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Cancer from Nutrigenomics point of veiw M. H Javanbakht MD, PhD Department of cellular & molecular nutrition, Faculty of Nutritional Sciences & Dietetics, TUMS.

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Nutrition-Gene Interaction 1. Direct interactions Nutrients, sometimes after interacting with a receptor, behave as transcription factors that can bind to DNA and acutely induce gene expression 2. Epigenetic interactions Nutrients can alter the structure of DNA so that gene expression is chronically altered 3. Genetic variation Common genetic variations such as single-nucleotide polymorphisms (SNPs) can alter the expression or functionality of genes 3

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Transcription-factor pathways mediating nutrient-gene interaction 4

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5 Nutritional Genomics

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Nutrigenomics vs. Nutrigenetics Nutrigenomics Nutrigenomics refers to the application of genomics in nutrition research, enabling associations to be made between specific nutrients and genetic factors, e.g. the way in which food or food ingredients influence gene. Chadwick R. (2004) Proceedings of the Nutrition Society 63:161-166. Nutrigenetics Nutrigenetics is the study of individual differences at the genetic level influencing response to diet. These individual differences may be at the level of single nucleotide polymorphisms rather than at the gene. Chadwick R. (2004) Proceedings of the Nutrition Society 63:161-166. 6

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Nutrigenomics Nutrigenomics attempts to study the genome-wide influences of nutrition[and] aims to identify the genes that influence the risk of diet- related diseases on a genome-wide scale, and to understand the mechanisms that underlie these genetic predispositions. Muller M & Kersten S. (2003) Nature Reviews Genetics 4:315-322. Nutrigenetics Nutrigenetics examines the effect of genetic variation on the interaction between diet and disease or on nutrient requirements. Genetics has a pivotal role in determining an individuals risk of developing a certain disease. Muller M & Kersten S. (2003) Nature Reviews Genetics 4:315- 322. 7

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Nutrigenomics Nutrigenomics describes the use of functional genomic tools to probe a biological system following a nutritional stimulus that will permit an increased understanding of how nutritional molecules affect metabolic pathways and homeostatic control. Mutch D, et al. (2005) FASEB Journal 19:1602- 1616. Nutrigenomics focuses on the effect of nutrients on the genome, proteome, and metabolome. Ordovas J & Mooser M. (2004) Current Opinion in Lipidology 15:101- 108. Nutrigenetics Nutrigenetics embodies the science of identifying and characterizing gene variants associated with differential responses to nutrients, and relating this variation to disease states. Mutch D, et al. (2005) FASEB Journal 19:1602-1616. Nutrigenetics examines the effect of genetic variation on the interaction between diet and exercise. This includesgene variants associated with, or responsible for, differential responses to nutrients. Ordovas J & Mooser M. (2004) Current Opinion in Lipidology 15:101-108. 8

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Nutrigenomics & Nutrigenetics: Two Sides of a Coin Mutch D, et al. (2005) FASEB Journal 19:1602-1616.

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Vitamin D 11

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System and Tissue Distribution of Nuclear Vitamin D Receptors (VDR) System Tissue Immune Thymus, bone marrow, macrophages, B cells, T cells Gastrointestinal Esophagus, stomach, small intestine, colon, rectum Cardiovascular Endothelial cells, smooth muscle cells, myocytes Respiratory Lung alveolar cells Hepatic Liver parenchyma cells Renal Proximal and distal tubules, collecting duct Endocrine Parathyroid, thyroid, pancreatic beta cells Exocrine Parotid gland, sebaceous gland CNS Brain neurons, astrocytes, microglia Epidermis/appendage Skin, breast, hair follicles Musculoskeletal Osteoblasts, osteocytes, chondrocytes, striated muscle Connective Tissue Fibroblasts, stroma Reproductive Testis, ovary, placenta, uterus, endometrium, yolk sac

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Vitamin D Deficiency Rickets, Osteomalacia Influenza, Tuberculosis MS, RA, SLE, Type I diabetes Hypertension, CAD, PVD, CHF Syndrome X, Type 2 Diabetes Chronic Fatigue, SAD, Depression Cataracts, Infertility Osteoporosis Cancer

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Endocrine, paracrine and intracrine functions of Vitamin D 15

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Deeb et al (2007) Nature Reviews Cancer 7, 684-700 16 24-Ohase (CYP24A1) 1 -OHase 25-OHase

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Vitamin D and Cancer May influence both incidence and mortality Linked with GI cancer, prostate and breast cancers, lymphomas, endometrial and lung cancers 17

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Something New Under the Sun? Apperly FL. The relation of solar radiation to cancer mortality in North America. Cancer Research.1941(1):191-195 18

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Northern vs. Southern U.S. 19 1 2 extra skin cancer deaths (per 100,000) 30 40 extra deaths for other major cancers (per 100,000)

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1979 - 1981 Vitamin D receptors found in malignant melanoma cells and myeloid leukemia cells 1,25(OH) 2 D inhibited melanoma cell proliferation and induced myeloid cell differentiation 22

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1998 Serum levels of 1,25(OH) 2 D are tightly controlled by the kidneys & dont vary by sun exposure so how could vitamin D contribute to the north-south gradients and African-American excess in cancer rates? Non-renal cells discovered to hydroxylate 25(OH)D and synthesize 1,25(OH) 2 D locally. 23

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19 Vitamin D-Sensitive Cancers (from several ecological and observational studies) Vitamin D-sensitive cancers with moderate-to-strong support after accounting for other factors: Gastrointestinal: colon, esophageal, gallbladder, gastric, pancreatic, rectal Urinary: bladder, kidney; Male: prostate Female: breast, cervical, endometrial, ovarian, vulvar Blood: Hodgkins and non-Hodgkins lymphoma, leukemia Miscellaneous: melanoma

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Vitamin D & Cancer Environmental: sunlight & diet Calcitriol (hormonal form of vitamin D) controls the differentiation of many cells that possess vitamin D receptors (VDR) Induce cell differentiation and apoptosis of cancer cells while inhibiting cell proliferation, angiogenesis, and metastasis Genetic: VDR polymorphisms 25

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Vitamin D Implications in Cancer 26 Breast Prostate/Ovarian ColonPancreas Lung

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0.11.010.0 0.50.2 2.05.0 Garland 1989 Bostick 1993 Kearney 1996 Martinez 1996 Pritchard 1996 Marcus 1998 Pietinen 1999 Jarvinen 2001 McCollough 2003 All Dietary Vitamin D and Colorectal Cancer 27 Gorham E., et al. J Steroid Biochem Mol Biol. 97:179-94, 2005 Odds ratio

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June, 2007 American Journal of Clinical Nutrition Women who regularly took vitamin D3 and calcium had a 60% reduction in all-cancer incidence compared with a group taking placebo and a 77% reduction when the analysis was confined to cancers diagnosed after the first 12 months. 28

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Lung cancer 1,25(OH) 2 D: Inhibits proliferation and induces differentiation of lung cancer cell lines (Higashimoto, et al., 1996, Guzey, et al., 1998) Inhibits metastatic growth and locoregional recurrence of lung cancer cells in mice (Wiers, et al., 2000) 29

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Lung cancer 456 patients with early stage NSCLC Median age 69 96% Caucasian Data collection: Season of surgery Food frequency questionnaire Recurrence free survival (RFS) Overall survival (OS) Zhou, et al., 2005 30

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Lung cancer Patients who had surgery during summer with the highest vitamin D intake had better RFS than patients who had surgery during winter with the lowest vitamin D intake. Similar associations were seen for overall survival. Zhou, et al., 2005 31

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Breast cancer 1,25(OH) 2 D: inhibits cell proliferation, induces differentiation & apoptosis, and inhibits angiogenesis in normal and breast cancer cells (Colston, et al, 1989, Saez, et al, 1993, Mantell, et al., 2000) suppresses high-fat diet-induced mammary tumorigenesis in rats (Jacobson, et al., 1989, Xue, 1999) 32

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Breast cancer Inverse association between vitamin D & calcium intake and breast density Inconclusive results in studies looking at VDR genetic polymorphisms and breast cancer Inverse association between high sunlight exposure and breast cancer risk Association may be stronger for premenopausal than postmenopausal women due to interactions between vitamin D, the VDR, estrogen and insulin- like growth factor-I (IGF-I) Cui & Rohan, 2006 33

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Breast cancer Case-control study 972 women with newly- diagnosed breast cancer & 1,135 healthy controls Interviews regarding vitamin D-related exposures, e.g. outdoor activities, use of sunscreen, dietary contributions Knight, 2007 34

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Breast cancer More frequent sun exposure during adolescence was associated with a 35% reduction in breast cancer risk later in life Lower risk also linked to cod liver oil and milk intake > 10 glasses / week Milder protection seen for people age 20 29 No protection for people over age 45 35

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Breast cancer Epidemiologic study of different regions of Norway, each with a different annual UV exposure Prognosis 15 25% better for women diagnosed / treated in the summer vs. winter Knight, 2007 36

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Endometrial cancer Is ultraviolet B irradiance inversely associated with incidence rates of endometrial cancer: an ecological study of 107 countries. Mohr, et al, 2007 37

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Endometrial cancer Objective: perform an ecological analysis of the relationship between low levels of ultraviolet B irradiance and age-standardized incidence rates of endometrial cancer by country, controlling for known confounders 38

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Endometrial cancer 107 countries: UVB irradiance cloud cover intake of energy from animal sources proportion overweight skin pigmentation cigarette consumption health expenditure total fertility rates vs. age-standardized incidence of endometrial cancer 39

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Endometrial cancer Association found between endometrial cancer incidence rates and: Low UVB irradiance High intake of energy from animal sources ( IGF-I?) Per capital health expenditure Proportion of population overweight 40

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Pancreatic cancer Prospectively collected diet and lifestyle data Nurses Health Study 75,427 women Health Professionals Follow-up Study 46,771 men Pancreatic cancer risk 41% lower among those who consumed > 600 IU of vitamin D / day vs. those who consumed < 150 IU / day Skinner, et al., 2006 41

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Cancer Survival Summer / Fall (vs. Winter / Spring) diagnosis associated with improved survival in: Colorectal cancer Hodgkins lymphoma NSCLC Breast cancer 42

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Cancer Survival Intermittent sun exposure associated with increased survival following a diagnosis of melanoma. Berwick, et al., 2005 43

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Vitamin D Overview It is a fat soluble vitamin. Not just a vitamin it is a prehormone Found in some food and made in the body after exposure to UV rays Major biological function is to maintain normal blood levels of Ca and Po4 Other tissues like macrophages, prostrate tissue also have vit D receptor 44

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History of Vitamin D Existed over 500 million years Industrial revolution : rickets Cod liver oil: common folklore medicine Discovery of Vit D as the antirachitic factor in cod liver oil(1920) Discovery of conversion of 7-dehydrocholesterol in the skin to vit D (1937) Antirachitic property in food Fortification of food with vitamin D was patented Complete eradication of rickets in US US public service issuing warnings about sun-induced health risk Over next 30 yrs skin cancer hazard of excessive sun exposure became well established 45

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Food Sources of Vitamin D Cod liver oil 1 TBS Salmon 3.5 oz. Mackerel 3.5 oz. Tuna, canned, in oil, 3 oz. Sardines 3.5 oz. Milk (fortified) 8 oz. Ready to eat cereal (fortified) - 1 cup Egg 1 whole Liver, 3.5 oz. Cheese, swiss 1 oz. 1,360 IU 360 345 200 250 98 40 20 15 12 46

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Annual Number of Vitamin D Publications Listed at Pubmed

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48 Infants

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49 Children

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50 Adolescents

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51 Adults

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52 Pregnant & lactating women

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Treatment with Sunshine

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Thanks 54