Gene expression profiles in stages II and III colon cancers: application of a 128-gene signature

Thorsteinsson, Morten; Kirkeby, Lene T.; Hansen, Raino K.; Lund, Leif R.; Sørensen, Lars Tue; Gerds, Thomas Alexander; Jess, Per; Olsen, Jørgen

doi:10.1007/s00384-012-1517-4

Cited by 27 publications

(26 citation statements)

References 28 publications

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“…S6 in Supplementary Appendix 1). 12,13,26,27 Patients were stratified into negative-to-low (negative) and high (positive) subgroups with regard to CDX2 and ALCAM gene-expression levels with the use of the StepMiner algorithm, implemented within the Hegemon 21 software (Fig. S7 through S10 in Supplementary Appendix 1).…”

Section: Methodsmentioning

confidence: 99%

CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer

et al. 2016

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Background The identification of high-risk stage II colon cancers is key to the selection of patients who require adjuvant treatment after surgery. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice. Methods We used a new bioinformatics approach to search for biomarkers of colon epithelial differentiation across gene-expression arrays and then ranked candidate genes according to the availability of clinical-grade diagnostic assays. With the use of subgroup analysis involving independent and retrospective cohorts of patients with stage II or stage III colon cancer, the top candidate gene was tested for its association with disease-free survival and a benefit from adjuvant chemotherapy. Results The transcription factor CDX2 ranked first in our screening test. A group of 87 of 2115 tumor samples (4.1%) lacked CDX2 expression. In the discovery data set, which included 466 patients, the rate of 5-year disease-free survival was lower among the 32 patients (6.9%) with CDX2-negative colon cancers than among the 434 (93.1%) with CDX2-positive colon cancers (hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P = 0.002). In the validation data set, which included 314 patients, the rate of 5-year disease-free survival was lower among the 38 patients (12.1%) with CDX2 protein–negative colon cancers than among the 276 (87.9%) with CDX2 protein–positive colon cancers (hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P = 0.003). In both these groups, these findings were independent of the patient's age, sex, and tumor stage and grade. Among patients with stage II cancer, the difference in 5-year disease-free survival was significant both in the discovery data set (49% among 15 patients with CDX2-negative tumors vs. 87% among 191 patients with CDX2-positive tumors, P = 0.003) and in the validation data set (51% among 15 patients with CDX2-negative tumors vs. 80% among 106 patients with CDX2-positive tumors, P = 0.004). In a pooled database of all patient cohorts, the rate of 5-year disease-free survival was higher among 23 patients with stage II CDX2-negative tumors who were treated with adjuvant chemotherapy than among 25 who were not treated with adjuvant chemotherapy (91% vs. 56%, P = 0.006). Conclusions Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. (Funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others.)

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Section: Methodsmentioning

confidence: 99%

CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer

et al. 2016

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“…It is often difficult to predict which patients with stage II and stage III colon cancer will benefit from chemotherapy [22,23]. Thorsteinsson, et al studied 37 patients with stage II and III colon cancer; TLR4 expression was significantly higher in stage III tumors than stage II for two of the four TLR4 probes (Medium, p = 0.061 and Long2, p = 0.092) (GSE31595) [24]. TLR4 expression was numerically, but not statistically, higher in stage III tumors for the remaining probes (Short, p = 0.466 and Long1, p = 0.117).…”

Section: Resultsmentioning

confidence: 99%

In silico and Ex vivo approaches identify a role for toll-like receptor 4 in colorectal cancer

Sussman

Santaolalla

Bejarano

et al. 2014

J Exp Clin Cancer Res

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Background: Inflammation increases the risk of colorectal cancer (CRC). We and others have described a role for TLR4, the receptor for LPS, in colon cancer. To explore the relationships between TLR4 expression and CRC, we combined the strength of transcriptome array data and immunohistochemical (IHC) staining. Methods: TLR4 signal intensity was scored in the stromal and epithelial compartments. Detection of differential expression between conditions of interest was performed using linear models, Cox proportional hazards models, and empirical Bayes methods. Results: A strong association between TLR4 expression and survival was noted, though a dichotomous relationship between survival and specific TLR4 transcripts was observed. Increasing TLR4 expression was seen with advancing tumor stage and was also over-expressed in some adenomas. IHC staining confirmed the positive relationship between TLR4 staining score in the CRC tumor stroma and epithelium with tumor stage, with up to 47% of colon cancer stroma positive for TLR4 staining. Increased TLR4 expression by IHC was also marginally associated with decreased survival. We now also describe that pericryptal myofibroblasts are responsible for a portion of the TLR4 stromal staining.

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“…Some studies used samples from non-targeted stage I and IV patients (who exhibit a clean separation) to distinguish between targeted high-risk and low-risk stage II and III patients [20, 23, 27]. By this design, the true boundary between recurrent and non-recurrent patients could not be determined in these studies, since targeted stage II and III patients were not included in the training.…”

Section: Discussionmentioning

confidence: 99%

“…By this design, the true boundary between recurrent and non-recurrent patients could not be determined in these studies, since targeted stage II and III patients were not included in the training. This could explain the contradictory conclusions of different studies in which this approach was used; for instance, one model predicted recurrence for stage III patients but not for stage II patients [20], while another model predicted recurrence for stage II patients but not for stage III patients [27]. In a third study, recurrence could be predicted for both stage II and III patients; however, the results were obtained from two different platforms, so further validation of the models was needed [23].…”

Section: Discussionmentioning

confidence: 99%

Building personalized treatment plans for early-stage colorectal cancer patients

Lin

Wei²,

Chou

et al. 2017

Oncotarget

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We developed a series of models to predict the likelihood of recurrence and the response to chemotherapy for the personalized treatment of stage I and II colorectal cancer patients. A recurrence prediction model was developed from 235 stage I/II patients. The model successfully distinguished between high-risk and low-risk groups, with a hazard ratio of recurrence of 4.66 (p < 0.0001). More importantly, the model was accurate for both stage I (hazard ratio = 5.87, p = 0.0006) and stage II (hazard ratio = 4.30, p < 0.0001) disease. This model performed much better than the Oncotype and ColoPrint commercial services in identifying patients at high risk for stage II recurrence. And unlike the commercial services, the robust model included recurrence prediction for stage I patients. As stage I/II CRC patients usually do not receive chemotherapy, we generated chemotherapy efficacy prediction models with data from 358 stage III patients. The predictions were highly accurate: the hazard ratio of recurrence for responders vs. non-responders was 4.13 for those treated with FOLFOX (p < 0.0001), and 3.16 (p = 0.0012) for those treated with fluorouracil. We have thus created a prognostic model that accurately identifies patients at high risk for recurrence, and the first accurate chemotherapy efficacy prediction model for individual patients. In the future, complete personalized treatment plans for stage I/II patients may be developed if the drug prediction models generated from stage III patients are verified to be effective for stage I and II patients in prospective studies.

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Gene expression profiles in stages II and III colon cancers: application of a 128-gene signature

Abstract: The 128-gene signature showed reproducibility in stage III colon cancer, but could not predict recurrence in stage II. Individual patient predictions in an independent Danish material were unsatisfactory. Additional validation in larger cohorts is warranted.

Cited by 27 publications

References 28 publications

CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer

CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer

In silico and Ex vivo approaches identify a role for toll-like receptor 4 in colorectal cancer

Building personalized treatment plans for early-stage colorectal cancer patients

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