Rebecca A. Barnetson and Malcolm G. Dunlop
Colon Cancer Genetics Group, University of Edinburgh, School of Molecular and Clinical Medicine and MRC Human Genetics Unit, Western General Hospital, Edinburgh, U.K.
The classic studies of Japanese migrants to the United States conducted in the 1960s revealed the overwhelming importance of environmental factors in colorectal cancer etiology (39) and the discussion below relates primarily to such factors. The evidence is summarized in Table 1.
More than 40 case–control or cohort studies of physical activity and the risk of colorectal cancers have been carried out (40). These provide consistent evidence that physical activity is associated with a reduced risk of colon cancer, with relative risks for the highest category of activity compared with the lowest in the range 0.4 to 0.9 (41). The relationship has been observed in women as well as men, in various ethnic groups, and in diverse geographical areas.
The association has been consistent in studies with widely different methods of assessing physical activity exposure, and persists after adjustment for other lifestyle factors. The data suggest that any activity is better than none (41) and that risk decreases in a dose–response fashion with increasing levels of activity (40). The volume of evidence specifically relating to cancer of the rectum is less substantial and suggests either a weak inverse association with higher levels of physical activity, or no association. The risk of adenomas is reduced among those reporting higher activity levels (42), and there is some suggestion that the relation may be stronger for adenomas with advanced features than for nonadvanced adenomas (43).
Body Mass Index
Excess weight raises the risk of developing colon cancer, with an increase of 15% in risk for an overweight person and 33% for an obese person (44).
- Colorectal Cancer definition
- Risk Factors
- Colorectal cancer Risk Factors
- General Considerations
- Incidence and Location
- Variations in Incidence Within Countries
- Anatomy and Pathogenesis
- Diagnosis and Screening
- Clinical Findings
- Differential Diagnosis
- Screening for Colorectal Neoplasms
- Classification Systems
- Colorectal Neoplasms Treatment
- Follow-Up after Surgery
- Risk factors for colorectal Neoplasia
Tobacco smoking has consistently been found to be associated with an increased risk for adenomas and hyperplastic polyps (30,47–49). In the earlier studies of smoking and cancer, which mainly covered the 1950s and 1960s, there was no association between smoking and colorectal cancer, even among heavy smokers. In more recent studies, long-term smokers have been found to be at an elevated risk, with relative risks typically in the range of 1.5 to 3.0, following an induction period of 35 to 40 years (50). However, a recent review by the International Agency for Research on Cancer (IARC) concluded that it is possible that this association could be due to inadequate control of confounding (51).
The aromatic amines, polycyclic aromatic hydrocarbons, and N-nitrosamines present in tobacco smoke are metabolized by a complex series of phase I and phase II activation and detoxification reactions. There is considerable interindividual variation in tobacco metabolism, and many of the genes controlling the production of the phase I and phase II enzymes are polymorphic. Several of these genes have been investigated in relation to colorectal neoplasia, with the most extensive evidence relating to the glutathionine-S-transferase genes GSTM1 and GSTT1, the cytochrome P450 1A1 gene CYP1A1, and the N-acteyltransferase genes NAT1 and NAT2.
As regards GSTM1 and GSTT1, combined analysis of studies suggests that there is no association between the GSTM1 genotype alone and colorectal cancer (52–54), but that there may be a positive association with homozygosity for the GSTT1 deletion variant (52). However, for both polymorphisms, there is heterogeneity between studies, which is likely to be due in part to methodological differences (55), and in part to publication bias (56,57). On the basis of current evidence, it seems unlikely that either the GSTM1 or GSTT1 genotype strongly modifies the association between smoking and colorectal neoplasia (53,58–61), but most of the available studies have been hampered by a lack of statistical power to detect interactions. Studies of the CYP1A1 m1 and m2 polymorphisms and colorectal neoplasia have reported inconsistent results (62–69). In a large study, Slattery et al. found that presence of a CYP1A1 m1 or m2 variant allele modified the relationship between current smoking and colorectal cancer (69). No evidence of interaction between CYP1A1genotype and smoking was found in two other studies, one of cancer and one of adenomas, but these were much smaller and so would have lacked statistical power to detect interactions (63,64). In a meta-analysis of 20 published case–control studies, the NAT2 genotype was not related to colon cancer risk (70). Similarly, pooled analysis of seven studies revealed no strong association between the NAT1 genotype and colorectal cancer (52). van der Hel et al. noted that cancer risk was raised in smokers who were imputed to be NAT2 rapid acetylators, compared to nonsmokers who were NAT2 slow acetylators (71). While this is compatible with the findings in a study of adenomas (72), other studies that have considered interactions between NAT1 or NAT2 and smoking have had inconsistent results (60,73–77).
The differences in the time trends in colorectal cancer in males and females (discussed earlier) could be explained by cohort effects in exposure to some sex-specific risk factor; one possibility that has been suggested is exposure to estrogens (19). There is, however, little evidence of an influence of endogenous hormones on the risk of colorectal cancer (78). In contrast, there is evidence that exogenous estrogens such as hormone replacement therapy (HRT), tamoxifen, or oral contraceptives might be associated with colorectal tumors.
In two large randomized controlled trials of the possible health benefits of HRT in postmenopausal women (79,80), the incidence of colorectal cancer was reduced by about one-third [relative risk (RR) in meta-analysis 0.64, 95% confidence interval (CI) 0.45–0.92] (81). These results were consistent with those of more than 20 case–control and cohort studies (82). When colon and rectal tumors have been considered separately, there was no evidence of an association between HRT and rectal cancer (83).
Interpretation of the results of observational studies has not been straightforward. In meta-analyses, there was significant heterogeneity in the magnitude of the effect between studies (78,83–85). While the RR appear to be lower for current than for past HRT users and there is an attenuation of the risk several years after stopping hormone use (85), there is a lack of information on the effect by hormone type, dose, and duration of use.
There has also been concern that unidentified confounding or the “healthy user effect” may have influenced the observed effect, but the observation of a similar effect in the two randomized controlled trials (RCTs) makes this a less likely explanation for the association. A potential issue of concern is that in the Women’s Health Initiative trial the colorectal tumors diagnosed in the group on estrogen plus progestin HRT were more advanced and had a greater number of positive lymph nodes than those that developed in women in the placebo arm. If confirmed, this would have important implications for the potential role for HRT in colon cancer prevention, in addition to the concerns about the increased risk of breast cancer, strokes, and Pulmonary embolism .
Regarding the use of the oral contraceptive pill, a meta-analysis of eight case–control studies and four cohort studies conducted up to 2000 was consistent with a moderate inverse association with risk of colorectal cancer (RR = 0.82, 95% CI 0.70–0.97). The relation was evident for both colon and rectal tumors. However, there was significant heterogeneity between the studies and risk did not decrease with increased duration of use.
Although available data are sparse, the risk of colorectal cancer may also be increased among women taking tamoxifen therapy.
Aspirin and Other Nonsteroidal Anti-inflammatory Drugs
The relationship between colorectal cancer and aspirin use has been assessed in more than 20 observational studies. These consistently show that aspirin use is associated with a reduction in the risk for colorectal cancer of approximately 40% to 50%. Similar results have been reported for adenomas. There have also been four randomized controlled trials of aspirin in the prevention of colorectal neoplasia. Three of these found that aspirin, in doses between 81 and 325 mg/day, reduced risk of recurrence of adenomas. While the fourth trial failed to observe an effect, it had not been designed to evaluate colorectal neoplasia as endpoints and had limited statistical power. Despite this body of evidence, issues relating to the effective dose and duration of treatment that would be necessary for prevention are still unclear. These gaps in knowledge are particularly important because of the toxic effects of aspirin, particularly at high doses.
As regards other types of nonsteroidal anti-inflammatory drugs (NSAIDs), three small randomized clinical trials have shown that sulindac reduces the number and size of colorectal polyps in patients with FAP, confirming the results of studies of nonrandomized case series.
However, in one trial in patients who were genotypically affected with FAP but were phenotypically unaffected, sulindac did not prevent the development of colorectal adenomas. In a small randomized trial, no regression of small adenomatous polyps in patients without FAP was observed. Celecoxib and rofecoxib specifically inhibit cyclooxygenase-2 (COX-2). Celecoxib has been found to reduce the number of colorectal adenomas in patients with FAP. In an analysis of data from a prescription drug database in the elderly in Quebec (Canada), there was an inverse association between colorectal adenomas and use of rofecoxib for a period of at least 90 days. In a secondary analysis relating to colorectal cancer, there were inverse associations with use of rofecoxib and celecoxib.
It is likely that aspirin, or other NSAID, prophylaxis might be of benefit to particular subgroups of the population, but these groups have not yet been identified. However, there is intriguing evidence that genetic variation may modify the effect of NSAIDs on the development of colorectal neoplasia. Martinez et al. investigated the joint effects of aspirin use and a polymorphism in the ornithine decarboxylase gene (ODC) on the risk for recurrence of colorectal adenomas. Overall, both aspirin use and homozygosity for a G to A substitution in intron 1 of ODC were associated with a reduced risk of adenoma recurrence. The joint effect of aspirin use and homozygosity for the intron 1 variant was greater than would be expected on the basis of either an additive or multiplicative effect. Polymorphic genes encoding the two isoforms of prostaglandin H synthase [also known as cyclooxygenase (COX)], which are inhibited by NSAIDs, have also been investigated. Lin et al. reported that risks of both adenomas and colorectal cancers were associated with a rare COX-2 variant in African-Americans. Cox et al., in an analysis of eight of the more frequent COX-2 polymorphisms in a study in Spain, observed that two variants in the untranslated region of exon 10 were associated with an increased risk of colorectal cancer. The protective effect of NSAIDs was not observed in those with the exon 10 variants, but this was based on small numbers. In a single study, in persons who carried either of two variants of COX-1, NSAID use was not associated with the decrease in adenoma risk observed in those without the variants. Other studies suggest interactions between aspirin and variants of the genes coding for interleukins IL6 and IL10, the insulin receptor substrate 1 (IRS1), the vitamin D receptor ( VDR), and the cyclin D1 gene (CCND1). It will be important to determine whether these findings can be replicated, and whether they hold for different types of NSAIDs.
Diet has long been regarded as the most important environmental influence on colorectal cancer, and this is reflected in the volume of studies that have tested hypotheses about specific foods and nutrients.
Virtually all of the studies have been observational and subject to three problems: (i) diet is related to other aspects of lifestyle, which may influence risk, (ii) people eat foods rather than nutrients, and (iii) misclassification of intake, both of the food group or nutrient being investigated, and of other food groups or nutrients that might confound the association could dilute or bias associations. In consequence, it has proved extremely difficult to identify the specific components of diet that influence risk.
Vegetables and Fruit
The comprehensive report of the World Cancer Research Fund (WCRF) and American Institute for Cancer Research (AICR) noted that of 21 case–control studies examining the association between vegetable and fruit consumption and colon cancer risk, 17 found some degree of reduced risk with higher consumption of at least one category of vegetable and fruit.
Less consistent evidence was observed in the four cohort studies considered in the review. Of 10 case–control studies of rectal cancer in which statistical significance was reported, eight showed a significant inverse association with at least one category of vegetables and/or fruit, and the one cohort study in which rectal cancer risk was reported suggested an inverse relationship with consumption of green salad. On this basis, it was concluded that the evidence that diets rich in vegetables protect against cancers of the colon and rectum was convincing, however, no judgment was possible regarding the relationship with fruit. Recent evidence suggests the relation between vegetables and fruit and colorectal neoplasia is complex. For example, the association is much stronger in case–control than cohort studies, and case–control studies are potentially more susceptible to bias than cohort studies.
There have been two meta-analyses of meat consumption reported in the last few years, one based on cohort studies only, the other based on both case–control and cohort studies. The association between total meat consumption and colorectal cancer is inconsistent, and both meta-analyses show no statistically significant overall association. There is considerable heterogeneity between the results of case–control studies. In the cohort studies in which a positive association was found, the possibility that confounding factors might account for the results could not be excluded.
Data on red meat and processed meat suggest positive associations with the risk for colorectal cancer. However, the volume of evidence on these is substantially less than for total meat consumption, and it is possible that publication bias has favored positive results.
Heterocyclic amines are generated during the cooking of red meat at high temperatures, and increased consumption of well-done red meat has been associated with increased risk of colorectal neoplasia in some studies. For the heterocylic amines to be carcinogenic they must be metabolized by enzymes including glutathione-S-transferase (GST), N-acetyltransferase 1 (NAT1), and N-acetyltransferase 2 (NAT2). This has prompted investigation of interactions between variants in phase I and phase II metabolism genes and meat intake with regard to risk of colorectal neoplasia. Ishibe et al. observed a sixfold increased risk of adenomas among rapid NAT1 acetylators (defined as those carrying the NAT1 10 allele) who were estimated, on the basis of reported meat intake, cooking methods and doneness level, to consume more than 27 ng/day of the heterocyclic amine MeIQx, whereas among slow acetylators the increase in risk was twofold. While other investigators have also reported patterns in risk suggestive of interactions between particular genetic variants and meat intake [e.g., Welfare et al. for NAT2; Gertig et al. for GSTM1 and GSTT1; Turner et al. for GSTT1 and GSTP1; Cortessis et al. for microsomal epoxide hydrolase (mEH)], the direction of the associations have not always been consistent with the underlying hypotheses.
Other studies have failed to find any evidence that the relationship between red meat intake and colorectal neoplasia is modified by genotype. In addition to differences between studies in the genes and polymorphisms that have been investigated, and different approaches to statistical analysis and low statistical power, the difficulty of adequately assessing exposure to carcinogens in cooked red meats further complicates this area of research.
Fat and Fiber
The contrast between low colorectal cancer rates in sub-Saharan Africa and high rates in industrialized countries was the basis for the suggestion that diet, in particular one with high levels of fat and low levels of fiber, might have a key role in causing the disease.
The results of epidemiological studies on macronutrients (fat, proteins, and carbohydrates) have been less consistent in establishing an associated risk of cancer than those on food groups. Although the hypothesis that high fat intake is a major risk factor of the diet of industrialized countries has been investigated in many epidemiological and laboratory studies, no clear relationship has been established with colorectal cancer. There is now increased emphasis on the effects of specific fatty acids. For example, in a single study, an intake of n-6 fatty acids above the median was associated with an increased risk of colon cancer in those who carried a variant of the promoter region of the COX-2 gene, but not in those who did not have the variant.
As regards dietary fiber, in a large multicenter cohort study in Europe, a 40% reduction in risk of colorectal cancer among those with the highest dietary fiber intake was observed. In contrast, in large cohort studies in the United States and Finland, no association has been found. Intervention studies examining the effect of bran and soluble fiber have not found any effect on adenoma recurrence, nor have trials of dietary modification to increase fiber and lower fat intake. The evaluation of the cancer–fiber relation is particularly challenging due to the varying composition of fiber from different sources and variations in assessment of intake.
It has been suggested that higher levels of fat and lower levels of fiber might increase colorectal cancer risk by altering fecal characteristics. In particular, it has been postulated that development of colorectal neoplasia may be promoted either by a high fecal total bile acid concentration or by an abnormal bile acid profile with a high ratio of lithocholic to deoxycholic acid. However, no consistent association between colorectal cancer and fecal bile acid concentrations has been observed. This inconsistency may be due in part to methodological factors such as selection bias and limited statistical power. It is also possible that fecal bile acid levels may have been affected by the presence of the tumor, either directly or indirectly; for example, as a result of changes in diet made because of symptoms or treatment. For this reason, colorectal adenomatous polyps have been investigated in some studies, however, the results have been inconclusive. Most of the studies have been based on small numbers of cases who have been ascertained as a result of symptoms. The factors causing the symptoms may have affected fecal constituents, including bile acids. In a study of asymptomatic subjects who had participated in FOB screening, no association between colorectal cancer and fecal bile acids was observed.
Vegetables, particularly green leafy vegetables, are a major source of folate.
Folate is involved in the synthesis and methylation of DNA, and mechanisms have been postulated by which low folate status might increase the risk of malignancy. This has prompted considerable investigation of the role of folate, and its synthetic form folic acid in colorectal neoplasia.
The majority of observational studies - either measuring blood folate or assessing intake - are compatible with an inverse association between folate level and risk of colon cancer and adenomas. Two of three prospective studies found an increased risk for colorectal cancer among people with reduced levels of serum or plasma folate, a short-term marker of folate intake. Two studies have reported an inverse association between red cell folate, a measure of folate status over a three- to four-month period, and adenoma risk. Almost all prospective studies of folate intake show an inverse association with risk of colon cancer (or colorectal cancer, where colon and rectal tumors have not been analyzed separately), with several reporting a dose–response relationship. While evidence from case–control studies is not as consistent, most have found at least a modest reduced risk of colon (or colorectal) cancer associated with higher intake, at least among subgroups. Moreover, use of dietary supplements containing folic acid has been related to lower risk of colon cancer in several studies and the association appears, albeit on limited evidence, to be stronger for longer periods of regular use, or for use of higher dose supplements. There appears to be no consistent association between folate and rectum cancer. As regards adenomas, both cohort and case–control studies have reported risk of adenoma occurrence to be reduced among those with higher folate intake, but it is not currently clear whether dietary folate intake is associated with adenoma recurrence.
Alcohol adversely affects the metabolism of folate, which has prompted interest in whether a composite dietary profile of lower folate and higher alcohol intake, together with low intakes of methionine and vitamins B6 and B12 (a “low methyl” diet) may be associated with colorectal neoplasia. Several studies suggest that persons with a low-methyl diet do indeed have higher risk for colon cancer than those with a high-methyl diet.
No consistent association between dietary carotenoids, or serum or plasma concentrations of beta-carotene, and colorectal cancer has been observed.
None of the trials of beta-carotene supplementation suggests a decrease in the occurrence of colorectal cancer, and two randomized control trials provide evidence of a lack of efficacy of short-term supplementation of beta-carotene in preventing occurrence of colorectal adenomas.
Several observational studies and three intervention trials have found a reduced risk of occurrence and recurrence of colorectal neoplasia associated with higher calcium intake, either from the diet or as supplements, but not all of the studies reached statistical significance. In a pooled analysis of 10 cohort studies of colorectal cancer, the relative risk for the highest versus lowest quintile of dietary intake was 0.86 (95% CI 0.78–0.95, p trend=0.02); for total intake, combining dietary and supplemental sources, the relative risk was 0.78 (95% CI 0.69–0.88, p trend < 0.001).
It has been postulated that fecal calcium may protect against colorectal carcinogenesis, because calcium ions in the colon would also precipitate the bile acids as their calcium salts and so would modulate their toxicity. In a study of subjects participating in FOB screening, high levels of fecal calcium were associated with a reduced risk of both colorectal cancer and colorectal adenomas, but these associations were not statistically significant.
Calcium homeostasis is maintained by vitamin D, in that the vitamin D metabolite 1–25(OH)2D3 mediates intestinal calcium absorption. Vitamin D mediates its effect through the vitamin D receptor ( VDR). This has led to investigation of associations between polymorphisms in the VDR gene and colorectal neoplasia. The FokI polymorphism has been associated with risk of large adenomas and of colorectal cancer, but the direction of the relationship differed for the two types of neoplasm. Moreover, two other studies failed to find similar associations. However, the study of Slattery et al. did observe a relation between colon cancer and three other VDR polymorphisms (which are in linkage disequilibrium). There is some evidence that the VDRgenotype might modify the association between calcium intake and risk; three studies of adenomas and one of colorectal cancer found patterns consistent with an interaction.
In the WCRF/AICR report, an association was noted between colon cancer and alcohol intake in four out of five general population cohort studies, in three out of three cohort studies on rectal cancer, and two out of three cohort studies that did not distinguish between colon and rectal cancer. In 9 out of 18 case–control studies of colon cancer and 9 out of 17 case–control studies of rectal cancer, there was a positive association with alcohol intake. In a meta-analysis of studies published in the period 1966–1998 there was significant heterogeneity in the colon cancer–alcohol relationship between the cohort and case–control studies included.
For the studies of rectal cancer, there was significant heterogeneity by study quality and gender. In a pooled analysis of eight cohort studies in five countries in North America and Europe, a small increase in risk (RR 1.23, 95% CI 1.07–1.42) of colorectal cancer associated with a reported intake of 30 g/day or more was observed.
Alcohol is metabolized to the carcinogen acetaldehyde by oxidation by the enzyme alcohol dehydrogenase (ADH) and is subsequently detoxified into acetate by aldehyde dehydrogenase (ALDH). The ADH isoenzymes involved in these reactions include subunits encoded by the ADH3 gene, which is polymorphic. Two studies of adenomas have reported patterns consistent with an interaction between ADH3 genotype and alcohol intake. Among subjects in the male Health Professional Follow-up Study (HPFS), high consumers of alcohol with the slow catabolism genotype (*2 /*2) had a substantially increased risk of disease [odds ratio (OR) > 30 g/day and *2/ *2 vs. ≤ 5 g/day and *1/*1 = 2.94, 95% CI 1.24–6.92] compared to those who consumed low levels of alcohol per day and carried the fast alcohol catabolism genotype (ADH3 *1/ *1). Those who consumed high quantities of alcohol but had the fast catabolism genotype had only minimally increased risk (OR > 30 g/day and *1/ *1 vs. ≤ 5 g/day and *1/*1 = 1.27, 95% CI 0.63–2.53). The pattern of interaction described in the other study, from the Netherlands, was very similar to the HPFS result, and the relationship was apparent in both male and female subjects.
Because of the link between alcohol and folate metabolism, Giovannucci et al. investigated, in the HPFS, whether ADH3 acted together with alcohol and folate intake to influence disease risk. Individuals with high alcohol and low folate and the slow catabolism genotype were at particularly high risk compared to fast catabolizers with low alcohol and high folate intake (OR = 17.1, 95% CI 2.13–137.0: p interaction =0.006), although the result was based on small numbers in the high alcohol/low folate/slow catabolism group. This study, along with three others of cancer and one of adenomas, has explored interactions between alcohol intake and the MTHFR genotype. Giovannucci et al. described a borderline significant interaction where the presence of the 677 TT genotype did not affect adenoma risk among persons consuming low amounts of alcohol (OR TT and ≤ 5 g/day vs. CC/CT and ≤ 5 g/day = 0.79, 95% CI 0.42–1.49), but was associated with increased risk among those with a high alcohol intake (OR TT and > 30 g/day vs. CC/CT and ≤ 5 g/day = 3.52, 95% CI 1.41–8.78:p interaction = 0.009). Yin et al., in a study of 685 colorectal cancer cases and 778 controls in Japan, observed a similar pattern of risk for the A1298C polymorphism, but not for C677T. The other studies of MTHFR, alcohol, and colorectal neoplasia, all of which were smaller than the HPFS and the study of Yin et al., had inconsistent results.
Insulin, Hyperinsulinemia, and Insulin-Like Growth Factors
The similarity of risk factors for colon cancer and diabetes, and the observation that insulin promotes the growth of colon cells in vitro and colon tumors in vivo, prompted suggestions that hyperinsulinemia and insulin resistance may lead to colorectal cancer through growth-promoting effects of elevated levels of insulin, glucose, or triglycerides. While several strands of epidemiological evidence support the hypothesis, inconsistencies remain and a number of areas require clarification.
Moderately increased risks of colorectal cancer and adenomas have been associated with type 2 diabetes, although the studies are not entirely consistent. Individuals with several risk factors consistent with insulin resistance syndrome (e.g., high systolic blood pressure, high BMI, etc.) were found to have an increased risk of death from colorectal cancer in two studies. Hyperglycemia has been associated with risk; higher fasting and nonfasting blood glucose levels are associated with an increased risk of colorectal cancer (incidence and mortality), carcinoma in situ, and adenomas. Two prospective studies observed a modest relationship between plasma insulin levels and colorectal cancer incidence, but a third study was negative. In two prospective studies from the United States, an increased concentration of plasma C-peptide, an indicator of insulin secretion, was associated with a significantly raised colorectal cancer risk.
Two large studies have found an approximately two- to threefold increased risk of colorectal cancer associated with being in the highest, compared to the lowest, quintile of dietary glycemic load. A single study of adenomas, however, found no evidence that glycemic load or glycemic index of the diet were related to risk.
One mechanism by which raised insulin levels could affect cancer risk is by increasing the bioactivity of insulin-like growth factor-1 (IGF-1) and inhibiting production of two main binding proteins, IGFBP-1 and IGFBP-2. IGF-1 has mitogenic effects on normal and neoplastic cells, inhibiting apoptosis and stimulating cell proliferation. Three prospective studies of colorectal cancer have observed a greater than twofold increased risk among those in the highest quantile of IGF-1, compared with those in the lowest. A further prospective study reported a positive relationship with colon cancer (OR highest vs. lowest quantile = 2.66; p trend = 0.03) and a negative one for rectal cancer (OR = 0.33;p trend = 0.09), although the result for rectal cancer did not reach statistical significance. Risk of intermediate/late-stage adenomas, but not early stage adenomas, has also been found to be positively related to IGF-1 levels. One prospective study observed an inverse relationship between IGFBP-1 and IGFBP-2 and colorectal cancer, but two others have been null.
A genetic variant at position 1663 in the human growth hormone-1 gene (GH1) is thought to be associated with lower IGF-1 levels. In a single study, the variant A allele was related, in a dose–response fashion, to a reduced risk of both colorectal cancer and adenomas. Also in a single study, polymorphisms in the genes encoding the insulin receptor substrates (IRS-1, IRS-2) were associated with risk of colon, but not rectal, cancer. In the same study, variants in the IGF-1 and IGFBP3 genes were not independently related to cancer but did appear to act together with IRS-1 to influence risk. Although requiring confirmation, the findings suggest that combinations of polymorphisms in the insulin-related signaling pathway may be important in colon cancer etiology.
Colorectal cancer continues to pose a major public health problem, with almost a million new cases being diagnosed each year worldwide, and over half a million deaths. The numbers are likely to increase as a result of population aging and increased life expectancy, especially in developing countries. Evidence that physical activity, a lower body mass index, use of aspirin and other NSAIDs, a higher intake of vegetables, and use of exogenous hormones in women are associated with decreased risk strongly suggest that there is considerable potential for primary prevention through lifestyle modification and, possibly, chemoprevention. While there remain challenges with implementation of lifestyle modification, and in developing methods of chemoprevention in either the general population or high-risk groups that maximize benefits and minimize harms, it is important that the potential power of primary prevention is not overlooked in developing strategies and guidelines for control of the disease, which tend to focus on treatment and screening.
An emerging theme is the investigation of associations with genetic polymorphisms, and interactions between these and established or putative risk factors. This is a challenging area of investigation. In many of the studies of gene–environment interaction and colorectal neoplasia that have been conducted to date, there has been limited statistical power to detect interaction. The methods used to test for the same putative interaction have differed between studies, making it difficult to integrate evidence across studies. It is important that evidence in these areas is synthesized and efforts made to minimize the likelihood of publication bias. Collaborative networks such as the Human Genome Epidemiology Network (258) should facilitate this.
1. Ferlay J, Bray F, Pisani P, Parkin DM. Globocan 2000: Cancer Incidence, Mortality and Prevalence worldwide. Lyon: International Agency for Research on Cancer, 2001.
2. Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of 25 major cancers in 1990. Int J Cancer 1999; 80:827–841.
3. Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB. (eds) Cancer Incidence in Five Continents. Vol. VIII. Lyon: International Agency for Research on Cancer, 2002.
4. Haenszel W, Correa P. Cancer of the colon and rectum and adenomatous polyps: a review of epidemiologic findings. Cancer 1971; 28:14–24.
5. Sharp L. Current trends in colorectal cancer: what they tell us and what we still do not know. Clin Oncol 2001; 13:444–447.
6. Thorn M, Bergstrom R, Kressner U, Sparen P, Zack M, Ekbom A. Trends in colorectal cancer incidence in Sweden 1959–93 by gender, localization, time period, and birth cohort. Cancer Causes Control 1998; 9:145–152.
7. Johansen C, Mellemgaard A, Skov T, Kjaergaard J, Lynge E. Colorectal cancer in Denmark 1943–1988. Int J Colorectal Dis 1993; 8:42–47.
8. Lopez-Abente G, Pollan M, Vergara A, et al. Age-period-cohort modeling of colorectal cancer incidence and mortality in Spain. Cancer Epidemiol Biomarkers Prev 2001; 6:999–1005.
9. De Angelis R, Valente F, Frova L, et al. Trends of colorectal cancer incidence and prevalence in Italian regions. Tumori 1998; 84:1–8.
10. Bell JC. Trends in colorectal cancer incidence and mortality in New South Wales 1973–1992. Med J Aust 1996; 166:175–176.
11. Cox B, Little J. Reduced risk of colorectal cancer among recent generations in New Zealand. Br J Cancer 1992; 66:386–390.
12. Hayne D, Brown RSD, McCormack M, Quinn MJ, Payne HA, Babb P. Current trends in colorectal cancer: site, incidence, mortality and survival in England and Wales. Clin Oncol 2001; 13:448–452.
13. Black RJ, Macfarlane GJ, Maisonneuve P, Boyle P. Cancer Incidence and Mortality in Scotland, 1960–1989. Edinburgh: Common Services Agency, 1995.
14. Harris V, Sandridge AL, Black RJ, Brewster DH, Gould A. Cancer Registration Statistics Scotland, 1986–1995. Edinburgh: ISD Scotland Publications, 1998.
15. Reis LAG, Wingo PA, Miller DS, et al. The annual report to the nation on the status of cancer, 1973–1997, with a special section on colorectal cancer. Cancer 2000; 88:2398–2424.
16. Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J. (eds) Cancer Incidence in Five Continents. Volume VII. Lyon: International Agency for Research on Cancer, 1997.
17. Jass JR. Subsite distribution and incidence of colorectal cancer in New Zealand 1974–1983. Dis Colon Rectum 1991; 34:56–59.
18. Devesa SS, Chow WH. Variation in colorectal cancer incidence in the United States by subsite of origin. Cancer 1993; 71:3819–3826.
19. dos Santos Silva I, Swerdlow AJ. Sex differences in time trends of colorectal cancer in England and Wales: the possible effect of female hormonal factors. Br J Cancer 1996; 73:692–697.
20. Rabeneck L, Davila JA, El-Serag HB. Is there a true “shift” to the right colon in the incidence of colorectal cancer?. Am J Gastroenterol 2003; 98:1400–1409.
21. Grulich AE, Swerdlow AJ, Head J, Marmot MG. Cancer mortality in African and Caribbean migrants to England and Wales. Br J Cancer 1992; 66:905–911.
22. Faggiano F, Partanen T, Kogevinas M, Boffetta P. Socioeconomic differences in cancer incidence and mortality. In: Kogevinas M, Pearce N, Susser M, Boffetta P, eds. Social Inequalities and Cancer. IARC Scientific Publications No. 138. Lyon: International Agency for Research on Cancer, 1997:65–176.
23. Coleman MP, Esteve J, Damiecki P, Arslan A, Renard H. Trends in Cancer Incidence and Mortality. Lyon: International Agency for Research on Cancer, 1993.
24. Robinson MHE, Thomas WM, Hardcastle JD, Chamberlain J, Mangham CM. Change towards earlier stage at presentation of colorectal cancer. Br J Surg 2002; 80:1610–1612.
25. Chu KC, Tarone RE, Chow WH, Hankey BF, Ries LAG. Temporal patterns in colorectal cancer incidence, survival, and mortality from 1950 through 1990. J Natl Cancer Inst 2002; 86:997–1006.
26. Sant M, Capocaccia R, Coleman MP, et al., EUROCARE Working Group. Cancer survival increases in Europe, but international differences remain wide. Eur J Cancer 2001; 37:1659–1667.
27. Gatta G, Ciccolallo L, Capocaccia R, et al. Differences in colorectal cancer survival between European and US populations: the importance of sub-site and morphology. Eur J Cancer 2003; 39:2214–2222.
28. Gillen C, Walmsley RS, Prior P, Andrews HA, Allan RN. Ulcerative colitis and Crohn’s disease: a comparison of the colorectal cancer risk in extensive colitis. Gut 1994; 35:1590–1592.
29. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001; 48:526–535.
30. Cotton S, Sharp L, Little J. The adenoma-carcinoma sequence and prospects for the prevention of colorectal neoplasia. Crit Rev Oncogen 1996; 7(5&6):293–342.
31. Winawer SJ, O’Brien MJ, Waye JD, et al. Risk and surveillance of individuals with colorectal polyps. Bull World Health Organ 1990; 68:789–795.
32. Peipins LA, Sandler RS. Epidemiology of colorectal adenomas. Epidemiol Rev 1994; 16:273–297.
33. Hawkins NJ, Ward RL. Sporadic colorectal cancers with microsatellite instability and their possible origin in hyperplastic polpys and serrated adenomas. J Natl Cancer Inst 2001; 93:1307–1313.
34. Mecklin JP, Ponz de Leon M. Epidemiology of HNPCC. Anticancer Res 1994; 14:1625–1629.
35. Fuchs CS, Giovannucci EL, Colditz GA, Hunter DJ, Speizer FE, Willett WC. A prospective study of family history and the risk of colorectal cancer. N Engl J Med 1994; 331:1669–1674.
36. Winawer SJ, Zauber AG, Gerdes H, et al. Risk of colorectal cancer in the families of patients with adenomatous polyps. N Engl J Med 1996; 334:82–87.
37. Johns LE, Houlston RS. A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol 2001; 96:2992–3003.
38. Khoury MJ, Beaty TH, Liang KY. Can familial aggregation of disease be explained by familial aggregation of environmental risk factors? Am J Epidemiol 1988; 127:674–683.
39. Haenszel W, Kurihara M. Studies of Japanese migrants: mortality from cancer and other diseases among Japanese in the United States. J Natl Cancer Inst 1968; 40:43–68.
40. Friedenreich CM. Physical activity and cancer prevention: from observational to intervention research. Cancer Epidemiol Biomarkers Prev 2001; 10: 287–301.
41. McTiernan A, Ulrich C, Slate S, Potter J. Physical activity and cancer etiology: associations and mechanisms. Cancer Causes Control 1998; 9:487–509.
42. IARC Working Group. IARC Handbooks of Cancer Prevention Vol. 6. In: The Role of Weight Control and Physical Activity in Cancer Prevention. Lyon: International Agency for Research on Cancer, 2002.
43. Terry MB, Neugut AI, Bostick RM, et al. Risk factors for advanced colorectal adenomas: a pooled analysis. Cancer Epidemiol Biomarkers Prev 2002; 11:622–629.
44. Bergstrom A, Pisani P, Tenet V, Wolk A, Adami HO. Overweight as an avoidable cause of cancer in Europe. Int J Cancer 2001; 91:421–430.
45. Bird CL, Frankl HD, Lee ER, Haile RW. Obesity, weight gain, large weight changes, and adenomatous polyps of the left colon and rectum. Am J Epidemiol 1998; 147:670–680.
46. Boutron-Ruault MC, Senesse P, Belghiti C, Faivre J. Energy intake, body mass index, physical activity, and the colorectal adenoma-carcinoma sequence. Nutr Cancer 2001; 39:50–57.
47. Martinez ME, McPherson RS, Levin B, Glober GA. A case–control study of dietary intake and other lifestyle risk factors for hyperplastic polyps. Gastroenetrology 1997; 113:423–429.
48. Morimoto LM, Newcomb PA, Ulrich CM, Bostick RM, Lais CJ, Potter JD. Risk factors for hyperplastic and adenomatous polyps: evidence for malignant potential? Cancer Epidemiol Biomarkers Prev 2002; 11:1012–1018.
49. Lieberman DA, Prindiville S, Weiss DG, Willet W. Risk factors for advanced colonic neoplasia and hyperplastic polyps in asymptomatic individuals. JAMA 2003; 290:2959–2967.
50. Giovannucci E. An updated review of the epidemiological evidence that cigarette smoking increases risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev 2001; 10:725–731.
51. IARC Working Group. IARC Monograph on the Evaluation of Carcinogenic Risks to Humans. Volume 83: Tobacco Smoke and Involuntary Smoking. Lyon: International Agency for Research on Cancer, 2004.
52. de Jong MM, Nolte IM, te Meerman GJ, et al. Low-penetrance genes and their involvement in colorectal cancer susceptibility. Cancer Epidemiol Biomarkers Prev 2002; 11:1332–1352.
53. Smits KM, Gaspari L, Weijenberg MP, et al. Interaction between smoking, GSTM1 deletion and colorectal cancer: results from the GSEC study. Biomar kers 2003; 8:299–310.
54. Ye Z, Parry JM. A meta-analysis of 20 case–control studies of the glutathione transferase M1 (GSTM1) status and colorectal cancer risk. Med Sci Monit 2003; 9:SR83–SR91.
55. Cotton SC, Sharp L, Little J, Brockton N. Glutathione S-transferase polymorphisms and colorectal cancer. Am J Epidemiol 2000; 151:7–32.
56. Ioannidis JPA, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG. Replication validity of genetic association studies. Nat Genet 2001; 29:306–309.
57. Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K. A comprehesive review of genetic association studies. Genet Med 2002; 4:45–61.
58. Katoh T, Nagata N, Kuroda Y, et al. Glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) genetic polymorphism and susceptibility to gastric and colorectal adenocarcinoma. Carcinogenesis 1996; 17:1855–1859.
59. Gertig DM, Stampfer M, Haiman CH, Hennekens CH, Kelsey K, Hunter DJ. Glutathione S-Transferase GSTM1 and GSTT1 polymorphisms and colorectal cancer risk: a prospective study. Cancer Epidemiol Biomarkers Prev 1998; 7:1001–1005.
60. Slattery ML, Potter JD, Samowitz W, Bigler J, Caan B, Leppert M. NAT2, GSTM-1, cigarette smoking, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev 1998; 7:1079–1084.
61. Slattery ML, Edwards S, Curtin K, Schaffer D, Neuhausen S. Associations between smoking, passive smoking, GSTM-1, NAT2, and rectal cancer. Cancer Epidemiol Biomarkers Prev 2003; 12:882–889.