Colon cancer - a civilization disorder

Alastair J.M. Watson1, Paul D. Collins2

1School of Medicine, Health Policy and Practice, Faculty of Health, University of East Anglia2Division of Gastroenterology, School of Clinical Sciences, University of Liverpool

*Address for correspondence

Professor Alastair WatsonSchool of Medicine, Health Policy and PracticeFaculty of HealthUniversity of East AngliaNorwich NR4 7TJ

Tel: +44 (0) 1603 5907266

Email: Alastair.watson@uea.ac.uk

Abstract

Colorectal cancer arises in individuals with acquired or inherited genetic

predisposition who are exposed to a range of risk factors. Many of these risk factors

are associated with affluent western societies. More than 95% of colorectal cancers

are sporadic arising in individuals without a significant hereditary risk.

Geographic variation in the incidence of colorectal cancer is considerable with a

higher incidence observed in the West. Environmental factors contribute

substantially to this variation. A number of these risk factors are associated with a

Western lifestyle and could be considered a product of “civilization”. Recently,

smoking has been recognized as a risk factor. Energy consumption also influences

colorectal cancer risk with obesity increasing risk and exercise reducing risk.

However, the strongest contribution to environmental risk for colorectal cancer is

dietary. Consumption of fat, alcohol and red meat is associated with an increased

risk. Fresh fruit and vegetables and dietary fibre may be protective.

Much has been learnt recently about the molecular pathogenesis of colorectal

cancer. Colorectal cancer always arises in the context of genomic instability. There is

inactivation of the tumour suppressor genes APC, p53, TGF-, activation of oncogene

pathways including K-ras and activation of the cyclo-oxygenase-2, Epidermal Growth

Factor Receptor and Vascular Endothelial Growth Factor pathways. The mechanisms

by which some environmental factors modify the mutation risk in these pathways

have been described.

INTRODUCTION

Colorectal cancer is the fourth most common cancer among men and the third most

common cancer among women worldwide. However, the incidence of colorectal

cancer has marked geographical variation with a 25-fold difference in incidence of

colorectal cancer between regions with the lowest rate (Middle Africa; 2.3 per 100

000) and those with the highest rate (Japan; 49.3 per 100 000).1

When countries are divided according to economic development, two-thirds of all

colorectal cancers are found to occur in developed countries.2 It is known that

colorectal cancer develops in individuals with acquired or inherited genetic

predisposition in response to exposure to environmental risk factors. It is the latter,

modifiable risk factors that are thought to contribute substantially to the variation in

incidence.

Epidemiology: Civilization and colorectal cancer incidence

Economic development is characterized by the advancement of agriculture and trade

with progressive urbanization of the population. Civilized societies tend to be

defined as those that have achieved an advanced level of this social progression.

Such development in the West has been associated with a number of changes in

lifestyle factors. Dietary changes have included an increased consumption of meat,

dairy products and processed foods. Other lifestyle changes have included a

reduction in physical activity and an increase in smoking and alcohol consumption.3;4

These changes have coincided with an increase in a number of diseases include

coronary artery disease, hypertension, asthma, and some cancers including

colorectal cancer, breast cancer and lung cancer.3;5 It has also been observed that

migrants to developed countries tend to acquire the higher risk of cancer of their

host country.3 Further, the rates for second generation migrants can be double that

of the first.6 It may be reasonable, therefore, to describe these diseases, including

colorectal cancer, as diseases of civilization in which a number of acquired risk

factors associated with civilization are implicated. Modification of lifestyle and

dietary factors may be expected to reduce the risk of colorectal cancer and it has

been estimated that up to 50% of cancer could be prevented through the

modification of lifestyle factors alone.7

It has recently been observed that the high incidence rate of colorectal cancer in

high-income countries has stabilised, but that within developing countries,

increasing levels of urbanisation have coincided with a dramatic increase in

incidence of colorectal cancer.8;9 The International Agency for Research on Cancer

(IARC) has collated incidence data from populations from which high quality data are

available. In 27 of 51 cancer registries, colorectal cancer rates increased significantly

from the period 1983-87 to 1998-2002.9 These increases have largely been limited to

countries undergoing economic transition (Eastern European countries, Asia, some

countries in South America). In the United States, colorectal cancer rates declined

during the same period. Worldwide, a smaller increase in the rate of colorectal

cancer has been in observed in women compared to men and it has been proposed

that this may reflect a slower adoption of risk behaviour amongst women.

The most dramatic increase in colorectal cancer incidence has been observed in

Japan, a developed nation with a strong economy. In the last four decades, two of

three registries recorded an increased incidence of colorectal cancer of more than

90%.9 During this period, there has been a Westernization of the Japanese diet with

an increased intake of dairy products, fat and meat.10;11 It has been speculated that

this may account for the major shift in colorectal cancer incidence.

Pathophysiology

Observational studies reporting associations between dietary and lifestyle factors

and the development of colorectal cancer highlight important potential risk factors,

but provide insufficient information to establish causation. Attempts have therefore

been made to provide biologically plausible, mechanistic explanations to understand

how acquired risk factors could influence the mutation risk or the expression of

these molecular pathways. Many of these studies have focused on in vitro or animal

models of colorectal cancer, but some provide information from human studies that

lend support to causative explanations for described associations.

Colorectal cancer arises as a consequence of genomic instability with an

accumulation of genetic errors resulting in dysregulation of molecular pathways

controlling cell migration, differentiation, apoptosis and proliferation.12

Chromosomal instability is the most common pathway by which colorectal cancer

develops and is present in 65-70% of cancers. It is characterized by loss or gains of

whole or large portions of chromosomes.13 Inactivation of the tumour suppressor

gene, adenomatous polyposis coli (APC) is an early initiating event. Activating

mutations in of the K-ras oncogene follow. Additional mutations, including mutations

in transforming growth factor-β (TGF-β) and p53, drive subsequent malignant

transformation,.13 The temporal acquisition of these genetic changes is matched by

the progression from normal colonic epithelium to adenoma formation and

subsequently colorectal cancer.

Up to 15% of all colorectal cancers harbour DNA microsatellite instability arising as a

consequence of loss of DNA mismatch repair activity.14 80% of cancers harbouring

MSI are sporadic with hypermethylation of the promoter region of the mismatch

repair gene MLH-1. The remainder occur as part of the Lynch syndrome (Hereditary

Non-Polyposis Colorectal Cancer (HNPCC)). Tumours with MSI tend to arise in the

proximal colon and have a slightly better prognosis than tumours without MSI.15

The mechanism whereby lifestyle factors may interact with the expression of the

above molecular pathways is explored in more detail below.

Lifestyle factors and development of colorectal cancer

Physical activity, obesity, diet, smoking and alcohol intake have been associated with

development of colorectal cancer. The quality of observational data is variable and

in some cases, contradictory.

Physical activity

People in Western societies have reduced physical activity compared with the rest of

the world and this has been identified as a poor determinant of health.16 Migration

to Western societies has a detrimental effect on health behaviour of migrant groups.

Physical inactivity is common in migrants and this appears to be a key factor

contributing to chronic disease in this group.17

Case control and cohort studies have reported an inverse relationship between

physical activity and risk of colorectal cancer.5;18-23 When those in the highest and

lowest categories of physical activity are compared , a reduction in risk of colorectal

cancer of up to 60% has been reported.5 After adjustment for potential confounding

factors of age, obesity or diet, the association remains strong. Although the

association between exercise and colorectal cancer risk holds for colorectal cancer as

a whole, the association is not seen when rectal cancer alone is considered.5

Consistent with the observation above is the finding that exercise may influence the

development of adenomatous polyps. The incidence rate ratio for the finding of

colonic adenomas amongst African-American women was 0.94 and 0.72 for groups

with low physical activity ( <5 metabolic equivalent (MET)-hours/wk) and high

physical activity (≥40 MET-hours/wk), respectively (Ptrend = 0.01).24

A number of potential mechanisms whereby physical activity could reduce the risk of

colorectal cancer have been described. Increase in gastrointestinal transit time (with

increased exposure of colorectal mucosa to faecal carcinogens), altered immune

function, increased prostaglandin levels and alterations in gastrointestinal and

pancreatic hormone profiles have all been proposed to play a role.25

However, a stronger case could be made for the role of insulin and insulin-like

growth factor-I (IGF-I) in the development of colorectal cancer in people taking little

exercise.5 High levels of insulin and IGF-I are associated with low exercise levels.

High levels of IGF-I increase the risk of colorectal cancer. Conversely, elevated levels

of insulin-like growth factor binding protein (IGFBP)-3, which are associated with

reduced levels of IGF-I, are associated with a lower risk of colorectal cancer.26 This

explored in more detail below.

It is interesting to note that genetic mutations associated with development of

colorectal cancer have been linked to levels of physical activity. Mutations in both k-

ras and p53 have been associated with reduced levels of physical activity. 27;28

Colonic adenomas that develop in patients with low levels of physical activity are

also more likely to harbor mutations in k-ras compared with individuals with higher

levels of physical activity.

Obesity

Increased consumption of energy-dense, nutrient-poor foods with high levels of

sugar and saturated fats, combined with reduced physical activity, have led to

obesity rates that have risen three-fold or more since 1980 in some areas of North

America, the United Kingdom, Eastern Europe, the Middle East, the Pacific Islands,

Australasia and China. The obesity epidemic is not restricted to industrialized

societies; this increase is often faster in developing countries than in the developed

world.29 The proportion of people classified as overweight or obese is high. In the

UK, 56% of women and 65% of men are overweight or obese,30 with higher rates

reported in the United States where 62% of women and 71 % of men are overweight

or obese.31 These figures are likely to increase further as the rate of childhood

obesity is increasing.32 In parts of Africa, the prevalence of obesity is as low as 5%.29

An elevated Body Mass Index (BMI) has been associated with both the development

of colonic adenomas and colorectal cancer,18 33-36 with raised bodyweight thought to

account for up to 11% of colorectal cancer.37 It has been estimated that the relative

risk of developing colorectal cancer in obese men and women is 1.24 – 1.59 and

1.09 – 1.22, respectively.38 The association is stronger for distal colonic lesions

compared with proximal lesions. Visceral adiposity is a stronger risk factor for

development of colorectal cancer compare than BMI alone with reports of an

elevated risk of colorectal cancer in patients with higher waist-to-hip ratios. 39-41

Obesity is associated with the metabolic syndrome which encompasses a group of

clinical measures including abdominal obesity, impaired glucose tolerance,

hyperinsulinaemia, hyperlipidaemia and hypertension. The driving force for the

development of metabolic syndrome is either the presence insulin resistance or

visceral adiposity.38 Clusters of some of the factors that make up the metabolic

syndrome have been associated in population cohort studies with an increased risk

of colorectal cancer.42-44

In vitro studies have demonstrated that insulin promotes cellular proliferation and

inhibits cellular apoptosis in colon cancer cell lines 45;46 and promotes the growth of

colorectal cancer in animal models. The effect of the hyperinsulinaemia may be

mediated by the IGF system. 38 Hyperinsulinaemia is associated with elevated levels

of IGF-I which has itself been associated with an increased risk of colorectal cancer.47

In in vitro studies, IGF-1 has been demonstrated to promote cell migration, cell

proliferation and angiogenesis and inhibit apoptosis and cellular adhesion via

mechanisms that include increased production of hypoxia inducible factor (HIF) 1,

vascular endothelial growth factor (VEGF) and activation of Wnt-signaling.38

Obesity is associated with increased serum levels of leptin and inversely associated

with adiponectin levels. Alterations in levels of these adipocytokines have effects on

cell proliferation, angiogenesis and promotion of tumourigenesis in in vitro studies

that could contribute to the development of colorectal neoplasia in obese

individuals.48;49

Visceral adiposity has also been associated with a state of chronic, low-grade

inflammation with persistent activation of the nuclear transcription factor NKkappaB

with subsequent transcription of genes that promote tumourigenesis.38

It is unclear whether interventions to reduce weight could have an impact on the

development of colorectal cancer. Sustained weight loss among obese patients is

rare,50 and adequately powered studies to investigate this have not been performed.

Diet

The diet in Western countries is characterised by increased quantities of processed

foods, red meat and reduced dietary fibre compares to those diets in developing

countries. A protective effect against colorectal cancer could be exerted by fibre,

antioxidant vitamins, folic acid, flavones and other micronutrients.51

Some observational studies have reported that diets that are low in fruits and

vegetables are associated with an increased risk of colorectal cancer. 52;53 When

groups with the highest and lowest intake of vegetables are compared, the relative

risk of colorectal cancer is approximately 0.5.51;53 In a large prospective investigation

into the impact of fruit and vegetable consumption on development of colorectal

cancer, a difference in fruit and vegetable consumption of one additional serving per

day was associated with a covariate-adjusted RR of 1.02 (95% confidence interval [CI]

= 0.98-1.05).54

A higher intake of fibre has been associated with a reduced risk of colorectal cancer

in some studies, 55-58 but not in others.54;59 A large prospective study of 88 757

women, failed to demonstrate a protective effect of dietary fibre on the risk of

colorectal cancer, with a relative risk of 0.95 (95% CI, 0.73 - 1.25) for the highest as

compared with the lowest quintile group with respect to fibre intake.59 A Cochrane

systematic review of randomised controlled trials that included five studies and a

total of 4349 subjects concluded that there was insufficient evidence to conclude

that increased dietary fibre intake reduces the incidence or recurrence of

adenomatous polyps within a two to four year period.60 In a pooled analysis of 13

prospective cohort studies dietary fiber intake was inversely associated with risk of

colorectal cancer in age-adjusted analyses (RR =0.84; 95% CI, 0.77 - 0.92).61 However,

after adjusting for other risk factors, the relative risk was no longer statistically

significant.

The significance of fruit, vegetables and fibre is therefore unclear, with studies

reporting contradictory results. It is not yet possible to draw firm conclusions as to

the potential role of these dietary factors.

Proposed mechanisms by which dietary fibre could reduce the development of

colorectal cancer have included decreased exposure of the colonic mucosa to

carcinogens and the fermentation of fibre by the colonic microbiota to produce the

short chain fatty acids acetate, propionate and butyrate.62 Butyrate has been

demonstrated to induce cell-cycle arrest, differentiation and/or apoptosis in vitro,

but in vivo studies of the effect of butyrate have provided conflicting results.63

Although there is some inconsistency in reports, observational studies have reported

an association between red meat consumption and the development of colorectal

cancer, with no increased risk reported for poultry and fish intake. 5 A prospective

study examining the outcome of consumption of red meat, poultry, fish and

processed meat on development of colorectal cancer red meat reported a Relative

Risk (RR) of 1.71 (95% CI, 1.15-2.52; P=.007) for development of rectal cancer. In the

same study, processed meat was associated with an increased risk of distal colon

cancer (RR = 1.50; 95% CI, 1.04-2.17).64 A meta-analysis of observational studies has

examined the association of ingestion of red meat and processed meat with

development of colorectal cancer. The relative risk for individuals in the highest

quartile of consumption for red meat was 1.35 (95% CI, 1.21-1.51) and for those in

the highest quartile for consumption of processed meat, the relative risk was 1.31

(95% CI, 1.13-1.51).65

The haem content of red meat could promote the development of colorectal cancer.

66;67 Red meat and haem iron supplement ingestion increase faecal levels of N-nitroso

compounds 68;69 Processed meat has also been found to contain N-nitroso

compounds. 70;71 This observation may be significant, as N-nitroso compounds are

potentially carcinogenic. Some classes of N-nitroso compounds have alkylating agent

properties and have been demonstrated to induce GC to AT transitions at the second

base of codon 12 or 13 in k-ras gene.72

Red meats and haem supplementation have also been associated with increased

levels of DNA adducts within colonocytes. DNA adducts are highly reactive agents

that react with nucleophilic centres in DNA bases and have been recognised as

playing a central role in carcinogenesis.73

The cholesterol content of the diet may also influence colorectal cancer risk. In an

observational study examining the relationship between habitual food consumption

and risk of colorectal cancer, the relative risk between the highest and lowest

quartiles of dietary cholesterol was 3.26 (95% confidence interval 1.54-6.88). 74

Smoking and alcohol

The World Health Report in 2002 highlighted the problem of increasing alcohol use

and smoking in recent decades, particularly in developing countries which still,

however, have lower rates of alcohol consumption and smoking-related disease than

developed countries.16

An increased relative risk of colorectal neoplasia among smokers has been reported

in a number of observational studies. 5 In a case-control study, the odds ratio for

development of adenomatous polyps in patients who smoke was 1.8 75 Prospective

studies have reported a relative risk of colon cancer of between 1.2 and 1.4 and a

relative risk of 1.4 to 2.0 for rectal cancer. 5 These associations should be interpreted

with caution as there is currently insufficient data to establish a causal relationship

between smoking and colorectal neoplasia.

It has been suggested that smoking may be associated only with particular tumour

sub-types. In a population-based case-control study on sporadic colorectal cancer,

cigarette smoking status was significantly differently related to p53 overexpression-

positive tumours (p53pos) compared to p53 overexpression-negative tumours(p53neg)

(p53pos versus p53neg, OR 0.4, 95% CI 0.2 - 0.9).76 Similarly, cigarette smoking status

was significantly differently related to tumours with transversion mutations in APC,

K-ras or p53 (transv+) compared with tumours without transversion mutations in one

of these genes (transv-) (transv+ versus transv-, OR 2.5, 95% CI 1.0 – 5.9).76 There was

no clear association between smoking status and MSI in this study, but it has been

reported elsewhere that smoking may be associated with a mismatch repair (MMR)

mutations which are associated with MSI.77;78

Alcohol

As with other environmental factors associated with colorectal cancer, there is some

disagreement as to the potential contribution that heavy alcohol use may make to

the development of colorectal cancer. In a pooled analysis of data from eight cohort

studies, the relative risk of developing colorectal cancer in those drinking > 45 g/d

was 1.41 (95% CI, 1.16 - 1.72). 79 Lower levels of alcohol intake were not associated

with an increased risk. (Relative risk 1.16 (95% CI, 0.99 to 1.36) for patients who

admitted to drinking 30 - 45 g/d). It has been suggested that a decrease in intake of

folate in patients with significant alcohol dependency could explain the observation

of a higher risk of colorectal cancer in this group.80;81

Conclusions

There is marked worldwide geographical variation in the incidence of colorectal

cancer with higher levels reported in developed countries. Modifiable lifestyle

factors are thought to contribute substantially to this marked variation. Results of

studies investigating the association between fibre, fruit and vegetables and

colorectal cancer are contradictory and firm conclusions cannot be drawn. Red meat

and processed meat consumption is associated with an increased colorectal cancer

risk. Smoking, alcohol and obesity are also associated with colorectal cancer.

Mechanisms whereby these lifestyle factors may influence molecular pathways

implicated in colorectal carcinogenesis have been described.

In some developed countries, rates of colorectal cancer have stabilized or even

reduced. Although economic development has been associated with lifestyle

changes associated with an increased risk of colorectal cancer, it may also provide a

means to modify that risk. Development of screening programmes, initiatives to

tackle inequalities in access to education and improved access to health care may all

play a part in reducing the risk of colorectal cancer in these countries.82

Reference List

(1) Coleman MP, Quaresma M, Berrino F, Lutz JM, De AR, Capocaccia R et al. Cancer survival in five continents: a worldwide population-based study (CONCORD). Lancet Oncol 2008; 9(8):730-756.

(2) Iarc. GLOBOCAN 2002, Cancer Incidence, Mortality and Prevalence Worldwide (2002 estimates). 2005.

Ref Type: Generic

(3) Key TJ, Allen NE, Spencer EA, Travis RC. The effect of diet on risk of cancer. Lancet 2002; 360(9336):861-868.

(4) Popkin BM. The nutrition transition in low-income countries: an emerging crisis. Nutr Rev 1994; 52(9):285-298.

(5) Coyle YM. Lifestyle, genes, and cancer. Methods Mol Biol 2009; 472:25-56.:25-56.

(6) Flood DM, Weiss NS, Cook LS, Emerson JC, Schwartz SM, Potter JD. Colorectal cancer incidence in Asian migrants to the United States and their descendants. Cancer Causes Control 2000; 11(5):403-411.

(7) Colditz GA, DeJong W, Hunter DJ, Trichopoulos D, Willett WC. Harvard report on cancer prevention. Cancer Causes Control 1996; 7(SUPPL.):1-59.

(8) Vano YA, Rodrigues MJ, Schneider SM. [Epidemiological link between eating habits and cancer: the example of colorectal cancer]. Bull Cancer 2009; 96(6):647-658.

(9) Center MM, Jemal A, Ward E. International trends in colorectal cancer incidence rates. Cancer Epidemiol Biomarkers Prev 2009; 18(6):1688-1694.

(10) Matsushita Y, Takahashi Y, Mizoue T, Inoue M, Noda M, Tsugane S. Overweight and obesity trends among Japanese adults: a 10-year follow-up of the JPHC Study. Int J Obes (Lond) 2008; 32(12):1861-1867.

(11) Kuriki K, Tajima K. The increasing incidence of colorectal cancer and the preventive strategy in Japan. Asian Pac J Cancer Prev 2006; 7(3):495-501.

(12) Yang VW, Lewis J, Wang TC, Rustgi AK. Colon Cancer: An Update and Future Directions. Gastroenterology 2010; 138(6):2027-2028.

(13) Pino MS, Chung DC. The Chromosomal Instability Pathway in Colon Cancer. Gastroenterology 2010; 138(6):2059-2072.

(14) Boland CR, Goel A. Microsatellite Instability in Colorectal Cancer. Gastroenterology 2010; 138(6):2073-2087.

(15) Jass JR, Whitehall VLJ, Young J, Leggett BA. Emerging concepts in colorectal neoplasia. Gastroenterology 2002; 123(3):862-876.

(16) WHO. The world health report 2002. Reducing risks, promoting healthy life. 2002. World Health Organisation, Geneva.

Ref Type: Report

(17) Caperchione CM, Kolt GS, Mummery WK. Physical activity in culturally and linguistically diverse migrant groups to Western society: a review of barriers, enablers and experiences. Sports Med 2009; 39(3):167-177.

(18) Iarc. IARC Handbook of Cancer Prevention, Vol 8, Fruit and Vegetables 2003.

(19) Slattery ML. Physical activity and colorectal cancer. Sports Medicine 2004; 34(4):239-252.

(20) Calton BA, Lacey J, Schatzkin A, Schairer C, Colbert LH, Albanes D et al. Physical activity and the risk of colon cancer among women: A prospective cohort study (United States). Int J Cancer 2006; 119(2):385-391.

(21) Larsson SC, Rutegård J, Bergkvist L, Wolk A. Physical activity, obesity, and risk of colon and rectal cancer in a cohort of Swedish men. Eur J Cancer 2006; 42(15):2590-2597.

(22) Friedenreich C, Norat T, Steindorf K, Boutron-Ruault MC, Pischon T, Mazuir M et al. Physical activity and risk of colon and rectal cancers: The European Prospective Investigation into Cancer and Nutrition. CANCER EPIDEMIOL BIOMARKERS PREV 2006; 15(12):2398-2407.

(23) Lee KJ, Inoue M, Otani T, Iwasaki M, Sasazuki S, Tsugane S. Physical activity and risk of colorectal cancer in Japanese men and women: The Japan Public Health Center-based prospective study. Cancer Causes and Control 2007; 18(2):199-209.

(24) Rosenberg L, Boggs D, Wise LA, Palmer JR, Roltsch MH, Makambi KH et al. A follow-up study of physical activity and incidence of colorectal polyps in African-American women. CANCER EPIDEMIOL BIOMARKERS PREV 2006; 15(8):1438-1442.

(25) Quadrilatero J, Hoffman-Goetz L. Physical activity and colon cancer: A systematic review of potential mechanisms. Journal of Sports Medicine and Physical Fitness 2003; 43(2):121-138.

(26) Kaaks R, Toniolo P, Akhmedkhanov A, Lukanova A, Biessy C, Dechaud H et al. Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women. J Natl Cancer Inst 2000; 92(19):1592-1600.

(27) Slattery ML, Anderson K, Curtin K, Khe-Ni M, Schaffer D, Edwards S et al. Lifestyle factors and Ki-ras mutations in colon cancer tumors. Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis 2001; 483(1-2):73-81.

(28) Slattery ML, Curtin K, Ma K, Edwards S, Schaffer D, Anderson K et al. Diet, activity, and lifestyle associations with p53 mutations in colon tumors. CANCER EPIDEMIOL BIOMARKERS PREV 2002; 11(6):541-548.

(29) James PT. Obesity: the worldwide epidemic. Clin Dermatol 2004; 22(4):276-280.

(30) Zaninotto P, Wardle H, Stamatakis E, Mindell J, Head J. Forecasting Obesity to 2010. 2006. National Centre for Social Research / Department of Health: London.

Ref Type: Report

(31) Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999-2004. J Am Med Assoc 2006; 295(13):1549-1555.

(32) Troiano RP, Flegal KM. Overweight prevalence among youth in the United States: Why so many different numbers? Int J Obes 1999; 23(SUPPL. 2).

(33) Boutron-Ruault MC, Senesse P, Méance S, Belghiti C, Faivre J. Energy intake, body mass index, physical activity, and the colorectal adenoma-carcinoma sequence. Nutrition and Cancer 2001; 39(1):50-57.

(34) Neugut AI, Lee WC, Garbowski GC, Waye JD, Forde KA, Treat MR et al. Obesity and colorectal adenomatous polyps. J Natl Cancer Inst 1991; 83(5):359-361.

(35) Lukanova A, Björ O, Kaaks R, Lenner P, Lindahl B, Hallmans G et al. Body mass index and cancer: Results from the Northern Sweden Health and Disease Cohort. Int J Cancer 2006; 118(2):458-466.

(36) 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(7):670-680.

(37) Vainio H, Bianchini F. Weight control and physical activity. IARC Handbooks of Cancer Prevention 2002; 6:1-315.

(38) Donohoe CL, Pidgeon GP, Lysaght J, Reynolds JV. Obesity and gastrointestinal cancer. Br J Surg 2010; 97(5):628-642.

(39) Pischon T, Lahmann PH, Boeing H, Friedenreich C, Norat T, Tjønneland A et al. Body size and risk of colon and rectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). J Natl Cancer Inst 2006; 98(13):920-931.

(40) Moore LL, Bradlee ML, Singer MR, Splansky GL, Proctor MH, Ellison RC et al. BMI and waist circumference as predictors of lifetime colon cancer risk in Framingham Study adults. Int J Obes 2004; 28(4):559-567.

(41) MacInnis RJ, English DR, Hopper JL, Haydon AM, Gertig DM, Giles GG. Body size and composition and colon cancer risk in men. CANCER EPIDEMIOL BIOMARKERS PREV 2004; 13(4):553-559.

(42) Colangelo LA, Gapstur SM, Gann PH, Dyer AR, Liu K. Colorectal cancer mortality and factors related to the insulin resistance syndrome. CANCER EPIDEMIOL BIOMARKERS PREV 2002; 11(4):385-391.

(43) Trevisan M, Liu J, Muti P, Misciagna G, Menotti A, Fucci F. Markers of insulin resistance and colorectal cancer mortality. CANCER EPIDEMIOL BIOMARKERS PREV 2001; 10(9):937-941.

(44) Bowers K, Albanes D, Limburg P, Pietinen P, Taylor PR, Virtamo J et al. A prospective study of anthropometric and clinical measurements associated with insulin resistance syndrome and colorectal cancer in male smokers. AM J EPIDEMIOL 2006; 164(7):652-664.

(45) Koenuma M, Yamori T, Tsuruo T. Insulin and insulin-like growth factor 1 stimulate proliferation of metastatic variants of colon carcinoma 26. Japanese Journal of Cancer Research 1989; 80(1):51-58.

(46) Wu X, Fan Z, Masui H, Rosen N, Mendelsohn J. Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin. J Clin Invest 1995; 95(4):1897-1905.

(47) Giovannucci E. Insulin, insulin-like growth factors and colon cancer: A review of the evidence. Journal of Nutrition 2001; 131(11 SUPPL.).

(48) Stattin P, Lukanova A, Biessy C, Söderberg S, Palmqvist R, Kaaks R et al. Obesity and colon cancer: Does leptin provide a link? Int J Cancer 2004; 109(1):149-152.

(49) Tilg H, Moschen AR. Adipocytokines: Mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 6(10):772-783.

(50) Levy RL, Finch EA, Crowell MD, Talley NJ, Jeffery RW. Behavioral intervention for the treatment of obesity: Strategies and effectiveness data. Am J Gastroenterol 2007; 102(10):2314-2321.

(51) Lin OS. Acquired risk factors for colorectal cancer. Methods Mol Biol 2009; 472:361-72.:361-372.

(52) Terry P, Giovannucci E, Michels KB, Bergkvist L, Hansen H, Holmberg L et al. Fruit, vegetables, dietary fiber, and risk of colorectal cancer. J Natl Cancer Inst 2001; 93(7):525-533.

(53) Slattery ML, Boucher KM, Caan BJ, Potter JD, Ma KN. Eating patterns and risk of colon cancer. AM J EPIDEMIOL 1998; 148(1):4-16.

(54) Michels KB, Giovannucci E, Chan AT, Singhania R, Fuchs CS, Willett WC. Fruit and vegetable consumption and colorectal adenomas in the nurses' health study. Cancer Res 2006; 66(7):3942-3953.

(55) Negri E, Franceschi S, Parpinel M, La Vecchia C. Fiber intake and risk of colorectal cancer. CANCER EPIDEMIOL BIOMARKERS PREV 1998; 7(8):667-671.

(56) Peters U, Sinha R, Chatterjee N, Subar AF, Ziegler RG, Kulldorff M et al. Dietary fibre and colorectal adenoma in a colorectal cancer early detection programme. Lancet 2003; 361(9368):1491-1495.

(57) Larsson SC, Giovannucci E, Bergkvist L, Wolk A. Whole grain consumption and risk of colorectal cancer: A population-based cohort of 60 000 women. Br J Cancer 2005; 92(9):1803-1807.

(58) Bingham SA, Day NE, Luben R, Ferrari P, Slimani N, Norat T et al. Dietary fibre in food and protection against colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC): An observational study. Lancet 2003; 361(9368):1496-1501.

(59) Fuchs CS, Giovannucci EL, Colditz GA, Hunter DJ, Stampfer MJ, Rosner B et al. Dietary fiber and the risk of colorectal cancer and adenoma in women. New Engl J Med 1999; 340(3):169-176.

(60) Asano T, McLeod RS. Dietary fibre for the prevention of colorectal adenomas and carcinomas. Cochrane Database Syst Rev 2002; 2(1).

(61) Park Y, Hunter DJ, Spiegelman D, Bergkvist L, Berrino F, Van Den Brandt PA et al. Dietary fiber intake and risk of colorectal cancer: A pooled analysis of prospective cohort studies. J Am Med Assoc 2005; 294(22):2849-2857.

(62) Bingham SA. Mechanisms and experimental and epidemiological evidence relating dietary fibre (non-starch polysaccharides) and starch to protection against large bowel cancer. Proceedings of the Nutrition Society 1990; 49(2):153-171.

(63) Bordonaro M, Lazarova DL, Sartorelli AC. Butyrate and Wnt signaling: a possible solution to the puzzle of dietary fiber and colon cancer risk? Cell Cycle 2008; 7(9):1178-1183.

(64) Chao A, Thun MJ, Connell CJ, McCullough ML, Jacobs EJ, Flanders WD et al. Meat consumption and risk of colorectal cancer. J Am Med Assoc 2005; 293(2):172-182.

(65) Norat T, Lukanova A, Ferrari P, Riboli E. Meat consumption and colorectal cancer risk: Dose-response meta-analysis of epidemiological studies. Int J Cancer 2002; 98(2):241-256.

(66) Cross AJ, Pollock JRA, Bingham SA. Haem, not protein or inorganic iron, is responsible for endogenous intestinal N-nitrosation arising from red meat. Cancer Res 2003; 63(10):2358-2360.

(67) Sesink ALA, Termont DSML, Kleibeuker JH, Van Der Meer RD. Red meat and colon cancer: The cytotoxic and hyperproliferative effects of dietary heme. Cancer Res 1999; 59(22):5704-5709.

(68) Hughes R, Cross AJ, Pollock JRA, Bingham S. Dose-dependent effect of dietary meat on endogenous colonic N-nitrosation. Carcinogenesis 2001; 22(1):199-202.

(69) Hughes R, Pollock JRA, Bingham S. Effect of vegetables, tea, and soy on endogenous N-nitrosation, fecal ammonia, and fecal water genotoxicity during a high red meat diet in humans. Nutrition and Cancer 2002; 42(1):70-77.

(70) Scanlan RA. Formation and occurrence of nitrosamines in food. Cancer Res 1983; 43(5 Suppl.):2435-2440.

(71) Hotchkiss JH. Preformed N-nitroso compounds in foods and beverages. Cancer Surveys 1989; 8(2):295-321.

(72) Bos JL. ras oncogenes in human cancer: a review. Cancer Res 1989; 49(17):4682-4689.

(73) Miller JA. Research in chemical carcinogenesis with Elizabeth Miller - A trail of discovery with our associates. Drug Metabolism Reviews 1994; 26(1-2):1-36.

(74) Järvinen R, Knekt P, Hakulinen T, Rissanen H, Heliövaara M. Dietary fat, cholesterol and colorectal cancer in a prospective study. Br J Cancer 2001; 85(3):357-361.

(75) Kato I, Tominaga S, Matsuura A, Yoshii Y, Shirai M, Kobayashi S. A comparative case-control study of colorectal cancer and adenoma. Japanese Journal of Cancer Research 1990; 81(11):1101-1108.

(76) Diergaarde B, Vrieling A, Van Kraats AA, van Muijen GN, Kok FJ, Kampman E. Cigarette smoking and genetic alterations in sporadic colon carcinomas. Carcinogenesis 2003; 24(3):565-571.

(77) Yu JH, Bigler J, Whitton J, Potter JD, Ulrich CM. Mismatch repair polymorphisms and colorectal polyps: hMLH1-93G>A variant modifies risk associated with smoking. Am J Gastroenterol 2006; 101(6):1313-1319.

(78) Slattery ML, Curtin K, Anderson K, Ma KN, Ballard L, Edwards S et al. Associations between cigarette smoking, lifestyle factors, and microsatellite instability in colon tumors. J Natl Cancer Inst 2000; 92(22):1831-1836.

(79) Cho E, Smith-Warner SA, Ritz J, Van Den Brandt PA, Colditz GA, Folsom AR et al. Alcohol Intake and Colorectal Cancer: A Pooled Analysis of 8 Cohort Studies. Ann Intern Med 2004; 140(8):603-613.

(80) Harnack L, Jacobs J, Nicodemus K, Lazovich D, Anderson K, Folsom AR. Relationship of folate, vitamin B-6, vitamin B-12, and methionine intake to incidence of colorectal cancers. Nutrition and Cancer 2002; 43(2):152-158.

(81) Giovannucci E, Stampfer MJ, Colditz GA, Rimm EB, Trichopoulos D, Rosner BA et al. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst 1993; 85(11):875-884.

(82) Gellad ZF, Provenzale D. Colorectal cancer: national and international perspective on the burden of disease and public health impact. Gastroenterology 2010; 138(6):2177-2190.