AS108 - Gene-environment Effects and Colorectal Cancer

This page provides study documentation for AS 108. For description of the specimen results, see Specimen Results Description (open to public). Data sets of the specimen results are included in the existing WHI datasets located on the WHI Data on this site (sign in and a completed Data Distribution Agreement are required; see details on the Data site).

Investigator Names and Contact Information

Henry J. Lin, MD, Harbor-UCLA, hlin@labiomed.org

Introduction/Intent

Epidemiologic studies have consistently shown an inverse association between cruciferous vegetables and colon cancer (Graham et al. 1978; Kune et al. 1987; Young and Wolf 1988; Lee et al. 1989; Benito et al. 1990; Witte et al. 1996; Steinmetz and Potter 1991).  Our goal is to clarify biochemical mechanisms for the observed effect.

Cruciferous vegetables, such as broccoli, contain isothiocyanate compounds, which induce carcinogen-detoxifying enzymes and inhibit carcinogen-activating enzymes (Mahéo et al. 1997).  Glutathione transferase enzymes M1, P1, and T1 conjugate isothiocyanates, leading to removal of the compounds from the body (Kolm et al. 1995; Zhang et al. 1995; Seow et al. 1998; Shapiro et al. 1998).  Roughly 50% of people (depending on ethnic group) completely lack GSTM1, and some 25% lack GSTT1, due to gene deletions.

Recent work tends to support the hypothesis, but more data are needed. Case-control analyses will use the Women’s Health Initiative cohort (800 cases) and a sigmoidoscopy-based case-control study of adenomas (850 cases). The pharmacokinetic study will use a well-characterized broccoli preparation as the source of isothiocyanates. The mouse study will used commercially-available sulforaphane. Results may improve understanding of how isothiocyanates and cruciferous vegetables prevent cancer and suggest chemoprevention approaches.

We hypothesize that isothiocyanate intake (i.e., broccoli) combined with GSTM1 and/or GSTT1 null genotypes may be associated with a lower prevalence of colorectal adenomas or cancer, due to slower elimination of protective isothiocyanates.  Specific aims are to:      

1.  Conduct case-control analyses on colorectal cancer and colorectal adenomas in relation to broccoli intake and GSTM1 and GSTT1 null genotypes.  We will use subjects and data from:

·          the Women’s Health Initiative observational study (at least 800 colorectal cancer cases) and

·          The USC/Kaiser sigmoidoscopy-based case-control study of adenomas (850 cases).

2.  Assess isothiocyanate pharmacokinetics in relation to GSTM1 and GSTT1 genotypes in healthy human subjects.  We will use a well-characterized preparation of broccoli as the source of isothiocyanates.  

3.  Analyze effects of dietary isothiocyanates in mouse mutants prone to intestinal neoplasms.

4.  Analyze effects of prostaglandin D synthase (H-PGDS) on risk for colorectal neoplasia.

Results/Findings

Ms507 - Tippin BL, Levine AJ, Materi AM, Song WL, Keku TO, Goodman JE, Sansbury LB, Das S, Dai A, Kwong AM, Lin AM, Lin JM, Park JM, Patterson RE, Chlebowski RT, Garavito RM, Inoue T, Cho W, Lawson JA, Kapoor S, Kolonel LN, Le Marchand L, Haile RW, Sandler RS, Lin HJ. Hematopoietic prostaglandin D synthase (HPGDS): a high stability, Val187Ile isoenzyme common among African Americans and its relationship to risk for colorectal cancer. Prostaglandins Other Lipid Mediat. 2012 Jan;97(1-2):22-8. doi: 10.1016/j.prostaglandins.2011.07.006. Epub 2011 Jul 28

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.