Experimentally Derived Metastasis Gene Expression Profile Predicts Recurrence and Death in Patients With Colon Cancer

Abstract

BACKGROUND & AIMS Staging inadequately predicts metastatic risk in patients with colon cancer. We used a gene expression profile derived from invasive, murine colon cancer cells that were highly metastatic in an immunocompetent mouse model to identify patients with colon cancer at risk of recurrence. METHODS This phase 1, exploratory biomarker study used 55 patients with colorectal cancer from Vanderbilt Medical Center (VMC) as the training dataset and 177 patients from the Moffitt Cancer Center as the independent dataset. The metastasis-associated gene expression profile developed from the mouse model was refined with comparative functional genomics in the VMC gene expression profiles to identify a 34-gene classifier associated with high risk of metastasis and death from colon cancer. A metastasis score derived from the biologically based classifier was tested in the Moffitt dataset. RESULTS A high score was significantly associated with increased risk of metastasis and death from colon cancer across all pathologic stages and specifically in stage II and stage III patients. The metastasis score was shown to independently predict risk of cancer recurrence and death in univariate and multivariate models. For example, among stage III patients, a high score translated to increased relative risk of cancer recurrence (hazard ratio, 4.7; 95% confidence interval, 1.566–14.05). Furthermore, the metastasis score identified patients with stage III disease whose 5-year recurrence-free survival was >88% and for whom adjuvant chemotherapy did not increase survival time. CONCLUSION A gene expression profile identified from an experimental model of colon cancer metastasis predicted cancer recurrence and death, independently of conventional measures, in patients with colon cancer.

UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression

“…Fifty-five patients come from Vanderbilt Medical Center and 177 from Moffitt Cancer Center (Smith et al, 2010). Out of these 232 patients, for UHRF1 expression 100 were included in the 1st quartile; 39 in the 2nd and 3rd quartiles; 93 in the 4th quartile.…”

miR-200 promotes the mesenchymal to epithelial transition by suppressing multiple members of the Zeb2 and Snail1 transcriptional repressor complexes

“…To validate these findings and determine whether the BPLER dependency genes are specific for breast cancer, the effect of BPLER dependency gene expression on survival and metastasis was assessed in 7 additional human tumor datasets (3 breast, 2 colon, 2 lung) comprising 1,296 human primary tumors (Figures 4E, 4F, S4B-D and Table S5) (Hou et al, 2010;Jorissen et al, 2009;Pawitan et al, 2005;Schmidt et al, 2008;Smith et al, 2010;Wang et al, 2005). In the 3 additional breast cancer cohorts, expression of the most selective and complete dependency genes again significantly correlated with poor survival and early metastasis.…”

Impact of chemotactic factors and receptors on the cancer immune infiltrate: a bioinformatics study revealing homogeneity and heterogeneity among patient cohorts

“…Five different datasets were included for several major cancer types, in particular breast carcinoma (TCGA consortium), 31–34 colorectal carcinoma (http://www.intgen.org or TCGA consortium), 35,36 non-small cell lung carcinoma (TCGA consortium) 37–40 and melanoma, 41–45 to study the correlation between the expression level of metagenes indicating the presence of immune cell types and a variety of chemotactic factors and receptors. An extra dataset concerning breast carcinoma 46 was used for studying expression variability and treatment response.…”