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Cancer Epidemiology, Biomarkers & Prevention
Cancer Epidemiology, Biomarkers & Prevention
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Review

The Potential for Markers of Epithelial–Mesenchymal Transition to Improve Colorectal Cancer Outcomes: A Systematic Review

Evan L. Busch, Kathleen A. McGraw and Robert S. Sandler
Evan L. Busch
Departments of 1Epidemiology and
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Kathleen A. McGraw
3Health Sciences Library, University of North Carolina, Chapel Hill, North Carolina
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Robert S. Sandler
Departments of 1Epidemiology and
2Medicine; and
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  • For correspondence: rsandler@med.unc.edu
DOI: 10.1158/1055-9965.EPI-14-0017 Published July 2014
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    Figure 1.

    Systematic identification of studies that measured the relationship between expression of selected EMT markers in colorectal cancer primary tumors and patient outcomes.

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  • Table 1.

    Summary of findings from studies that measured protein expression of selected EMT markers and patient outcomes in colorectal cancer tumorsa

    Percent positivebSurvivalEffect estimates
    Marker# StudiesRange# Studies# With difference by marker status# Studies# With effect on outcomes
    β-catenin542%–90%2010
    Cytokeratins29%–85%2110
    E-cadherin1529%–92%4331
    Fibronectin0—0000
    Integrins219%–88%1111
    N-cadherin20%–44%0010
    Slug230%–37%2111
    Snail540%–79%322Mixed
    TGFβ282%–89%1000
    Twist448%–100%113Mixed
    Vimentin40%–49%0000
    ZEB1129%1100
    ZEB2248%–90%111Mixed

    NOTE: Mixed, at least one study of a given marker reported both statistically significant and nonsignificant estimates of the effect of marker expression levels on outcomes.

    • ↵aThe number of studies under percentage of tumors with positive marker expression, survival, or effect estimates refers to the number of studies that reported values for that measurement for a given marker.

    • ↵bDefinitions of positive marker expression in a tumor generally varied across multiple studies of a given marker.

  • Table 2.

    Summary of findings from studies that measured RNA expression of selected EMT markers and patient outcomes in colorectal cancer tumorsa

    Percent positivebSurvivalEffect estimates
    Marker# StudiesRange# Studies# With difference by marker status# Studies# With effect on outcomes
    miRNAs248%–76%2200
    Twist186%1111
    • ↵aThe number of studies under percentage of tumors with positive marker expression, survival, or effect estimates refers to the number of studies that reported values for that measurement for a given marker.

    • ↵bDefinitions of positive marker expression in a tumor varied across multiple studies of a given marker.

  • Table 3.

    Multivariate modeling performed in included studies

    First authorEMT markers examinedType of regressionAdjustment covariates
    Bates et al. (45)Integrin α-v-β-6CoxAge, sex, tumor type (colon vs. rectal), tumor stage
    Bellovin et al. (34)E-cadherinCoxAge, sex, tumor stage, lymph node status
    Bellovin et al. (35)E-cadherinCoxAge, sex, tumor stage, lymph node status
    Fan et al. (20)E-cadherin, N-cadherin, Twist, Snail, β-cateninLogisticSupport vector machine, tumor stage, CEA, CA19-9, CA125
    Fan et al. (36)E-cadherin, Twist, SnailLogisticAge, sex, histologic grade, tumor class
    Fujikawa et al. (37)E-cadherinCoxAge, pathologic T category, lymph node metastasis
    Gomez et al. (48)Twist, Slug (RNA only for both)CoxAge, sex, lymph node metastasis status, tumor stage, treatment protocol (e.g., chemo vs. surgery)
    Harbaum et al. (30)Cytokeratin-7, E-cadherinCoxAge, sex, T classification, N classification, tumor grade
    Kahlert et al. (50)ZEB2CoxAge, sex, tumor stage, grade, type of resection (curative vs. noncurative), microsatellite stability, KRAS mutation status
    Kevans et al. (23)E-cadherin, β-cateninCoxAge, sex, T-stage, tumor site, tumor differentiation, tumor budding, lymphovascular invasion, neural invasion, microsatellite status
    Khanh et al. (26)Cytokeratin, TGFβCoxTumor grade, tumor depth, node status
    Knosel et al. (29)CytokeratinsCoxNot listed
    Knosel et al. (38)E-cadherinCoxPathologic stage, venous invasion, PITX1 expression
    Koelzer et al. (31)E-cadherinCoxT-stage, M-stage, N-stage, postoperative therapy
    Kroepil et al. (39)E-cadherin, SnailCoxAge, sex, T-stage, N-stage, tumor grade
    Meng et al. (47)miRNACoxTumor size, CEA, histologic grade
    Mesker et al. (24)TGFβ, β-cateninCoxNo adjustment covariates reported
    Saito et al. (41)E-cadherin, vimentinCoxAge, sex, location (colon vs. rectal), tumor size, histological type, lymphatic invasion, venous invasion, invasion of primary tumor, lymph node metastasis
    Shioiri et al. (42)E-cadherin, SlugCoxAge, distant metastasis, lymph node metastasis, lymphatic invasion, vessel invasion
    Spaderna et al. (27)E-cadherin, β-catenin, ZEB1, vimentinCoxNot listed
    Yu et al. (44)E-cadherin, Twist2CoxAge, sex, T-stage, N-stage, M-stage, tumor differentiation, vascular invasion, tumor location, CEA level
    Zlobec (28)CytokeratinCoxTumor budding, TNM stage, tumor grade, KRAS status, BRAF status, MGMT status, microsatellite instability status, CpG island methylator status

    Abbreviations: TNM, tumor–node–metastasis; CEA, carcinoembryonic antigen.

    • Table 4.

      Recommendations for future studies of EMT markers in clinical cancer primary tumors and patient outcomes

      1. Standardize definitions of positive and negative marker expression status across studies of a given EMT marker measured using the same laboratory technique. To facilitate this for studies of protein expression using immunohistochemistry, score using computer-assisted image analysis to obtain continuous measures of marker staining (e.g., H scores, average intensities) that can be used to develop clinically useful cut points.

      2. Make study sample sizes as large as possible.

      3. For every EMT marker measured, present Kaplan–Meier survival curves stratified by marker expression status as well as Cox time-to-event modeling of the association between marker expression and patient time-to-mortality (or other outcomes).

      4. Develop consensus about what set of covariates should be included in multivariate models to produce valid estimates of the association between EMT marker expression in primary tumor cancer cells and patient time-to-mortality (or other outcomes).

      5. Measure EMT markers of interest as both RNA and protein in the same set of tumors to clarify which form of marker expression is more clinically useful.

      6. For studies using immunohistochemistry, report quantitative measures of inter-rater and intra-rater reliability for scoring images.

      7. To assess marker expression heterogeneity throughout a primary tumor, measure the marker in multiple cores taken from different parts of the tumor, including the invasive front, tumor center, and surface of the tumor away from the invasive front.

    Additional Files

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    • Supplementary Data

      Files in this Data Supplement:

      • Supplementary Search Terms - PDF file - 98K, This file presents the set of search terms we used as applied to PubMed. It provides information about the structure of the search and how it could be adapted to search for studies of EMT markers and patient outcomes in tumor sites other than colorectal cancer.
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    Cancer Epidemiology Biomarkers & Prevention: 23 (7)
    July 2014
    Volume 23, Issue 7
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    The Potential for Markers of Epithelial–Mesenchymal Transition to Improve Colorectal Cancer Outcomes: A Systematic Review
    Evan L. Busch, Kathleen A. McGraw and Robert S. Sandler
    Cancer Epidemiol Biomarkers Prev July 1 2014 (23) (7) 1164-1175; DOI: 10.1158/1055-9965.EPI-14-0017

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    The Potential for Markers of Epithelial–Mesenchymal Transition to Improve Colorectal Cancer Outcomes: A Systematic Review
    Evan L. Busch, Kathleen A. McGraw and Robert S. Sandler
    Cancer Epidemiol Biomarkers Prev July 1 2014 (23) (7) 1164-1175; DOI: 10.1158/1055-9965.EPI-14-0017
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