AS206 - Genetic variation in selenoenzymes and colorectal cancer

Investigator Names and Contact Information

Ulrike Peters (upeters@fredhutch.org)

Introduction/Intent

Introduction/Intent

Colorectal cancer (CRC) is the third leading cause of cancer in US women with mortality of 50%. Identifying modifiable risk factors will be important for the prevention of this common and severe disease. Both epidemiological studies and animal studies support the beneficial effect of selenium on CRC prevention. Because selenium intake must be assessed in blood samples, most epidemiological studies are small and are therefore difficult to interpret. The effect of selenium is mediated though antioxidative properties of selenium-dependent enzymes. These selenoenzymes are abundantly expressed in the colon suggesting an important role as antioxidative defense in the colon, which is exposed to food-borne oxidants. We propose to investigate the association of a) prediagnostic selenium blood levels and b) genetic variations in selenoenzymes with CRC risk in a case-control study nested within the Women’s Health Initiative (WHI) observational study, including about 925 CRC cases and 1338 matched controls. The WHI cohort offers an excellent opportunity to study the effect of selenium and the genetic profile of selenoenzymes due to the sizable number of cases with prediagnostic blood and DNA samples and wide range of selenium intake. We will only use a small sample (0.08ml serum or plasma and 0.8μg DNA).

Currently one in every 20 women in the United States will be diagnosed with colorectal cancer (CRC) during the course of her life and one in every 40 women will die of CRC. Identifying modifiable risk factors will be important for the prevention of the severe disease. Both epidemiological and animal studies suggest that higher intake of the essential element selenium prevents CRC. Selenium intake can not be accurately measured by dietary questionnaires and must be analyzed directly in blood or toenail samples. Therefore, most epidemiological studies are small and cannot provide definitive evidence. The antioxidative properties of selenium—the prevention of oxidative damage to DNA and other important biomolecules—is thought to be a main underlying mechanism for selenium’s tumor-preventive effect. In order to act as an antioxidant, selenium needs to be incorporated into the active center of specific enzymes called selenoenzymes [i.e., glutathione peroxidases (GPXs), thioredoxin reductase 1 (TXNRD1), or selenoprotein P (SEPP1)]. The antioxidative properties of these selenoenzymes are especially important for the prevention of CRC because the colon is exposed to food-borne oxidants and selenoenzymes are abundantly expressed in the colon. In addition, activity of selenoenzymes may modulate inflammation and DNA methylation; both pathways are involved in the development of CRC. Because variations in genes related to tumor-preventive effects can alter risk of cancer, we are interested if genetic variations in selenoenzymes modify CRC risk. Our central hypothesis is that selenium intake prevents CRC through antioxidative activity of selenoenzymes and that common genetic variations in these enzymes alter the risk of CRC. In support of this research, we have recently sequenced several selenoenzymes to identify genetic variations, which will allow a complete analysis of genotypes and haplotypes for the entire region of these selenoenzyme genes.

To assess our hypothesis we propose to conduct a nested case-control study within the Women’s Health Initiative (WHI) observational study (OS) including about 925 women with CRC and 1338 randomly selected matched controls. We propose the following specific aims:

• 1: To investigate the association between selenium and CRC risk. We will analyze selenium levels in serum or plasma of women with CRC and control women.
• 2: To determine if common genetic variations in antioxidative selenoenzymes are associated with CRC risk. We will include the following six selenoenzymes that are abundantly expressed in the colon: GPX1, GPX2, GPX3, GPX4, TXNRD1, and SEPP1. Genotype and haplotype analysis will be conducted using identified tagging single nucleotide polymorphisms (tagSNPs).

As secondary aims, we will investigate:

• 1: Interactions between selenium and genetic variations in selenoenzymes. We will analyze selenium-gene interactions and gene-gene interactions in relation to CRC risk.
• 2: Interactions of selenium and selenoenzymes with the two potentially related pathways: inflammation and folate/DNA methylation. Therefore, we will collaborate with other WHI investigators who examine these complementary pathways.

Results/Findings

Some of the publications related to this ancillary study are:

Ms815 - Hutter CM, Slattery ML, Duggan DJ, Muehling J, Curtin K, Hsu L, Beresford SA, Rajkovic A, Sarto GE, Marshall JR, Hammad N, Wallace R, Makar KW, Prentice RL, Caan BJ, Potter JD, Peters U. Characterization of the association between 8q24 and colon cancer: gene-environment exploration and meta-analysis. BMC Cancer. 2010 Dec 4;10:670. doi: 10.1186/1471-2407-10-670

Ms828 - Takata Y, Kristal AR, King I, Song X, Diamond AM, Foster CB, Hutter CM, Hsu L, Duggan DJ, Langer R, Petrovich H, Shikany J, Vaughan TL, Lampe JW, Prentice RL, and Peters U. Serum selenium, selenoenzymes and risk of colorectal cancer: Primary analysis in the Women's Health Initiative and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2011 Jul 15. [Epub ahead of print]

Ms1026 - Kocarnik JD, Hutter CM, Slattery ML, Berndt SI, Hsu L, Duggan DJ, Muehling J, Caan BJ, Beresford SA, Rajkovic A, Sarto G, Marshall JR, Hammad N, Wallace RB, Makar KW, Prentice RL, Potter JD, Hayes RB, Peters U. Characterization of 9p24 risk locus and colorectal adenoma and cancer: gene-environment interaction and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2010 Oct 26. [Epub ahead of print]

For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Bibliography section of this website. To search for papers by study number, access the Simple Search, and enter the study number in the “Related Studies” field.