The results from this large prospective cohort study indicate that the association between obesity and risk of CRC varies by gender, cancer site and tumour aggressiveness. All anthropometric factors except bodyfat percentage were significantly associated with an increased risk of CRC in general, which corresponds well to previous findings [3, 4, 6, 12, 13, 15, 18, 19, 32]. When studying men and women separately, we found an increased risk of CRC for all anthropometric variables, except for height, in men, which is also consistent with previous results [4–6, 12, 15, 16]. However, the finding of a stronger association of obesity and risk of being diagnosed with clinically more advanced CRC in men has, to our knowledge, not been demonstrated before. We also found an overall increased risk of CRC with obesity defined as weight, BMI and WHR in women, which has only been shown in a few previous studies [4, 10, 15, 18, 20].
To our knowledge, only two previous studies [13, 18] have examined the associations between anthropometric factors and risk of CRC according to tumour aggressiveness, as reflected in TNM-classification of the disease. These two studies examined the association between anthropometry and risk of colon cancer according to late (Stage III and IV) vs early (Stage I and II) stage colon cancer in men and women, respectively, and neither found any statistically significant associations.
We have thus been able to demonstrate an increased risk of more advanced tumours with increased anthropometric measures, particularly in men, among whom several anthropometric variables were significantly associated with risk of a more advanced T-stage, N2 disease, and both M0 and M1-tumours. In women, several anthropometric variables were associated with an increased risk of more advanced T-stage, but not node-positive disease. Furthermore, increased anthropometric measures were only associated with non-metastatic (M0) disease in women. Taken together, these findings suggest that overweight persons have an increased risk of developing more advanced colorectal cancer forms, but that this risk may differ according to gender.
Moreover, our findings provide further evidence of gender-related differences in tumour susceptibility of cancer in the colon and rectum, respectively, as we found a positive association between obesity and risk of developing colon cancer in men and rectal cancer in women. This has to our knowledge not been shown previously, since only a few studies have examined risk of colon and rectal cancer separately. However, two previous studies [4, 14] have shown a positive relationship between BMI, overweight and rectal cancer risk in men, which is in contrast to our findings. Moreover, subgroup analysis related to risk of more advanced disease in colon and rectal cancer, respectively, also revealed a more pronounced association between anthropometric factors and risk of advanced disease in men.
Body weight or BMI have been the most commonly used anthropometric measurements to examine the associations of obesity and colorectal cancer risk in previous studies, the majority of which have shown a positive relationship between BMI and risk of CRC in men, but week or no associations in women [3–16]. However, these measurements may not be ideal because of the changes in physiologic functions that to a certain extent depend on regional adipose tissue distribution . Some prospective studies have examined the association of body fat distribution, reflected as waist- and hip circumference, and colorectal cancer risk [6, 8, 12, 13, 18–22], but available epidemiologic evidence suggests that abdominal obesity (high waist circumference and waist-hip-ratio) may be more predictive of colorectal cancer risk than overall obesity [6, 8, 12, 13, 18]. Increased bodyweight has been suggested to be more closely related to abdominal obesity in men, and to gluteofemoral obesity in women .
The exact biologic mechanisms underlying the association between obesity and increased risk of CRC are not fully understood. Some authors have suggested components of the metabolic syndrome, in particular insulin-resistance and subsequent hyperinsulinemia, to be the underlying link, which may reflect the growth-promoting effects of insulin [32, 34]. These speculations are also supported by studies that found an increased risk of CRC in patients with Type 2 diabetes [35–37], as hyperinsulinemia is also related to increased levels of insulin-like growth factor 1, which is known to have cancer promoting effects [38–40]. Further potential mediators include leptin, elevated serum levels of which have been demonstrated to stimulate growth of colonic epithelial cells [41–43], and adinopectin, that is secreted from visceral adipose tissue, correlates inversely to BMI, and has been demonstrated to have antiangionenic and antitumour activities [44, 45]. Obesity, in particular abdominal obesity, is linked to insulin-resistance, hyperinsulinemia and Type 2 diabetes .
Several epidemiological studies have shown that elevated levels of estrogen and progesterone is associated with lower risk of developing CRC [47–49]. Recent studies found no reduced risk of CRC in women with higher levels of estradiol and estrone, suggesting that progesterone is the key factor for reduction of CRC risk in women [50–52]. Use of hormone replacement therapy (HRT) in post-menopausal women could in part explain sex-related differences in the association between adiposity and CRC risk, as BMI is positively associated with circulating levels of estradiol in postmenopausal women and HRT has been associated with a reduced risk of CRC in observational and interventional studies [53–56]. The associations between sex hormones and risk of CRC in men is poorly understood, but two studies have supported the hypothesis that lower androgenecity may increase men’s risk of developing CRC [57, 58]. Lower androgen levels seem to be more frequent in obese men, and treatment with testosterone reduces insulin resistance, suggesting a role of androgens in promoting insuline sensitivity and hereby one possible mechanism in the development of CRC.
In agreement with most previous reports, we found a stronger association between body size and risk of colon compared to rectal cancer in general, in particular in men . In line with these findings, a meta-analysis showed that physical activity, which is related to improved insulin sensitivity [59, 60], was associated with a reduced risk of colon cancer, but not of rectal cancer . This may suggest that insulin resistance, hyperinsulinemia and other factors related to obesity are stronger risk factors for colon than rectal cancer. Several prospective studies reported that circulating C-peptide [39, 42, 62, 63] and leptin [42, 43] concentrations were more strongly associated with risk of colon cancer than overall colorectal cancer or rectal cancer. Our findings of a significant association between high weight, bodyfat percentage, hip and waist, and an increased risk of rectal cancer in women but not men are in contrast to most previous studies, including a large meta-analysis demonstrating a statistically significant association between obesity and an increased risk of rectal cancer in men . While these findings indeed suggest differences in tumour susceptibility related to location, the potential mechanisms accounting for these differences need further investigation.
A limitation to the present study is the relatively small number of cases in some subgroups, i.e. it is possible that some of the non-significant findings in relation to gender or tumour stages may have been caused by a potential type II error. Therefore, these data need to be validated in larger patient cohorts. It should also be pointed out that since mean age at diagnosis was >70 years for women , interpretations relying on sex as evidence for influence of sex hormones must be made with caution until further knowledge has been gained. To this end, future studies are warranted to explore the effects of e.g. hormone replacement therapy on clinicopathological factors, molecular correlates and survival from CRC.
Certain methodological aspects need further attention. The validity of the anthropometric measurements is one aspect as there may be a potential inter-observer variation. Recommendations for the nurses performing baseline examinations described how participants should be dressed, in which position the participants should be examined, and location for the estimation of waist- and hip measurements. We therefore consider the risk of misclassification of anthropometric measurements to be low. In contrast, most previous studies have used self-reported anthropometric measures.
It is also possible that participation in the MDCS was associated with body constitution, which may have lead to potential selection bias. In a previous paper, Manjer et al  compared BMI in the MDCS in relation to the background population, and found an equal distribution of overweight/obesity.
Another aspect is the validity of collected data. As anthropometric data was assessed only at baseline, it is possible that some individuals have gained and some have lost weight. Such a misclassification is likely to lead to an attenuation of risks and, if anything, observed risks may be underestimated.
In addition, it might be difficult to apply incidence rates from the MDCS to the background population as participants may to some degree have been selected in terms of socio-economic factors and risk of CRC. Nevertheless, we consider it possible to make internal comparisons comparing subjects with high versus low levels of the study measurements in order to obtain relative risks.