Body size and composition and colon cancer risk in women
Studies of colon cancer risk in males have reported strong positive associations with obesity, particularly with central adiposity. The association has been weaker and less consistent for women. In a prospective cohort study of women, body measurements were taken directly; fat mass and fat-free mass being estimated by bioelectrical impedance analysis and central adiposity by waist circumference and waist-to-hip ratio (WHR). Among 24,072 women followed on average for 10.4 years, 212 colon cancers were ascertained via the population cancer registry. We reviewed medical records of all cases and classified them according to anatomic site and stage. The central adiposity measures of WHR (hazard ratio per 0.1 unit increase = 1.31, 95% confidence interval (CI) 1.08–1.58) and waist circumference (hazard ratio per 10 cm increase = 1.14, 95% CI 1.02–1.28) were positively associated with colon cancer risk. There was little or no association between other anthropometric measures and risk of colon cancer. There was some evidence that the associations were stronger for proximal tumors, but no evidence that risk differed by stage for any of the anthropometric measures. Central adiposity appears to be associated with colon cancer risk in women. © 2005 Wiley-Liss, Inc.
Colon cancer is the second most common cancer of Australian women, the world standardised colon cancer incidence rate being 22.5 per 100,000, which is similar to estimates for North American white populations.1 Much international effort is being expended in the search for modifiable risk factors for colon cancer.2, 3 In this regard, studies of colon cancer risk in males have reported strong positive associations with obesity, particularly with central adiposity.4 The association with body mass index (BMI) is less consistent and weaker for women,5, 6, 7, 8, 9, 10, 11, 12 and 3 cohort studies of women that examined central adiposity found only weak associations.7, 8, 13 Two of these studies used self-reported measurements of waist and hip circumferences to estimate the waist-to-hip ratio (WHR),7, 8 which may be inaccurate and imprecise and result in attenuation of any true association. To our knowledge, none have reported results using direct measures of overall adipose and nonadipose mass.
It is also uncertain whether any association with elements of body size and composition might be limited to a particular tumor subsite or stage of disease. Cohort studies have reported mixed results when examining body size associations with proximal and distal colon cancer separately,5, 6, 7, 9, 14, 15 while the results were uncertain from 1 cohort study that reported associations by stage of disease.14 Effect modification by menopausal status may also explain the inconsistent findings.6
We assessed the relationship between body size and composition and incidence of colon cancer in women in a prospective cohort study by using direct anthropometric measurements. These measures included waist and hip circumferences as well as estimates of nonadipose mass and adipose mass from bioelectrical impedance analysis. We also analysed risk by tumor stage and subsite.
Material and methods
The Melbourne Collaborative Cohort Study (MCCS) is a prospective cohort study of 41,528 people (24,479 women) aged between 27 and 75 at baseline, 99.3% of whom were aged 40–69 at recruitment.16 Recruitment occurred between 1990 and 1994. The Cancer Council Victoria's Human Research Ethics Committee approved the study protocol. Southern European migrants to Australia (including 3,008 Italian women and 2,461 Greek women) were deliberately recruited to extend the range of lifestyle exposures and to increase genetic variation.
Subjects were recruited via the Electoral Rolls (registration to vote is compulsory for adults in Australia), advertisements and community announcements in local media (e.g., television, radio and newspapers). Comprehensive lists of Italian and Greek surnames were used to target southern European migrants in the phone book and Electoral Rolls.
We recruited 24,479 women, of whom 97 were excluded from analysis because they had colorectal cancer before baseline. A further 310 women were excluded because they did not have a complete set of valid measurements, leaving 24,072 women available for analysis.
Height, weight and waist and hip circumferences were measured once at baseline attendance for each participant according to written protocols that were based on standard procedures.17 Weight was measured to 100 g using digital electronic scales, height to 1 mm using a stadiometer and waist and hip circumferences were measured to 1 mm using a 2-meter metal anthropometric tape. Bioelectrical impedance analysis was performed with a single frequency (50 kHz) electric current produced by a BIA-101A RJL system analyzer (RJL systems, Detroit, MI). Resistance and reactance were measured with subjects in a supine position.
At interview, questions were asked about conventional risk factors such as reproductive history, country of birth, diet, alcohol, physical activity and highest level of education. Additionally, women were asked to report their use of hormone replacement therapy (HRT) and oral contraceptives.
Age at menopause was determined by the age at which a woman's periods had ceased naturally for at least the past 12 months (regardless of their use of HRT) or at which they had a bilateral oophorectomy (if this was the reason for cessation of periods). The remaining women who indicated having had a hysterectomy without bilateral oophorectomy were considered postmenopausal, with unknown age at menopause if their age at baseline was greater than 55 years (age at which natural menopause had occurred in 90 percent of the total cohort).
Cohort follow-up and case ascertainment
Addresses and vital status of the subjects were determined by record linkage to Electoral Rolls, Victorian death records, the National Death Index, from electronic phone books, and from responses to mailed questionnaires and newsletters. By 31 December 2003, 396 (1.6%) subjects had left Victoria and 1,069 (4.4%) had died. None of the participants whose deaths were identified through the National Death Index had colorectal cancer listed as a cause of death.
All subjects gave written consent, allowing access to their medical records to confirm diagnoses. Cases were identified from notifications to the Victorian Cancer Registry of diagnoses of adenocarcinoma of the colon (International Classification of Diseases 9th revision rubric 153.0–153.4, 153.6–153.9 or 10th revision rubric C18.0, C18.2–C18.9). We reviewed medical records of all reported colorectal tumors and classified them according to anatomic site (subsite within the colon) and stage. Tumours arising in the caecum, ascending colon, hepatic flexure and transverse colon were defined as proximal, while tumors arising in the descending and sigmoid colons were defined as distal. Stage was categorized into 4 groups based on the American Joint Committee on Cancer (AJCC) staging system: stage I (T1–2, N0, M0), stage II (T3–4, N0, M0), stage III (Tany, N1–2, M0) and stage IV (Tany, Nany, M1).
Cox's proportional hazards regression models, with age as the time axis,18 were used to estimate the hazard ratios associated with each anthropometric measure. Follow-up began at baseline and ended at diagnosis of colon cancer, rectal cancer or cancer of unknown primary site, death, the date last known to be in Victoria or 31 December 2003 (the date that ascertainment of colon cases by the Victorian Cancer Registry was complete), whichever came first.
We performed additional analyses restricted to women who were postmenopausal at baseline attendance. The temporal nature of the associations with body size and composition was assessed by estimating the hazard ratio for each anthropometric measure as a function of years since menopause, using a time-varying covariate. We compared hazard ratios in 2 time-varying strata, <20 and ≥20 years since menopause because this cut point approximately equally divided the number of colon cases into 2 groups. Women who were both less than and greater than 20 years post menopause at any time during follow-up were included in both time-varying strata. These women left the first stratum at the age in which they became 20 years post menopause and entered the second stratum at the same age.
We used bioelectrical impedance analysis to estimate nonadipose mass, hereafter termed fat-free mass (FFM), as 7.7435 + (0.4542 × height2/resistance) + (0.1190 × weight) + (0.0455 × reactance).19 Adipose mass, hereafter termed fat mass (weight – FFM), and percentage fat (fat mass divided by weight), were subsequently calculated. BMI was calculated as weight in kg divided by the square of height in meters. WHR (waist circumference divided by hip circumference) was also computed.
Anthropometric measures were fitted as continuous covariates to estimate linear trends on the log hazard scale, and as categorical variables based on approximate tertiles according to their baseline distribution in the entire study population (the cut-points used were height, 156 and 161 cm; weight, 62 and 72 kg; hips circumference, 98 and 105 cm; FFM, 38 and 41 kg; fat mass, 24 and 31 kg and percent fat, 38% and 44%), except for BMI (<25, 25–29 and ≥30 kg/m2), waist circumference (<80 cm, 80–87 cm and ≥88 cm), and WHR (<0.75, 0.75–0.79 and ≥0.80). BMI categories (healthy weight/underweight, overweight and obese) were based on WHO recommendations,20 and the waist circumference categories (the middle and highest categories are known as waist action levels 1 and 2, respectively) and the WHR ≥0.80 category were chosen according to commonly used levels of abdominal fat accumulation,4, 21, 22 while the remaining WHR categories were based upon grouping the remainder of people <0.80 into 2 approximately equal groups. The lowest category was used as the referent category.
Country of birth (Australia/United Kingdom, Greece/Italy,) and HRT use (never, former, current) were included in all models. Other potential confounders were included in all final analyses if they changed the hazard ratios of any of the anthropometric measures by at least 5%. Initially, education (primary school, some high/technical school, completed high school and completed tertiary degree/diploma), current level of physical activity (none, low, moderate and high, [see ref.23] for further details), total dietary energy intake (kJ/day), meat, fruit and vegetable (servings/day) intake, fibre from cereal products, multivitamin and fibre supplements (yes/no), smoking status (current smoker, former smoker, non-smoker), current alcohol consumption (0, 1–39, ≥40 g/day), parity, total months of lactation for all live births, age at first live birth, age at menarche and oral contraceptive pill usage (never, ever) were added. Adjustments for total dietary energy intake, meat, fruit, vegetable and fibre from cereal were made excluding those in the top 1 percent and bottom 1 percent of total dietary energy intake. Of these potential confounders, only education was retained. Finally, age at menopause was tested for women with a natural menopause or a bilateral oophorectomy in the same way, but had little effect on the hazards ratios for the anthropometric variables.
To test for heterogeneity in the hazard ratios for body size due to cancer subsite (proximal versus distal) and early (I and II) and late (III and IV) stage disease, Cox's proportional hazards regression models were fitted using a competing risks model based on a generalized Wald statistic.24 Tests based on Schoenfeld residuals and graphical methods using Kaplan-Meier curves25 showed no evidence that proportional hazard assumptions were violated for any of the anthropometric measures. Statistical analyses were performed using Stata/SE 8.2 (Stata Corporation, College Station, TX).
A total of 212 incident colon cancer cases were identified over an average of 10.4 person-years of follow-up between 1990 and 2003. The participants' demographic characteristics are shown in Table I. The mean age at diagnosis of colon cancer was 66 years (range 42–80 years). Information on stage was available for 187 (88%) cases, and of those, 38 (20%) were stage I, 63 (34%) were stage II, 55 (29%) were stage III and 31 (17%) were stage IV. A history of HRT use was reported by 25% of all women, and of these, 66% (including 24 cases) were current users and 34% (including 22 cases) were past users. About 58% of women were overweight or obese, while 46% of women were of waist action level 1 or 2.
Table I. Distribution of Demographic and Anthropometric Characteristics Among Colon Cancer Cases and Noncases
|Mean age at baseline||60 (40–69)||54 (31–72)|
|Australian and U.K. born (%)||82||78|
|Highest level of education (%)|
| Primary school||20||20|
| Some high/technical school||45||43|
| Completed high school||20||18|
| Completed tertiary degree/diploma||15||19|
|Menopausal status (%)|
|HRT use (%)|
|Anthropometric measures(mean ± standard deviation)|
| Height (cm)||159.6 ± 6.5||159.9 ± 6.7|
| Weight (kg)||68.9 ± 12.3||68.2 ± 12.4|
| BMI (kg/m2)||27.1 ± 4.9||26.7 ± 4.9|
| Waist circumference (cm)||82.8 ± 12.3||79.9 ± 11.8|
| Hip circumference (cm)||102.4 ± 10.2||101.6 ± 10.0|
| Waist-to-hip ratio||0.81 ± 0.07||0.78 ± 0.07|
| Fat-free mass (kg)||40.1 ± 4.2||40.3 ± 4.3|
| Fat mass (kg)||28.7 ± 9.4||27.9 ± 9.6|
| Percent fat (%)||40.8 ± 6.5||39.9 ± 7.0|
Table II shows the hazard ratios by tertiles and by continuous linear trend for each anthropometric variable after adjusting for age, country of birth, education level and HRT use. Women in the highest category of measures of central adiposity were at increased risk of colon cancer compared with women in the lowest category: the hazard ratios (95% CI) were 1.4 (1.0–1.9) for waist circumference and 1.7 (1.1–2.4) for WHR. Similar associations for measures of central adiposity were seen using the continuous measure. There was little or no association with risk of colon cancer for the other anthropometric measures. The positive relationship between central adiposity and the risk of colon cancer remained after further adjustment for height, in which case the corresponding hazard ratios (95% CI) became 1.14 (1.01–1.28) for waist circumference (per 10 cm increase) and 1.31 (1.09–1.58) for WHR (per 0.1 unit increase). Of the other variables in the models, country of birth and education level showed little association with risk of colon cancer (not shown), but there was a protective effect for current users of HRT compared with never users (hazard ratio 0.64 (95% CI 0.41–1.00)).
Table II. Hazards Ratios for Colon Cancer Risk in Relation to Anthropometric Measurements
|Height (per 10 cm)||1||1.2 (0.8–1.7)||1.1 (0.8–1.5)||1.17 (0.93–1.48)||0.17|
|Weight (per 10 kg)||1||0.9 (0.6–1.2)||1.1 (0.8–1.6)||1.06 (0.95–1.18)||0.29|
|Body mass index (per 5 kg/m2)4||1||0.8 (0.6–1.1)||1.0 (0.7–1.4)||1.04 (0.90–1.20)||0.59|
|Waist circumference (per 10 cm)5||1||1.4 (1.0–1.9)||1.4 (1.0–1.9)||1.14 (1.02–1.28)||0.02|
|Hip circumference (per 10 cm)||1||1.1 (0.8–1.5)||1.0 (0.7–1.4)||1.05 (0.92–1.21)||0.44|
|Waist-to-hip ratio (per 0.1 unit)6||1||1.4 (1.0–2.1)||1.7 (1.1–2.4)||1.31 (1.08–1.58)||0.005|
|Fat-free mass (per 10 kg)||1||0.8 (0.5–1.1)||1.0 (0.8–1.4)||1.07 (0.78–1.46)||0.68|
|Fat mass (per 10 kg)||1||0.8 (0.6–1.1)||1.1 (0.8–1.5)||1.09 (0.95–1.25)||0.23|
|Percent fat (per 10%)||1||0.9 (0.6–1.2)||1.2 (0.9–1.6)||1.14 (0.94–1.40)||0.19|
Results were similar when analyses were restricted to women who were postmenopausal at baseline, although the risk due to height was slightly increased. For example, the hazard ratios (95% CI) were 1.29 (0.99–1.67) for height (per 10 cm increase), 1.16 (1.02–1.32) for waist circumference (per 10 cm increase) and 1.33 (1.07–1.64) for WHR (per 0.1 unit increase). There was no evidence that risk varied by time since menopause (results not shown), with all tests for interaction having large p values (i.e., all p > 0.33).
Hazard ratios for each anthropometric measurement for the proximal and distal colon separately are presented in Table III. The association with height appeared to be confined to the proximal colon (test of homogeneity of trends, p = 0.04). All other measures except percent fat showed slightly stronger associations with proximal cancer, although the statistical evidence for heterogeneity was weak. Apart from WHR, the associations were stronger for late stage, although none of these differences in associations by stage was statistically significant (Table IV).
Table III. Hazard Ratios for Colon Cancer Risk in Relation to Anthropometric Measurements by Tumor Location1
|Height (per 10 cm)||1.50 (1.10–2.05)||0.90 (0.62–1.30)||0.04|
|Weight (per 10 kg)||1.10 (0.95–1.27)||0.94 (0.78–1.14)||0.21|
|Body mass index (per 5 kg/m2)||1.02 (0.84–1.24)||0.96 (0.75–1.23)||0.71|
|Waist circumference (per 10 cm)||1.16 (1.00–1.36)||1.02 (0.84–1.24)||0.30|
|Hip circumference (per 10 cm)||1.10 (0.92–1.31)||0.93 (0.74–1.18)||0.28|
|Waist-to-hip ratio (per 0.1 unit)||1.29 (1.00–1.67)||1.18 (0.85–1.62)||0.65|
|Fat-free mass (per 10 kg)||1.33 (0.90–1.98)||0.66 (0.38–1.16)||0.05|
|Fat mass (per 10 kg)||1.10 (0.91–1.33)||0.99 (0.78–1.25)||0.46|
|Percent fat (per 10%)||1.09 (0.83–1.43)||1.10 (0.79–1.53)||0.97|
Table IV. Hazard Ratios for Colon Cancer Risk in Relation to Anthropometric Measurements by Stage of Disease1
|Height (per 10 cm)||1.05 (0.75–1.47)||1.38 (0.97–1.98)||0.27|
|Weight (per 10 kg)||1.03 (0.87–1.20)||1.09 (0.93–1.29)||0.58|
|Body mass index (per 5 kg/m2)||1.02 (0.83–1.26)||1.04 (0.83–1.31)||0.89|
|Waist circumference (per 10 cm)||1.12 (0,95–1.33)||1.14 (0.95–1.37)||0.90|
|Hip circumference (per 10 cm)||1.01 (0.83–1.24)||1.06 (0.86–1.31)||0.77|
|Waist-to-hip ratio (per 0.1 unit)||1.35 (1.03–1.76)||1.28 (0.95–1.73)||0.79|
|Fat-free mass (per 10 kg)||1.00 (0.63–1.58)||1.13 (0.69–1.84)||0.71|
|Fat mass (per 10 kg)||1.04 (0.85–1.29)||1.14 (0.91–1.41)||0.58|
|Percent fat (per 10%)||1.11 (0.83–1.48)||1.21 (0.88–1.66)||0.70|
The following additional analyses were performed but did not materially change the hazard ratio estimates (results not shown): excluding the first 2 years of follow-up; only using women with a natural menopause; excluding women who ever used HRT and excluding women with any cancer before baseline attendance.
We found an increased risk of colon cancer with increased central adiposity. Height was also weakly related with proximal colon cancer. None of the other body size measures, including adipose and nonadipose mass measured by bioimpedance, appeared to be associated with colon cancer risk. There was no evidence that the associations with increased body size differed by tumor stage.
We had virtually complete follow-up in this prospective study, as the identification of incident colon cancers was performed by record linkage to the Victorian population cancer registry that has complete coverage of the cohort participants. Because few women have left Victoria, it is unlikely that we have missed more than 2 or 3 cases. Surveillance bias was unlikely, as during this period there was no organized screening program for colorectal cancer.
Our study used measures of body size made by direct physical examination according to standard protocols. Issues concerning the measurement of FFM and fat mass have been addressed previously.23, 26 Briefly, we chose a formula that had been developed using subjects of similar ethnicity, age and BMI distribution to our own.19 As the algorithm to compute FFM and fat mass includes height, weight, resistance and reactance, in theory, any measurement errors in these would have reduced the precision of FFM and fat mass estimates. In practice, however, these measurement errors are generally small, and so, the consequences for precision are likely to have been minimal. On the other hand, the associations would have been attenuated if the baseline measures were not representative of the participant's body size during the etiologically relevant period. Although it is possible that reproductive factors, dietary factors and current alcohol consumption could have confounded these relationships, the hazard ratios did not differ by more than 5% after adjustment for our measures of these factors. Similarly, physical activity did not appear to confound the association, but our measurement of activity was imprecise. Family history of colorectal cancer was not collected at baseline attendance, and thus, we could not assess its possible impact. Analyses restricted to premenopausal women were not performed because, apart from the small number of cases (15% of total cases), we had no data on their menopausal status at the time of their cancer diagnosis.
Other cohort studies have also found a positive relationship between height and risk of colon cancer.8, 14, 15 Although we found a stronger association for the proximal colon, others found little difference between subsites.14, 15 Height may be a reflection of nutrition during childhood and adolescence and the action of growth factors, including androgens and insulin-like growth factors (IGF). One study has shown that patients with acromegaly were at greater risk of developing colorectal cancer than those without, particularly those patients with high IGF-1 levels.27 Others have speculated that height may reflect the number of cells at risk of carcinogenesis,28 though whether colon length is correlated with height is unclear.29, 30
Cohort studies, including our own, have generally found stronger associations between BMI and colon cancer for males than for females.4, 5, 6, 7, 8, 9, 10, 11, 12, 23 Some, including the current study, have found no association with BMI and colon cancer for women,5, 6, 12 though others found a positive association.7, 8, 9, 10, 11, 13 We also found that fat mass, which is a more sensitive measure of adipose tissue than BMI, was not associated with colon cancer. Conversely, we found a greater risk of colon cancer for increased WHR than was reported from 2 cohort studies that relied upon self-reported measures.7, 8 Our results for waist circumference, however, were similar to those of another cohort study that used direct measures from physical examinations.13
A decade ago, it was hypothesized that insulin resistance and its consequent hyperinsulinaemia underlie the association between colon cancer incidence and risk factors such as obesity.31, 32 Central adiposity, and in particular, visceral adiposity increases insulin level.11, 33 Animal and in vitro experiments suggest a role for insulin in tumor development and growth (reviewed in4, 33, 34). In cohort studies, C-peptide, which is secreted in equimolar amounts with insulin, has been positively associated with risk of colon cancer,35, 36 although evidence from cohort studies that insulin itself is related to colon cancer risk is inconclusive.37, 38 The clearer association with C-peptide may be due to less measurement error because of its longer half-life. The effect of insulin may be mediated through the insulin-like growth factor (IGF) axis. Insulin lowers levels of IGF binding protein 1,39 thereby increasing the bioactivity of IGF-1. As for insulin, there is experimental evidence for a role of IGF-1 in carcinogenesis,33, 34 but limited evidence from cohort studies of a relationship with risk of colorectal cancer.40
There are a number of other possible mechanisms whereby obesity may be associated with an increased incidence of colon cancer. High levels of physical activity have consistently been shown to reduce the risk of colon cancer4 and may be linked to the mechanism whereby obesity predisposes to colon cancer. Leptin, which has been shown to be associated with colon cancer (at least in men), may be another possible link between obesity and colon cancer,41 and has been shown to stimulate the growth of colonic epithelial cells.42
Like others, we also found that the association between central adiposity and colon cancer was weaker in women than in men; the hazard ratio for a 10 cm increase in waist circumference in men being 1.37 (1.18–1.60).23 The use of exogenous hormones reduces risk of colon cancer in postmenopausal women43 and it is possible that the production of estrogens in adipose tissue of obese postmenopausal women may at least partially offset its potentially harmful effects.
In conclusion, our prospective study has found evidence that central adiposity is positively associated with the risk of colon cancer in women. This raises the possibility that women could reduce their risk of colon cancer by maintaining ideal body weight throughout adult life.
This study was made possible by the contribution of many people, including the original investigators and the diligent team who recruited the participants and who continue working on follow up. We would also like to express our gratitude to the many thousands of Melbourne residents who continue to participate in the study.
Cohort recruitment was funded by VicHealth and The Cancer Council Victoria.