Noninvasive Detection of Candidate Molecular Biomarkers in Subjects with a History of Insulin Resistance and Colorectal Adenomas

Abstract

We have developed novel molecular methods using a stool sample, which contains intact sloughed colon cells, to quantify colonic gene expression profiles. In this study, our goal was to identify diagnostic gene sets (combinations) for the noninvasive classification of different phenotypes. For this purpose, the effects of a legume-enriched, low glycemic index, high fermentable fiber diet was evaluated in subjects with four possible combinations of risk factors, including insulin resistance and a history of adenomatous polyps. In a randomized crossover design controlled feeding study, each participant (a total of 23; 5-12 per group) consumed the experimental diet (1.5 cups of cooked dry beans) and a control diet (isocaloric average American diet) for 4 weeks with a 3-week washout period between diets. Using prior biological knowledge, the complexity of feature selection was reduced to perform an exhaustive search on all allowable feature (gene) sets of size 3, and among these, 27 had (unbiased) error estimates of 0.15 or less. Linear discriminant analysis was successfully used to identify the best single genes and two-to three-gene combinations for distinguishing subjects with insulin resistance, a history of polyps, or exposure to a chemoprotective legumerich diet. These results support our premise that gene products (RNA) isolated from stool have diagnostic value in terms of assessing colon cancer risk.

Epigenetic Alteration of DNA in Mucosal Wash Fluid Predicts Invasiveness of Colorectal Tumors

“…Analysis of nuclear staining, DNA methylation, and K-ras mutation suggest that wash fluidderived DNA from invasive tumors contains higher concentrations of tumor-derived DNA than wash fluid from (36,37). In that context, there are several possible explanations for the higher concentration of DNA from invasive tumor cells in colonoscopy wash fluid.…”

Association of Insulin-Related Serum Factors with Colorectal Polyp Number and Type in Adult Males

“…Given the outcomes of recent clinical trials (10) showing that anti-IGF-1 receptor treatments are ineffective in treating cancer, our results demonstrating the IGF-1 and its binding proteins are not associated with early steps in the progression to colon cancer are less surprising. Additionally, IGF signaling in the colon rather than blood may be more predictive of colon cancer risk (22). …”

Detecting Multivariate Gene Interactions in RNA-Seq Data Using Optimal Bayesian Classification

“…3. Using prior biological knowledge, 858 genes were selected for investigation with this dataset from a list of putative colonic expression biomarkers [19]. To further aid biological interpretation, we filtered out genes with an FPKM value and average read count of less than one in both groups of the comparison.…”