Excess body weight, exogenous hormones, and polymorphisms in steroid metabolism: Links with hereditary colorectal cancer

Consistent with the theme of hormonal influence on colorectal cancer, the second objective in this thesis sought to identify the associations between risk of incident colorectal cancer and exogenous hormone-use (hormonal contraceptives and postmenopausal hormone-use). As above, a case-control study design was implemented. Hormonal contraceptives (OR: 0.79) and postmenopausal hormones (OR: 0.67) were inversely linked with colorectal cancer risk. The reduced risks were quite consistent across subgroups of familial risk of cancer and microsatellite instability status. A potential age effect was indicated for age at first use of hormonal contraceptives; women who began using these agents prior to age 22 years experienced a greater reduced risk of colorectal cancer (OR: 0.6) than did women who initiated use at age>30 y (OR: 0.92). The objective of this thesis was to examine the influence of hormonal factors on the risk of colorectal cancer from three perspectives. First, adiposity, height, and weight gain (e.g. indicators of endogenous hormone exposure) were assessed as risk factors for incident colorectal cancer in a population based case-control study from Ontario and Newfoundland. Self-reported family history of cancer and information on lifestyle and demographic factors were collected; data were used from 2,696 cases and 2,668 controls. Colorectal cancer was positively linked with obesity (ORs: 1.75 and 1.82; recent and past BMI, respectively) and weight gain since age 20 years (OR: 1.59) in men; the observed risks were consistent in subgroups of familial risk of cancer and tumour microsate1lite instability status. Among women, no associations were observed between adiposity or weight gain and colorectal cancer risk. The null associations persisted in premenopausal and postmenopausal women, and across strata of familial risk of cancer and microsatellite instability. Height, however, was positively linked with disease risk in women (OR: 2.36). That obesity was associated with increased risk in men, but not in women, may be explained by androgen conversion to estradiol in the adipocyte, as several lines of evidence suggest that estrogen-related hormones are inversely linked with colorectal cancer risk. These data provide support for a hormonal influence on colorectal tumourigenesis. From a clinical and public health perspective, these findings suggest that men who are overweight or obese and who report a familial risk of cancer may represent a key group for interventions aimed at the prevention and control of colorectal cancer. The third objective of this work was motivated by evidence that common variation in certain genes correlates with hormone levels. Since genotype is constant, genotypic variation may act as a proxy measure for lifetime exposure to steroid hormones. A candidate gene approach was selected to address whether or not common variants in genes involved in steroid production (CYP17) and estrogen metabolism (COMT) were linked with age at onset of colon cancer among a cohort of confirmed Lynch syndrome mutation carriers in Newfoundland and Labrador (n = 153). This cohort experiences a dramatic predilection to colon and certain extracolonic cancers. The variant allele in CYP17 was linked with earlier age at colon cancer onset and overall increased risk of colon cancer (HR: 3.83). The COMT variant was not related to the outcomes in this thesis.

Keywords: Colon (Anatomy), Cancer
Rectum, Cancer
Cancer, Endocrine aspects
Overweight persons, Health risk assessment