1. Biomarkers in the detection of Colon and Rectal Cancer Gina Wallar, MPH

2. Colorectal CRC  2009 Stats (US)  Risk Factors  Biomarkers  Current Screening Guidelines  Transferrin

3. Colorectal Cancer (CRC) Picture in the U.S.  3 rd most common cancer in men and women  2 nd major cancer killer  Detectable  Treatable  Screening- Compliance a major factor

4. 2009 CRC Statistics  106,100 cases of colon cancer expected  40,870 cases of rectal cancer expected Accounts for 9% of all cancer deaths Accounts for 9% of all cancer deaths 5-year survival rate for Stage I is 90% 5-year survival rate for Stage I is 90% 5-year survival rate for Stage IV is 11% 5-year survival rate for Stage IV is 11%  Less than half of colon cancer cases are detected when the cancer is localized

5. Colon Cancer-Risk Factors  Family History/Genetics  Age  History of colon cancer, polyps, bowel disease  Race/Ethnicity  Alcohol  Smoking  Diet  Sedentary Lifestyle  Obesity  Diabetes

6. Smoking (Incidence versus Mortality)

7. Alcohol and Colon Cancer

8. Alcohol and Rectal Cancer

9. 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

10. Red Meat Consumption

11. Geelen, A. et al. Am. J. Epidemiol. 2007 0:kwm197v1-197; doi:10.1093/aje/kwm197 CRC and Fish Consumption

12. Green Tea

13. 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

14. Obesity and Colon Cancer

15. Obesity and Rectal Cancer

16. 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

17. 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?

18. Mechanism Adipose tissue Testosterone Ovary Adrenal Secretion Androstenedione Age, Obesity Aromatase Cholesterol pathway Estradiol Testis Pituitary LH/FSH Hypothalamus/GnRH LiverSHBG hi SHBG Estrogens Hyperthyroidism Anorexia Pregnancy lo SHBG Androgens Glucocorticoids Hypothyroidism Obesity Insulin/IGF-1 PCOS Diabetes Free T + Bound T Free E + Bound E Androgens Estrogens

19. 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

20. 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

21. Diabetes and Colon Cancer

22. Mechanism Adiposity Varying levels of Adipocytokines Insulin Resistance Insulin Increases IGF-1 Increases Activates IGFR Activates IR Cell Proliferation Increases Apoptosis Decreases Tumor Development

23. 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

24. 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), Double- Contrast Barium Enema (DCBE), and Computed Tomographic Colongraphy (CTC))

25. 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)

26. 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

27. Biomarkers Srivastava et al Biomarkers for Early Detection of Colon Cancer

28. Meta-Analysis of GWAS

29. Transferrin  77KD, β-globulin  Main Function: Transport extracellular iron into cells through membrane receptor- mediated endocytosis  More stable than hemoglobin  Required for cell growth and survival  Increased Tf level in serum and body fluid in several cancer types

30. Transferrin Dipstick DiseaseNIFOBTTf Tf + IFOBT +-+-+- Colorectal Cancer 4030(75)10(25)32(80)8(20)36(90)4(10) Premalignant3616(44)20(56)26(72)10(28)28(78)8(22) Low risk 344(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

31. 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

32. Thank You