylation; coding somatic mutations rarely occur. Here we use the presence of a colorectal cancer (CRC) risk variant (rs1800734) within the MLH1 promoter to investigate the poorly understood mechanisms of MLH1 promoter methylation and loss of expression. We confirm the association of rs1800734 with MSI+ but not MSS cancer risk in our own data and by meta-analysis. Using sensitive allele-specific detection methods, we demonstrate that MLH1 is the target gene for rs1800734 mediated cancer risk. In normal colon tissue, small allele-specific differences exist only in MLH1 promoter methylation, but not gene expression. In contrast, allele-specific differences in both MLH1 methylation and expression are present in MSI+ cancers. We show that MLH1 transcriptional repression is dependent on DNA methylation and can be reversed by a methylation inhibitor. The rs1800734 allele influences the rate of methylation loss and amount of re-expression. The transcription factor TFAP4 binds to the rs1800734 region but with much weaker binding to the risk than the protective allele. TFAP4 binding is absent on both alleles when promoter methylation is present. Thus we propose that TFAP4 binding shields the protective rs1800734 allele of the MLH1 promoter from BRAF induced DNA methylation more effectively than the risk allele.

scholarly journals Comprehensive characterization of HNPCC-related colorectal cancers reveals striking molecular features in families with no germline mismatch repair gene mutations

Oncogene ◽  
2005 ◽  
Vol 24 (9) ◽  
pp. 1542-1551 ◽  
Author(s):  
Wael M Abdel-Rahman ◽  
Miina Ollikainen ◽  
Reetta Kariola ◽  
Heikki J Järvinen ◽  
Jukka-Pekka Mecklin ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Gene Mutations ◽  
Colorectal Cancers ◽  
Mismatch Repair Gene ◽  
Repair Gene ◽  
Molecular Features ◽  
Comprehensive Characterization ◽  
Mismatch Repair Gene Mutations

Frequency and prognostic role of tumor infiltrating lymphocytes and MMR status in advanced non-colorectal GI malignancies.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 89-89
Author(s):  
Uqba Khan ◽  
Ameer Hamza ◽  
Renny Abraham ◽  
Muhammad S Khurram ◽  
Tarik H. Hadid ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Medical Center ◽  
Tumor Infiltrating Lymphocytes ◽  
Mismatch Repair Gene ◽  
High Power Field ◽  
Repair Gene ◽  
Number Of Patients ◽  
Significant Difference ◽  
Infiltrating Lymphocytes ◽  
The Impact

89 Background: Tumor infiltrating lymphocytes (TILs) and mismatch repair gene mutation (MMR) status are emerging biomarkers in immunotherapy. MMR status and TILs have significant clinical implications with respect to treatment with checkpoint inhibitors. We designed a study to determine the frequency and prognostic utility of TILs and MMR in advanced unresectable non-colorectal GI (NCGI) cancers. Methods: This is a retrospective cohort study of patients who were diagnosed with metastatic or unresectable NCGI cancers between 2009 and 2015 at St. John Hospital and Medical Center. Immunohistochemistry panels were performed on representative tissue sections for MMR testing. TILs were assessed on the hematoxylin and eosin stained slide of the same tissue section. MMR was interpreted as deficient (d) or proficient and TILs were categorized as ≤5 or > 5 per high power field. Descriptive statistics were generated using frequency distributions, medians and means. Kaplan-Meier analysis was performed to determine the impact of TILS and MMR on survival; differences by factor were assessed with the Log_Rank test. Results: We analyzed 132 patients; the mean age at diagnosis was 66.7 years, 62.1% were male. All samples had proficient MMR status. The percentage of patients with TILs ≤ 5 was 46.2. There was no statistically significant difference in median overall survival (OS) by TILs when stratified by stage of tumor. When stratified by type of tumor, median OS by TILs level was significantly different only for hepatocellular cancers (HCC) (≤ 5 TILs, 86 days vs. > 5 TILs 312 days, p = 0.031), table 1. Conclusions: Our study suggests that MMR-d tumors are quite rare in advanced NCGI malignancies. TILs can be present in tumor microenvironment of NCGI malignancies. Though the number of patients in our study was small, there was a statistically significant difference in median OS of patients with HCC when stratified by TILs status.[Table: see text]

scholarly journals A Novel Mechanism Driving Poor-Prognosis Prostate Cancer: Overexpression of the DNA Repair Gene, Ribonucleotide Reductase Small Subunit M2 (RRM2)

2019 ◽  
Vol 25 (14) ◽  
pp. 4480-4492 ◽  
Author(s):  
Ying Z. Mazzu ◽  
Joshua Armenia ◽  
Goutam Chakraborty ◽  
Yuki Yoshikawa ◽  
Si'Ana A. Coggins ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Ribonucleotide Reductase ◽  
Poor Prognosis ◽  
Small Subunit ◽  
Repair Gene ◽  
Dna Repair Gene

Four new mutations in the DNA mismatch repair gene MLH1 in colorectal cancers with microsatellite instability

1998 ◽  
Vol 12 (1) ◽  
pp. 73-73 ◽  
Author(s):  
Klaus K.-F. Herfarth ◽  
Olagunju A. Ogunbiyi ◽  
Jeffrey F. Moley ◽  
Ira J. Kodner ◽  
Samuel A. Wells ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Colorectal Cancers ◽  
Mismatch Repair Gene ◽  
Repair Gene ◽  
Dna Mismatch ◽  
Dna Mismatch Repair Gene ◽  
New Mutations

Frequency and prognostic utility of MSI and TILs in advanced noncolorectal GI malignancies.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 313-313
Author(s):  
Uqba Khan ◽  
Ameer Hamza ◽  
Muhammad S Khurram ◽  
Renny Abraham ◽  
Paul Mazzara ◽  
...  
Keyword(s):  
Median Survival ◽  
Checkpoint Inhibitors ◽  
Medical Center ◽  
Adoptive T Cell Therapy ◽  
Mismatch Repair Gene ◽  
Repair Gene ◽  
T Cell Therapy ◽  
Number Of Patients ◽  
Significant Difference ◽  
The Impact

313 Background: Mismatch repair gene mutation status not only has a role in pathogenesis but also has significant clinical implications with respect to treatment with checkpoint inhibitors. Additionally tumor infiltrating lymphocytes (TILs) are also emerging prognostic biomarker and are utilized in adoptive T-cell therapy as well. Methods: This is a retrospective cohort study of patients who were diagnosed with advanced unresectable non-colorectal GI (NCGI) cancers. Biopsy specimens of patients diagnosed between 2009 and 2015 at St. John Hospital and Medical Center were analyzed. Immunohistochemistry panels were performed on a representative tissue sections for microsatellite instability (MSI) testing. TILs were assessed on the hematoxylin and Eosin stained slide of the same tissue section. MSI was interpreted as stable or high and TILs were categorized as ≤5 and > 5 per high power field. Descriptive statistics were generated using frequency distributions, medians and means. Kaplan-Meier analysis was performed to determine the impact of TILs and MSI on survival; differences by factor were assessed with the Log_Rank test. Results: We analyzed 114 patients; the mean age at diagnosis was 66.8 ± 10.7 years, 61.4% were male. All samples were MSI stable. The percentage of patients with TILs ≤ 5 was 46.5. When stratified by tumor stage, overall median survival by TILs level did not differ significantly. When stratified by type of tumor, overall median survival by TILs level was significantly different only for hepatocellular cancers (HCC) (≤ 5 TILs, 86 days vs. > 5 TILs 312 days, p = 0.031) only, (see table). Conclusions: Our study shows that MSI-H tumors are very rare in advanced NCGI malignancies. TILs are definitely present in tumor microenvironment of NCGI malignancies. Though the number of patients of our study was small, there was a statistically significant difference in median overall survival of patients with HCC when stratified by TILs status.[Table: see text]

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