scholarly journals Interconnectivity between molecular subtypes and tumor stage in colorectal cancer

2020 ◽  
Author(s):  
R.R.J. Coebergh van den Braak ◽  
Sanne ten Hoorn ◽  
A.M. Sieuwerts ◽  
J.B. Tuynman ◽  
M. Smid ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colon Cancer ◽  
Molecular Subtypes ◽  
Tnm Classification ◽  
Tumor Biology ◽  
Tumor Stage ◽  
Stage Ii ◽  
Colon Cancers ◽  
Advanced Stages ◽  
Stage Ii Colon Cancer

Abstract Background There are profound individual differences in clinical outcome 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 (III-IV). The observed differential gene expression between cancer stages is predominantly explained by the biological differences as reflected by CMS subtypes. Gene signatures for stage III-IV and CMS4 were highly correlated. CMS4 cancers showed an increased progression rate to more advanced stages. Indeed, determining CMSs was a relevant addition to TNM classification in identifying stage II colon cancer patients with high-risk of disease recurrence. 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, also reflects distinct biological disease entities. These insights can be utilized to optimize identification of high-risk stage II colon cancers.

scholarly journals Interconnectivity between molecular subtypes and tumor stage in colorectal cancer

2020 ◽  
Author(s):  
R.R.J. Coebergh van den Braak ◽  
Sanne ten Hoorn ◽  
A.M. Sieuwerts ◽  
J.B. Tuynman ◽  
M. Smid ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Risk ◽  
Molecular Subtypes ◽  
Tumor Biology ◽  
Tumor Stage ◽  
Stage Ii ◽  
Disease Stage ◽  
Progression Rate ◽  
Advanced Stages ◽  
Clinical Records

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.

scholarly journals Prognosis of stage II colon cancer by non-neoplastic mucosa gene expression profiling

Oncogene ◽  
2006 ◽  
Vol 26 (18) ◽  
pp. 2642-2648 ◽  
Author(s):  
A Barrier ◽  
F Roser ◽  
P-Y Boëlle ◽  
B Franc ◽  
C Tse ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colon Cancer ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Stage Ii ◽  
Stage Ii Colon Cancer

scholarly journals A comparison of 12-gene colon cancer assay gene expression in African American and Caucasian patients with stage II colon cancer

BMC Cancer ◽  
2016 ◽  
Vol 16 (1) ◽  
Author(s):  
Rangaswamy Govindarajan ◽  
James Posey ◽  
Calvin Y. Chao ◽  
Ruixiao Lu ◽  
Trafina Jadhav ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colon Cancer ◽  
African American ◽  
Stage Ii ◽  
Caucasian Patients ◽  
Stage Ii Colon Cancer

Prognosis prediction of stage II colon cancer by gene expression profiling

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3565-3565
Author(s):  
A. Barrier ◽  
D. Brault ◽  
S. Houry ◽  
S. Dudoit ◽  
A. Lemoine ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colon Cancer ◽  
Expression Profiling ◽  
Prediction Accuracy ◽  
Stage Ii ◽  
Microarray Gene Expression ◽  
Prognosis Prediction ◽  
Learning Set ◽  
Stage Ii Colon Cancer ◽  
High Instability

3565 Background: The aims of the present study were: 1) to identify a prognosis signature (PS), based on microarray gene expression measures, in stage II colon cancer patients and to assess its accuracy with resampling techniques ; 2) to assess the accuracy, also with resampling techniques, of a previously proposed 23-gene PS. Methods: Colon tumor mRNA samples from 50 patients were profiled using the Affymetrix HGU133A GeneChip (22283 sequences). In a first part, the 50 patients were randomly divided into 2 groups (G1 and G2) of equal size that were considered alternately as training and validation sets. In a second part, the 50 patients were randomly divided into 1600 training (size=n) and validation (size=50-n) sets. Informative genes were selected on the training set by taking the 30 most differentially expressed genes between patients who recurred and those who remained disease-free; the accuracy of this PS was assessed by comparing the predicted prognosis (using a diagonal linear discriminant analysis (DLDA)) and the actual evolution for all the validation set patients. Using the same random splits, the accuracy of the 23-gene PS was assessed with a DLDA that used learning set patients as reference samples. Results: The 30-gene PS that was identified from G1 (G2) patients yielded a 80% (84%) prognosis prediction accuracy when applied on G2 (G1) patients. With resampling techniques, the prediction accuracy regularly increased with the learning set (LS) size: 65.5% (range=52.5–75%) with LS of size 10, and 82.7% (range=60–100%) with LS of size 40. Comparisons of compositions of the 100 PS for a given value of n suggested a high instability of informative genes; with LS of size 10, 7 genes were part of at least 10% of signatures; with LS of size 40, 7 genes were part of all the 100 signatures. The accuracy of the previously proposed 23-gene PS also increased with the learning set size. Conclusion: Microarray gene expression profiling represents a promising technique to predict the prognosis of stage II colon cancer patients. The present study also outlines the high instability of informative gene selection and suggests the usefulness of resampling techniques to obtain an honest assessment of prognosis prediction accuracy. No significant financial relationships to disclose.

Recurrence score distributions in stage II colon cancers of African American (AA) and Caucasian (CA) patients.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 613-613 ◽  
Author(s):  
Rangaswamy Govindarajan ◽  
James Posey ◽  
Calvin Y. Chao ◽  
Ruixiao Lu ◽  
Trafina Jadhav ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colon Cancer ◽  
Cancer Patients ◽  
Medical Center ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Recurrence Score ◽  
Stage Ii ◽  
Racial Groups ◽  
Stage Ii Colon Cancer

613 Background: The 12-gene colon cancer assay (Oncotype DX) can identify groups of stage II colon cancer patients with lower or higher recurrence risk, but distribution of scores based on race/ethnicity has not been assessed. This study compared the distribution of Recurrence Score results and gene expression profiles between African American (AA) and Caucasian (CA) stage II colon cancer patients. Methods: Stage II colon cancer patients were identified from tumor registry data from four institutions: University of Arkansas for Medical Sciences, Little Rock; Veterans Administration Medical Center, Little Rock; Baptist Medical Center, Memphis, and University of Alabama at Birmingham. The 12-gene assay and mismatch repair (MMR) status were performed on formalin-fixed paraffin-embedded tissues by Genomic Health (Redwood City, CA). T-test and Wilcoxon test were used to compare data from the two groups (SAS Enterprise Guide 5.1). Results: Of the 244 subjects, there were 118 women (63 AA, 55 CA) and 126 men (59 AA, 67 CA). Median ages (years) were 66 for AAs and 68 for CAs. Age, gender, surgery year, pathologic T-Stage, tumor location, number of nodes examined, lympho-vascular invasion, and MMR status were not significantly different between groups (p>0.05). Recurrence Score results between AAs (mean 27.9; SD 12.8) and CAs (mean 28.1; SD 11.8) were not statistically different (p>0.05). The proportion of patients with high Recurrence Score values (≥41) was similar between the groups (17/122 AA; 15/122 CA). None of the gene expression variables, either single genes or gene groups, (cell cycle group, stromal group, BGN1, FAP, INHBA1, Ki67, MYBL2, cMYC3 and GADD45B) was significantly different between the racial groups (p>0.05). After controlling for clinical and pathologic covariates, means and distributions of Recurrence Score and gene expression profiles still showed no statistical significance between racial groups (p>0.05). Conclusions: In a cohort of AA and CA stage II colon cancer patients with similar clinical characteristics, the distribution of Recurrence Score results and gene expression data were similar between AA and CA patients.

Validation Study of a Quantitative Multigene Reverse Transcriptase–Polymerase Chain Reaction Assay for Assessment of Recurrence Risk in Patients With Stage II Colon Cancer

2011 ◽  
Vol 29 (35) ◽  
pp. 4611-4619 ◽  
Author(s):  
Richard G. Gray ◽  
Philip Quirke ◽  
Kelly Handley ◽  
Margarita Lopatin ◽  
Laura Magill ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colon Cancer ◽  
Recurrence Score ◽  
Recurrence Risk ◽  
Cox Proportional Hazards ◽  
Stage Ii ◽  
Treatment Benefit ◽  
Risk Of Recurrence ◽  
T Stage ◽  
Stage Ii Colon Cancer

Purpose We developed quantitative gene expression assays to assess recurrence risk and benefits from chemotherapy in patients with stage II colon cancer. Patients and Methods We sought validation by using RNA extracted from fixed paraffin-embedded primary colon tumor blocks from 1,436 patients with stage II colon cancer in the QUASAR (Quick and Simple and Reliable) study of adjuvant fluoropyrimidine chemotherapy versus surgery alone. A recurrence score (RS) and a treatment score (TS) were calculated from gene expression levels of 13 cancer-related genes (n = 7 recurrence genes and n = 6 treatment benefit genes) and from five reference genes with prespecified algorithms. Cox proportional hazards regression models and log-rank methods were used to analyze the relationship between the RS and risk of recurrence in patients treated with surgery alone and between TS and benefits of chemotherapy. Results Risk of recurrence was significantly associated with RS (hazard ratio [HR] per interquartile range, 1.38; 95% CI, 1.11 to 1.74; P = .004). Recurrence risks at 3 years were 12%, 18%, and 22% for predefined low, intermediate, and high recurrence risk groups, respectively. T stage (HR, 1.94; P < .001) and mismatch repair (MMR) status (HR, 0.31; P < .001) were the strongest histopathologic prognostic factors. The continuous RS was associated with risk of recurrence (P = .006) beyond these and other covariates. There was no trend for increased benefit from chemotherapy at higher TS (P = .95). Conclusion The continuous 12-gene RS has been validated in a prospective study for assessment of recurrence risk in patients with stage II colon cancer after surgery and provides prognostic value that complements T stage and MMR. The TS was not predictive of chemotherapy benefit.

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

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 384-384 ◽  
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.

Microsatellite instability and adjuvant chemotherapy in stage II colon cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 767-767
Author(s):  
Julie L. Koenig ◽  
Albert Y. Lin ◽  
Erqi L. Pollom ◽  
Daniel Tandel Chang
Keyword(s):  
Colon Cancer ◽  
Adjuvant Chemotherapy ◽  
Microsatellite Instability ◽  
Univariate Analysis ◽  
Population Based ◽  
Stage Ii ◽  
Chi Square ◽  
Colon Cancers ◽  
Multiple Characteristics ◽  
Stage Ii Colon Cancer

767 Background: Randomized control trials and population-based studies have not demonstrated a definitive benefit for adjuvant chemotherapy in stage II colon cancers. Tumor side and microsatellite instability (MSI) have been proposed as prognostic and predictive factors, but there is little consensus about their utility. Previous studies have been limited by the availability of MSI data. Because microsatellite stability (MSS) is associated with worse prognosis and higher risk of metastases, we hypothesized patients with MSS would have increased benefit from chemotherapy. Methods: Using the National Cancer Database, we preformed a retrospective cohort study of patients with resected stage II colon cancer diagnosed 2006-2013. Patient and disease characteristics were compared with chi-square tests. Survival was evaluated with Cox proportional hazard models. Results: We identified 59,475 patients with stage II colon cancer. 11.4% of patients had known MSI status (n = 6,763) of which 88% had MSS (n = 5,953) and 12% had MSI (n = 810). Patients with MSS were more likely to receive chemotherapy (28.2% vs 19.9%, p < 0.001) and have left-sided tumors (38.8% vs 16.7%, p < 0.001). MSI (adjusted hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.48-0.87; p = 0.003) and receipt of chemotherapy (HR 0.54, 95% CI 0.42-0.69; p < 0.001) were associated with better survival after controlling for multiple characteristics including tumor side. Although left-sided tumors had better survival on univariate analysis (HR 0.91, 95% CI 0.88-0.94; p < 0.001), side was not an independent predictor of survival after controlling for MSI and other characteristics (HR 1.01, 95% CI 0.86-1.20; p = 0.860). Among patients with MSS, chemotherapy remained associated with improved survival (HR 0.54, 95% CI 0.43-0.70; p < 0.001) and this benefit did not vary by tumor side (interaction p = 0.380). There was no interaction between MSI status and chemotherapy (p = 0.139), but we observed less of a survival benefit for chemotherapy in patients with MSI (HR 0.81, 95% CI 0.38-1.75; p = 0.595). Conclusions: Our data suggest a benefit for adjuvant chemotherapy in stage II colon cancer even after adjusting for MSI status. However, tumor side was not prognostic after controlling for MSI status.

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