Content area
Full Text
During the past decade, disease-free survival among patients with stage III colon cancer has increased significantly owing to the introduction of new adjuvant chemotherapy regimens.1–3 This therapeutic success, however, has not translated into longer disease-free survival among patients with earlier-stage (stage I or II) cancer.4 The lack of simple, reliable criteria for the identification of patients with early-stage disease who are at high risk for relapse has made it difficult to identify patients in whom the hazards of multiagent chemotherapy may be offset by benefits with respect to disease-specific survival.4–9
To address this problem, researchers have explored the possibility of stratifying patients with colon cancer according to the gene-expression profile of their tumor tissues, and they have developed multigene-expression signatures that can be used to identify high-risk colon cancers.10–15 Although gene-expression signatures hold promise, they are difficult to use in clinical practice16 and are often not predictive of benefit from adjuvant chemotherapy.17
Among the gene-expression signatures with the greatest promise are those derived from stem cells and progenitor cells.18,19 Therefore, we initiated a systematic search for a biomarker that could be used to identify undifferentiated tumors (i.e., tumors depleted of cells with a mature phenotype) by means of immunohistochemical analysis.
To perform this search, we adopted a bioinformatics approach using Boolean logic. This approach, which was designed to discover developmentally regulated genes,20,21 was used to identify genes with expression in colon cancer that was negatively linked to the activated leukocyte-cell adhesion molecule (ALCAM/CD166). This marker of immature colon epithelial cells is preferentially expressed at the bottom of colon crypts22,23 and on human colon-cancer cells with enriched tumorigenic capacity in mouse xenotransplantation models.24
This screening test led us to identify caudal-type homeobox transcription factor 2 (CDX2) as a candidate biomarker of mature colon epithelial tissues. Using subgroup analysis involving retrospective patient cohorts, we evaluated the association of this biomarker with 5-year disease-free survival and benefit from adjuvant chemotherapy among patients with colon cancer (Figure 1).
Methods
Bioinformatics Analysis of Gene-Expression Array Databases
We searched for genes that fulfilled the “X-negative implies ALCAM-positive” Boolean relationship in a collection of 2329 human colon gene-expression array experiments...