Biomarkers in the detection of Colon and Rectal Cancer Gina Wallar, MPH Colorectal CRC 2009 Stats (US) Risk Factors Biomarkers Current Screening Guidelines Transferrin Colorectal Cancer (CRC) Picture in the U.S. 3rd most common cancer in men and women 2nd major cancer killer Detectable Treatable Screening- Compliance a major factor 2009 CRC Statistics 106,100 cases of colon cancer expected 40,870 cases of rectal cancer expected • Accounts for 9% of all cancer deaths • 5-year survival rate for Stage I is 90% • 5-year survival rate for Stage IV is 11% Less than half of colon cancer cases are detected when the cancer is localized Colon Cancer-Risk Factors Family History/Genetics Age History of colon cancer, polyps, bowel disease Race/Ethnicity Alcohol Smoking Diet Sedentary Lifestyle Obesity Diabetes Smoking (Incidence versus Mortality) Alcohol and Colon Cancer Alcohol and Rectal Cancer Colon Cancer and Diet “Western Civilization” High in Animal Fat-Bile acid production Low Fiber Refined sugar-Hyperinsulinaemia Low Vegetable Intake No longer considered a main contributor to CRC Red Meat Consumption CRC and Fish Consumption Geelen, A. et al. Am. J. Epidemiol. 2007 0:kwm197v1-197; doi:10.1093/aje/kwm197 Green Tea Colon Cancer and Physical Activity Sedentary lifestyle is positively associated with colon cancer (Giovannucci) Physical activity- obesity connection Sex steroid hormone levels change with physical activity initiation Estradiol decreases SHBG increases Testosterone increases Obesity and Colon Cancer Obesity and Rectal Cancer Colon Cancer and Obesity Increase in adipose tissue Increase in insulin Association stronger in men and premenopausal women Gender as an effect modifier on the obesity colon cancer association suggest that sex steroid hormones play a role though the mechanism is not well understood Biomarkers of Obesity With Obesity Decreased SHBG Decreased total T (men) Increased free and total E Does obesity drive these changes in hormones or do hormones drive changes in body shape, weight, and adiposity? Mechanism Hypothalamus/GnRH Adipose tissue Adrenal Secretion Pituitary LH/FSH Ovary Androstenedione Testis Cholesterol pathway Liver Testosterone lo SHBG Estrogens Androgens Hyperthyroidism Glucocorticoids Hypothyroidism Anorexia Pregnancy Obesity Insulin/IGF-1 PCOS Diabetes Free T + Aromatase Androgens Bound T SHBG hi SHBG Age, Obesity Estradiol Free E + Bound E Estrogens Adipose Tissue Features Established relationship with insulin resistance Play a role in the regulation of insulin signaling and action Source of inflammation Adipocytokines Leptin Adiponectin IL-6 TNFalpha FFA Resistin Diabetes and Colon Cancer Similarity of lifestyle/environmental risk factors Positively associated Hyperinsulinaemia initiates carcinogenesis Insulin is a growth factor for colonic epithelial cells and can reduce apoptosis Insulin is a mitogen of tumor cells in vitro Diabetes and Colon Cancer Mechanism Adiposity Varying levels of Adipocytokines Insulin Resistance IGF-1 Increases Insulin Increases Cell Proliferation Increases Apoptosis Decreases Activates IR Tumor Development Activates IGFR Growth Hormones Insulin increases IGF-1 IGF-1 activates the IGF receptor Decreases apoptosis Increases cell proliferation Physicians Health Study reported RR of 2.51 for those in the high IGF-1 quintile Current CRC Screening Goal: Reduce mortality via a reduction in incidence of advanced disease 1-Stool-based tests (Occult Blood and DNA) 2-Structural exams (Colonscopy (CSPY), Flexible Sigmoidoscopy (FSIG), DoubleContrast Barium Enema (DCBE), and Computed Tomographic Colongraphy (CTC)) Current Recommendations for Average-Risk Individuals aged >50 Detection of adenomatous polyps and cancer: Every 5 years (1 of the following): FSIG, DCBE, CTC or Every 10 years: CSPY Detection of cancer: Annual Stool Blood Test sDNA Test (Interval unknown) Biomarkers APC (~70%) p53 (~50%-70%) K-ras (~50%) IGF-1 and CEA MSI Stool DNA Stool DNA, tissue Stool and colonic DNA Serum Tissue, Stool and Plasma DNA Other various biomarkers in tissue: Src, SMAd4, SMAD2, DCC, hMSH2, hMLH1, hPMS1, hPHMS2, hMSH6, Ploidy Biomarkers Srivastava et al Biomarkers for Early Detection of Colon Cancer Meta-Analysis of GWAS Transferrin 77KD, β-globulin Main Function: Transport extracellular iron into cells through membrane receptormediated endocytosis More stable than hemoglobin Required for cell growth and survival Increased Tf level in serum and body fluid in several cancer types Transferrin Dipstick Disease N IFOBT Tf Tf + IFOBT + - + - + - Colorectal Cancer 40 30 (75) 10 (25) 32 (80) 8 (20) 36 (90) 4 (10) Premalignant 36 16 (44) 20 (56) 26 (72) 10 (28) 28 (78) 8 (22) Low risk 34 4 (12) 30 (88) 8 (24) 26 (76) 10 (29) 24 (71) Rao et al Transferrin Dipstick as a Potential Novel Test for Colon Cancer Screening Summary Much research has been conducted on risk factors and biomarkers for CRC Room for improvement in early detection New types of biomarkers New dipsticks/combinations with better performance to potentially increase compliance Thank You