Identification of High-Risk Stage II Colorectal Tumors by Combined Analysis of the NDRG1 Gene Expression and the Depth of Tumor Invasion

Abstract Background: There are profound individual differences in clinical outcomes between colorectal cancers (CRCs) presenting with identical stage of disease. Molecular stratification, in conjunction with the traditional TNM staging, is a promising way to predict patient outcomes. We investigated the interconnectivity between tumor stage and tumor biology reflected by the Consensus Molecular Subtypes (CMSs) in CRC, and explored the possible value of these insights in patients with stage II colon cancer.Methods: We performed a retrospective analysis using clinical records and gene expression profiling in a meta-cohort of 1040 CRC patients. The interconnectivity of tumor biology and disease stage was assessed by investigating the association between CMSs and TNM classification. In order to validate the clinical applicability of our findings we employed a meta-cohort of 197 stage II colon cancers.Results: CMS4 was significantly more prevalent in advanced stages of disease (stage I 9.8% versus stage IV 38.5%, p<0.001). The observed differential gene expression between cancer stages is at least partly explained by the biological differences as reflected by CMS subtypes. Gene signatures for stage III-IV and CMS4 were highly correlated (r=0.77, p<0.001). CMS4 cancers showed an increased progression rate to more advanced stages (CMS4 compared to CMS2: 1.25, 95% CI: 1.08-1.46). Patients with a CMS4 cancer had worse survival in the high-risk stage II tumors compared to the total stage II cohort (5-year DFS 41.7% versus 100.0%, p=0.008).Conclusions: Considerable interconnectivity between tumor biology and tumor stage in CRC exists. This implies that the TNM stage, in addition to the stage of progression, might also reflect distinct biological disease entities. These insights can potentially be utilized to optimize identification of high-risk stage II colon cancers.

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Gene Expression Signature to Improve Prognosis Prediction of Stage II and III Colorectal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2010.30.1077 ◽

2011 ◽

Vol 29 (1) ◽

pp. 17-24 ◽

Cited By ~ 365

Author(s):

Ramon Salazar ◽

Paul Roepman ◽

Gabriel Capella ◽

Victor Moreno ◽

Iris Simon ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

High Risk ◽

Early Stage ◽

Survival Rates ◽

Gene Expression Signature ◽

Stage I ◽

Stage Ii ◽

Free Survival ◽

Risk Of Cancer

Purpose This study aims to develop a robust gene expression classifier that can predict disease relapse in patients with early-stage colorectal cancer (CRC). Patients and Methods Fresh frozen tumor tissue from 188 patients with stage I to IV CRC undergoing surgery was analyzed using Agilent 44K oligonucleotide arrays. Median follow-up time was 65.1 months, and the majority of patients (83.6%) did not receive adjuvant chemotherapy. A nearest mean classifier was developed using a cross-validation procedure to score all genes for their association with 5-year distant metastasis–free survival. Results An optimal set of 18 genes was identified and used to construct a prognostic classifier (ColoPrint). The signature was validated on an independent set of 206 samples from patients with stage I, II, and III CRC. The signature classified 60% of patients as low risk and 40% as high risk. Five-year relapse-free survival rates were 87.6% (95% CI, 81.5% to 93.7%) and 67.2% (95% CI, 55.4% to 79.0%) for low- and high-risk patients, respectively, with a hazard ratio (HR) of 2.5 (95% CI, 1.33 to 4.73; P = .005). In multivariate analysis, the signature remained one of the most significant prognostic factors, with an HR of 2.69 (95% CI, 1.41 to 5.14; P = .003). In patients with stage II CRC, the signature had an HR of 3.34 (P = .017) and was superior to American Society of Clinical Oncology criteria in assessing the risk of cancer recurrence without prescreening for microsatellite instability (MSI). Conclusion ColoPrint significantly improves the prognostic accuracy of pathologic factors and MSI in patients with stage II and III CRC and facilitates the identification of patients with stage II disease who may be safely managed without chemotherapy.

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Clinical and technical validation of a genomic classifier (ColoPrint) for predicting outcome of patients with stage II colon cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.384 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 384-384 ◽

Cited By ~ 6

Author(s):

Josep Tabernero ◽

Victor Moreno ◽

Robert Rosenberg ◽

Ulrich Nitsche ◽

Thomas Bachleitner-Hofmann ◽

...

Keyword(s):

Gene Expression ◽

Colon Cancer ◽

Multivariate Analysis ◽

High Risk ◽

Low Risk ◽

Stage Ii ◽

Clinical Parameters ◽

Risk Patients ◽

Stage Ii Colon Cancer

384 Background: Between 25 and 35% of stage II colon cancer patients will experience a relapse of their disease and may benefit from adjuvant chemotherapy. ColoPrint is a gene expression classifier that can predict disease relapse in patients with early-stage colorectal cancer (Salazar et al. JCO 2011). Methods: ColoPrint was developed using gene expression data from whole genome microarrays and was validated in in-silico datasets and independent patient cohorts from 5 European hospitals. Fresh frozen tissues, clinical parameters, MSI-status and follow-up data for patients were available. Samples were hybridized to Agilent microarrays and the ColoPrint index was determined. Uni-and multivariate analysis was performed on the pooled stage II patient set (n=320) who had a median follow-up of 70 months. Reproducibility and precision studies were performed using clinical and control samples specific for each outcome level (high risk, low risk). Experiments were performed on 20 days with 2 runs per day by multiple technicians reflecting daily diagnostic conditions. Results: Performance of the prognostic classifier was confirmed in reproducibility and stability assays and stringent quality controls were established. In the clinical validation, ColoPrint classified two-third of patients (209/320) as low risk. The 3-year relapse-free survival was 94% for low risk patients and 79% for high risk patients with a HR of 2.74 (95% CI 1.54-4.88; p=0.006). MSI-status and the number of assessed lymph nodes were the only significant clinical parameters in the univariate analysis. Using parameters from the ASCO recommendation (T4, perforation, less than 12 LN assessed and/ or high grade) for the identification of high risk patients was not significant (HR 1.43, 95% CI 0.81-2.55; p= 0.22) and no clinical parameter added power to the ColoPrint classification in multivariate analysis. Conclusions: ColoPrint is available as a routine diagnostic test with a high precision and reproducibility. ColoPrint significantly improves the prognostic accuracy of pathologic factors and MSI and facilitates the identification of low risk patients with stage II disease who may be safely managed without chemotherapy.

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Association Between Results of a Gene Expression Signature Assay and Recurrence-Free Interval in Patients With Stage II Colon Cancer in Cancer and Leukemia Group B 9581 (Alliance)

Journal of Clinical Oncology ◽

10.1200/jco.2015.65.4699 ◽

2016 ◽

Vol 34 (25) ◽

pp. 3047-3053 ◽

Cited By ~ 21

Author(s):

Donna Niedzwiecki ◽

Wendy L. Frankel ◽

Alan P. Venook ◽

Xing Ye ◽

Paula N. Friedman ◽

...

Keyword(s):

Gene Expression ◽

Colon Cancer ◽

High Risk ◽

Gene Expression Signature ◽

Stage Ii ◽

Phase Iii ◽

Prognostic Variables ◽

Free Interval ◽

Mmr Deficiency ◽

Stage Ii Colon Cancer

Purpose Conventional staging methods are inadequate to identify patients with stage II colon cancer (CC) who are at high risk of recurrence after surgery with curative intent. ColDx is a gene expression, microarray-based assay shown to be independently prognostic for recurrence-free interval (RFI) and overall survival in CC. The objective of this study was to further validate ColDx using formalin-fixed, paraffin-embedded specimens collected as part of the Alliance phase III trial, C9581. Patients and Methods C9581 evaluated edrecolomab versus observation in patients with stage II CC and reported no survival benefit. Under an initial case-cohort sampling design, a randomly selected subcohort (RS) comprised 514 patients from 901 eligible patients with available tissue. Forty-nine additional patients with recurrence events were included in the analysis. Final analysis comprised 393 patients: 360 RS (58 events) and 33 non-RS events. Risk status was determined for each patient by ColDx. The Self-Prentice method was used to test the association between the resulting ColDx risk score and RFI adjusting for standard prognostic variables. Results Fifty-five percent of patients (216 of 393) were classified as high risk. After adjustment for prognostic variables that included mismatch repair (MMR) deficiency, ColDx high-risk patients exhibited significantly worse RFI (multivariable hazard ratio, 2.13; 95% CI, 1.3 to 3.5; P < .01). Age and MMR status were marginally significant. RFI at 5 years for patients classified as high risk was 82% (95% CI, 79% to 85%), compared with 91% (95% CI, 89% to 93%) for patients classified as low risk. Conclusion ColDx is associated with RFI in the C9581 subsample in the presence of other prognostic factors, including MMR deficiency. ColDx could be incorporated with the traditional clinical markers of risk to refine patient prognosis.

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Faculty Opinions recommendation of Stage II Differentiated Thyroid Cancer Is a High-risk Disease in Patients <45/55 Years Old.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.735805679.793560741 ◽

2019 ◽

Author(s):

Iain Nixon

Keyword(s):

Thyroid Cancer ◽

High Risk ◽

Differentiated Thyroid Cancer ◽

Stage Ii ◽

High Risk Disease

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The efficacy of adjuvant chemotherapy for resected high-risk stage II and stage III colorectal cancer in frail patients

International Journal of Clinical Oncology ◽

10.1007/s10147-021-01876-1 ◽

2021 ◽

Author(s):

Kosuke Mima ◽

Nobutomo Miyanari ◽

Keisuke Kosumi ◽

Takuya Tajiri ◽

Kosuke Kanemitsu ◽

...

Keyword(s):

Colorectal Cancer ◽

High Risk ◽

Adjuvant Chemotherapy ◽

Stage Ii ◽

Stage Iii ◽

Frail Patients

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Comparison between oxaliplatin therapy and capecitabine monotherapy for high-risk stage II–III elderly colon cancer patients

Asian Journal of Surgery ◽

10.1016/j.asjsur.2021.07.067 ◽

2021 ◽

Author(s):

Jueun Park ◽

HyungJoo Baik ◽

Sang Hyun Kang ◽

Sang Hyuk Seo ◽

Kwang Hee Kim ◽

...

Keyword(s):

Colon Cancer ◽

High Risk ◽

Cancer Patients ◽

Stage Ii

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The Human Papillomavirus Type 31 Late 3′ Untranslated Region Contains a Complex Bipartite Negative Regulatory Element

Journal of Virology ◽

10.1128/jvi.76.12.5993-6003.2002 ◽

2002 ◽

Vol 76 (12) ◽

pp. 5993-6003 ◽

Cited By ~ 26

Author(s):

Sarah A. Cumming ◽

Claire E. Repellin ◽

Maria McPhillips ◽

Jonathan C. Radford ◽

J. Barklie Clements ◽

...

Keyword(s):

Gene Expression ◽

Human Papillomavirus ◽

High Risk ◽

Epithelial Cells ◽

Regulatory Element ◽

Capsid Proteins ◽

Cellular Proteins ◽

Late Gene Expression ◽

Hpv 16 ◽

Negative Regulatory Element

ABSTRACT The papillomavirus life cycle is tightly linked to epithelial cell differentiation. Production of virus capsid proteins is restricted to the most terminally differentiated keratinocytes in the upper layers of the epithelium. However, mRNAs encoding the capsid proteins can be detected in less-differentiated cells, suggesting that late gene expression is controlled posttranscriptionally. Short sequence elements (less than 80 nucleotides in length) that inhibit gene expression in undifferentiated epithelial cells have been identified in the late 3′ untranslated regions (UTRs) of several papillomaviruses, including the high-risk mucosal type human papillomavirus type 16 (HPV-16). Here we show that closely related high-risk mucosal type HPV-31 also contains elements that can act to repress gene expression in undifferentiated epithelial cells. However, the HPV-31 negative regulatory element is surprisingly complex, comprising a major inhibitory element of approximately 130 nucleotides upstream of the late polyadenylation site and a minor element of approximately 110 nucleotides mapping downstream. The first 60 nucleotides of the major element have 68% identity to the negative regulatory element of HPV-16, and these elements bind the same cellular proteins, CstF-64, U2AF65, and HuR. The minor inhibitory element binds some cellular proteins in common with the major inhibitory element, though it also binds certain proteins that do not bind the upstream element.

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