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Non-invasive detection of molecular biomarkers in subjects with a history of insulin resistance and colorectal adenomas

ABSTRACT: We have developed novel molecular methodology utilizing a stool sample, which contains intact sloughed colon cells, in order 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 (IR) and a history of adenomatous polyps. In a randomized crossover design controlled feeding study each participant (a total of 23, 5-12/group) consumed the experimental diet (1.5 cups of cooked dry beans) and a control diet (isocaloric average American diet) for 4 wk with a 3 wk washout period between diets. Using prior biological knowledge, the complexity of feature selection was reduced in order 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 (LDA) was successfully used to identify the best single genes and two- to three-gene combinations for distinguishing subjects with IR, a history of polyps or exposure to a chemoprotective legume-rich diet. These results support our premise that gene products (RNA) isolated from stool have diagnostic value in terms of assessing colon cancer risk. Keywords: Exfoliated cells, legumes, insulin resistance, polyps

ORGANISM(S): Homo sapiens

PROVIDER: GSE14797 | GEO | 2010/02/11

SECONDARY ACCESSION(S): PRJNA112083

REPOSITORIES: GEO

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Project description:This study, sponsored by the National Cancer Institute and Penn State University, will examine how a diet high in legumes (dried beans) influences risk factors for colon cancer and polyps. Many scientists believe that colon and rectal cancers develop from polyps (tumors of the lining of the large bowel). This study will test whether a high-legume diet can reduce levels of certain factors (blood insulin, blood glucose, and markers of inflammation such as C-reactive protein) that at elevated levels are known to increase the risk of colorectal polyps and colon cancer. Healthy men between 35 and 75 years of age may be eligible for this study, conducted at Penn State University in University Park, Pennsylvania. Candidates are screened with blood tests and measurements of height, weight, and blood pressure. All candidates must have had a colonoscopy within 2 years of entering the study. They may or may not have had adenomas and may or may not be insulin-resistant. Candidates must not have cancer, heart disease, kidney disease, diabetes, or other serious medical condition, and they must have no history of colorectal cancer, polyp removal, bowel surgery, polyposis syndrome, or inflammatory bowel disease. Participants undergo the following tests and procedures: * Caloric requirement testing: The subject’s resting metabolic rate is measured while fasting and in the early morning at rest to determine daily calorie requirement before beginning the study diet. A special clear plastic hood is placed over the subject’s head while his breathing is measured. He can communicate with the technician at all times during the 30-minute test. * Study diet: Subjects follow two required 4-week diets with a 3-week break in between, followed by an optional third 4-week diet. Subjects eat a healthy American diet for both of the required 4-week diet periods; about 1-1/2 cups of cooked legumes, such as pinto, baked, and navy beans are added to one of the two required diets. For the third (optional) diet period, subjects are given the same 1-1/2 cups of legumes, but are allowed to lose weight. Participants are given packages with all of the food they are to consume during the three diet periods. They may add up to five caffeine-containing beverages per day and up to two alcoholic drinks per week. They must eat all of the food they are given and only the food they are given. Subjects are expected to maintain a constant body weight during the two 4-week required diets, and their caloric intake may be increased or decreased as needed to maintain their screening weight. * Weight measurements: Subjects are weighed regularly at the clinic. * Blood samples: Subjects have blood samples drawn at the mid-point of each of the two required 4-week diets and at the beginning and end of each of the three 4-week diets. * Urine and stool samples: Urine and stool samples are collected at the beginning and end of the two required 4-week diets.

Project description:Fish oil supplementation has been shown to alter gene expression of mononuclear cells both in vitro and in vivo. However, little is known about the total transcriptomic profile in healthy subjects after intake of fish oil compared to a control group. The objective was to examine the gene expression profile in peripheral blood mononuclear cells (PBMCs) in healthy subjects after intake of fish oil for seven weeks using whole-genome transcriptomic analysis. In a double-blinded randomized controlled study, healthy subjects received capsules containing either 8 g/d of fish oil (1.6 g/d EPA+DHA) (n=17) or 8 g/d of high oleic sunflower oil (n=19) for seven weeks. The results provide important information on how fish oil may modulate basic cellular processes involved in normal cell function and lymphocyte activation such as ER stress, cell cycle and apoptosis. The subjects were taking 16 capsules/d containing 8 g/d of either fish oil (FO) or high oleic sunflower oil (HOSO) for seven weeks. Subjects in the FO group received capsules containing 0.7 g/d EPA + 0.9 g/d DHA from cod liver oil (Gadidae sp., TINE EPADHA Oil 1200) provided by TINE SA (Oslo, Norway) and subjects in HOSO group received high oleic sunflower oil purchased from AarhusKarlshamn AB (Malmӧ, Sweden). Prior to the baseline visit (visit 2, wk 0), the subjects conducted a four-week washout period, where foods containing marine n-3 fatty acids were excluded from the diet. The first three weeks of the intervention period the subjects conducted a fully-controlled isocaloric diet, provided with all food and beverages at Akershus University College, Norway. During the last four weeks of the intervention the subjects returned to their habitual diet. Use of fish, fish products, marine n-3 enriched food or dietary supplements was not allowed during the entire study period of 11 weeks. The study was registered at www.clinicaltrial.gov (IDno. NCT01034423). The subjects met for four visits and blood samples for the transcriptome analyses were collected at wk 0, 3 and 7. After blood collection, PBMCs were isolated by using the BD Vacutainer Cell Preparation tubes according to the manufacturer's instructions (Becton, Dickinson and Company, NJ 07417, USA). Pellets were frozen and stored at -80o C for further RNA isolation.

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Non-invasive detection of molecular biomarkers in subjects with a history of insulin resistance and colorectal adenomas

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