Lifestyle factors and risk for colorectal polyps and cancer at index colonoscopy in a FIT-positive screening population

Abstract

Background

Many countries have adopted the fecal immunochemical test (FIT) as the primary colorectal cancer (CRC) screening tool; however, its accuracy is limited. Epidemiological studies have shown that obesity and type 2 diabetes increase risk for the disease.

Objective

The objective of this article is to evaluate the association of colorectal polyps and cancer with comorbidities and lifestyle factors in a population that is part of a FIT-based CRC screening program.

Methods

Between 2005 and 2013, we analyzed 3894 FIT + patients who underwent total colonoscopy. The impact of lifestyle factors on polyps and cancer was assessed using individuals with a negative colonoscopy as the control group. A multivariate logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

Results

We collected data from 3894 FIT + patients. Obesity (OR 1.29; 95% CI 1.05–1.60) and smoking (OR 1.45; 95% CI 1.24–1.71) were significantly associated with high-risk adenomas. Smoking and heavy alcohol drinking were both independently associated with high risk of CRC (OR 1.50; 95% CI 1.10–2.04 and OR 2.29; 95% CI 1.15–4.58) and colon cancer alone (OR 1.43; 95% CI 1.01–2.02 and OR 3.09; 95% CI 1.53–6.23). Positivity to first round of FIT was associated with high-risk adenomas (OR 1.47; CI 95% 1.26–1.71) and CRC (OR 1.74; 95% CI 1.29–2.36). No associations were found for diabetes.

Conclusion

In our FIT + population, lifestyle factors are significantly associated with the risk of carrying high-risk adenomas and CRC. In the future, studies could be aimed at finding better screening strategies through the development of clinical algorithms based on lifestyle changes/comorbidities.

Keywords

Colon cancer screening obesity fecal immunochemical test adenoma alcohol diabetes

Key summary

Summarize the established knowledge on this subject:

Most population-based colorectal cancer (CRC) screening programs rely on the fecal immunochemical test (FIT). However, FIT accuracy is hampered by high false-positive results.

Epidemiological data obtained from the general population have shown that obesity, alcohol consumption and cigarette smoking are associated with an increased risk of CRC.

What are the new significant and new findings?

Obesity and smoking are significantly associated with high-risk adenomas while smoking and heavy alcohol drinking are associated with high-risk for CRC and colon cancer in FIT + individuals.

Based on our data, future studies could be aimed at improving screening strategies among FIT + patients through the development of clinical algorithms based on lifestyle changes/comorbidities.

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the fourth leading cause of cancer death in the world, accounting for about 1.4 million new cases and almost 700,000 deaths in 2012; its burden is expected to increase by 60% to more than 2.2 million new cases and 1.1 million cancer deaths by 2030.¹

In the past four decades, the prevalence of obesity has dramatically increased globally. In particular, in 2014, worldwide age-standardized prevalence was 10.8% in men and 14.9% in women, which was more than doubled compared to 1975.²

Epidemiological studies obtained from several world areas have shown that obesity and type 2 diabetes increase the risk for developing CRC in the general population.^3,4

A recent meta-analysis of epidemiological studies has shown that an increase of 5 kg/m² in body mass index (BMI) confers a significantly high relative risk of developing colon cancer in men.⁵ Furthermore, an increased visceral adiposity is associated with a higher risk for developing adenomatous polyps.⁶

Many European countries have adopted population-based screening programs to prevent CRC through the use of the fecal immunochemical test (FIT). Prevention of CRC relies on the recognition of high-risk lesions and their removal. However, FIT carries a significant rate of false-positive results. The aim of this study is to determine the association between obesity, diabetes mellitus, alcohol use, smoking and colonoscopy findings in a FIT + screening population. The identification of possible risk factors associated with high-risk adenomas or CRC among FIT + individuals might help develop future strategies aimed at increasing awareness of CRC screening in populations at increased risk.

Methods

Study population

We obtained data on all FIT + patients who underwent total colonoscopy at the Sant'Orsola Malpighi University Hospital in Bologna, Italy, from March 2005 to December 2013 within the regional CRC screening program, which targets the asymptomatic population 50–69 years of age. At the time of enrollment, information regarding personal history, comorbidities, risk factors, current medication use, and family history of cancers was collected. Information about FIT positivity (≥100 ng/ml) in relation to the rounds of screening was recorded. All colonoscopies were performed by dedicated personnel strictly following the guidelines provided by the Regional Colorectal Cancer Screening Program of Emilia-Romagna.

From the total cohort of FIT + patients, we excluded: (1) those younger than age 50 who were offered, in the very early phase of the program, screening based on family history; (2) those who initially underwent a computed tomography (CT) colonography; (3) those who fulfilled the World Health Organization (WHO) criteria for serrated polyposis syndrome (SPS), or the criteria for hyperplastic polyposis syndrome (HPS)⁷; and (4) cases with incomplete histological information. The chart of each included patient was retrospectively thoroughly reviewed.

The study was approved by the institutional review board of the Sant'Orsola-Malpighi University Hospital.

Assessments

All covariates were collected by review of medical records. Age at diagnosis was calculated at the time of colonoscopy. Based on body mass index (BMI), patients were stratified into four groups: underweight (BMI < 18.5), normoweight (18.5 ≥ BMI < 25), overweight (25 ≥ BMI < 30) and obese (BMI ≥ 30). Smokers were considered those who either claimed to have smoked throughout their life at least 100 cigarettes and to be a smoker at the time of interview, or to have quit less than 10 years prior to undergoing screening. Heavy drinkers were considered those with alcohol consumption greater than 35 gr/daily. CRCs were defined based on TNM staging. Histologically, the lesions were divided into adenomas, sessile-serrated adenoma/polyps, traditional serrated polyps and cancer; individuals with hyperplastic polyps, not fulfilling the criteria for SPS/HPS, were considered as having no lesions. High-risk adenomas were considered patients having: (1) adenomas ≥ 1 cm in diameter, (2) adenomas with high-grade dysplasia, (3) adenomas with a villous component, (4) ≥ 3 adenomas, (5) sessile-serrated adenoma/polyps or traditional serrated polyps ≥1 cm in diameter or any size with dysplasia.

Statistical methods

For descriptive analyses, data based on dichotomic variables were expressed as proportions, while those based on continuous variables as mean with standard deviation (SD). The associations of colorectal polyps and CRC with lifestyle factors were evaluated using a multivariable logistic regression analysis. Risk was assessed using individuals with negative colonoscopy and normoweight as the baseline group. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated following adjustment for age, sex, BMI, smoking status, alcohol consumption, presence of diabetes and positivity to the first round of FIT. All p values were two sided and values < 0.05 were considered statistically significant. All statistical analyses were carried out using STATA software, version 11.0 (STATA Corp, College, Station, TX, USA).

Results

Baseline characteristics of participants

From March 2005 to December 2013, 4007 FIT + patients were referred to the Endoscopy Unit of the Sant'Orsola Malpighi University Hospital to undergo colonoscopy and were interviewed. Of these, 19 FIT + individuals, younger than 50 years and belonging to the very early phase of the program that targeted also those with a positive family history, were excluded. We also excluded 75 people who underwent CT colonography instead of colonoscopy, and seven individuals for incomplete histological information. Furthermore, 12 patients were excluded because they fulfilled the diagnostic criteria for SPS or HPS and are reported elsewhere.⁷ A total of 3894 participants were included in the study.

Patient information and risk factors are shown in Table 1. The median age at the time of diagnosis was 61.2 years ( ± 6.1), and 52.3% were males. Based on BMI, 24 patients (0.6%) were underweight, 1494 (38.4%) were normoweight, 1613 (41.4%) were overweight and 762 (19.6%) were obese; BMI was unknown in one individual . A total of 1150 participants (29.5%) were current smokers. There were 104 patients who were heavy drinkers (2.7%). A total of 284 participants (7.3%) had a diagnosis of diabetes (among them two with insulin-dependent diabetes mellitus).

Table 1.

Baseline characteristics of the study population.

	TOTAL PARTICIPANTS (n = 3894)
	n (%)
Age (years)
Mean (SD)	61.2 (6.1)
Sex
Female	1859 (47.7)
Male	2035 (52.3)
Body mass index^a
Underweight	24 (0.6)
Normoweight	1494 (38.4)
Overweight	1613 (41.4)
Obesity	762 (19.6)
Ever smoking
No	2744 (70.5)
Yes	1150 (29.5)
Alcohol
No	3790 (97.3)
Yes	104 (2.7)
Diabetes
No	3610 (92.7)
Yes	284 (7.3)
Colonic lesions
No lesions	1751 (45.0)
Adenomatous/serrated polyps	1919 (49.3)
Cancer	224 (5.7)

One missing.

SD: standard deviation.

The algorithm for the study is shown in Figure 1. Of the 3894 participants, 1751 (45.0%) had a negative colonoscopy or hyperplastic polyps, 1919 (49.3%) showed at least one adenoma or sessile-serrated adenoma/polyps or traditional serrated polyps during colonoscopy while 224 (5.7%) individuals were diagnosed with CRC. Among the latter group, 174 (77.7%) had cancer located in the colon, and 49 (21.9%) in the rectum; for one participant the exact site of CRC could not be retrieved from the records.

Figure 1.

Flowchart of the study.

BMI, diabetes, smoking and alcohol intake and risk of colorectal lesions in FIT + individuals

The lesions group included adenomas, sessile-serrated lesion/polyps or traditional serrated polyps and CRC patients. Data on the prevalence and multivariate analysis of lesions are listed in Table 2. Overweight (OR 1.15; 96% CI 1.00–1.33), obesity (OR, 1.36; 95% CI, 1.13–1.64) and smoking (OR 1.42; 95% CI 1.23–1.64) were significantly associated with the presence of colonic lesions. No association was found with alcohol intake or diabetes.

Table 2.

Characteristics of participants with polyps or colorectal cancer in comparison with those with no lesions.

	NO LESIONS (n = 1751)	LESIONS (n = 2143)
	n (%)	n (%)	OR (95% CI)
Age (years)
Mean (SD)	60.8 (6.1)	61.5 (6.0)	1.02 (1.02–1.04)
Sex
Female	988 (56.4)	871 (40.6)	1.0
Male	763 (43.6)	1272 (59,4)	1.84 (1.61–2.10)
BMI
Underweight	12 (0.7)	12 (0.6)	1.05 (0.46–2.38)
Normoweight	738 (42.2)	756 (35.3)	1.0
Overweight	694 (39.7)	919 (42.9)	1.15 (1.00–1.33)
Obesity	306 (17.5)	456 (21.3)	1.36 (1.13–1.64)
Ever smoking
No	1300 (74.2)	1444 (67.4)	1.0
Yes	451 (25.8)	699 (32.6)	1.42 (1.23–1.64)
Alcohol
No	1717 (98.1)	2073 (96.7)	1.0
Yes	34 (1.9)	70 (3.3)	1.27 (0.83–1.95)
Diabetes
No	1627 (93)	1983 (92.6)	1.0
Yes	123 (7)	159 (7.4)	0.88 (0.68–1.13)

BMI: body mass index; CI: confidence interval; OR: odds ratio; SD: standard deviation.

BMI, diabetes, smoking and alcohol intake and risk of high-risk adenomas in FIT + individuals

Overweight and obese participants showed a statistically significant association for carrying a high-risk adenoma, with OR 1.18 (95% CI 1.0–1.39) and OR 1.29 (95% CI 1.05–1.60), respectively. Furthermore, we found a significant association between smoking and high-risk adenomas (OR 1.45; 95% CI 1.24–1.71) (Table 3). Also, positivity at the first round of FIT was associated with carrying a high-risk adenoma (OR 1.47: CI 95%, 1.26–1.71). No associations were found between high-risk adenoma and alcohol intake or diabetes.

Table 3.

Characteristics of participants with high-risk adenomas in comparison with those with no lesions.

	NO LESIONS (n = 1751)	HIGH-RISK ADENOMAS (n = 1349)
	n (%)	n (%)	OR (95% CI)
Age (years)
Mean (SD)	60.8 (6.1)	61.5 (6.0)	1.03 (1.02–1.04)
Sex
Female	988 (56.4)	531 (39.4)	1.0
Male	763 (43.6)	818 (60.6)	1.96 (1.69–2.29)
BMI
Underweight	12 (0.7)	6 (0.4)	0.74 (0.27–2.02)
Normoweight	738 (42.2)	547(35.1)	1.0
Overweight	694 (39.7)	597 (44.3)	1.18 (1.0–1.39)
Obesity	306 (17.5)	272 (20.2)	1.29 (1.05–1.60)
Ever smoking
No	1300 (74.2)	905 (67.1)	1.0
Yes	451 (25.8)	444 (32.9)	1.45 (1.24–1.71)
Alcohol
No	1717 (98.1)	1301 (96.5)	1.0
Yes	34 (1.9)	47 (3.5)	1.27 (0.80–2.03)
Diabetes^a
No	1627 (93)	1262 (93.5)	1.0
Yes	123 (7)	87 (6.5)	0.75 (0.56–1.01)
FIT + at first round^b
No	755 (43.3)	477 (35.4)	1.0
Yes	988 (56.7)	869 (64.6)	1.47 (1.26–1.71)

One patient with no lesion had diabetes type 1.

Twelve missing (no lesions = 8; high-risk adenomas = 3).

BMI: body mass index; CI: confidence interval; FIT: fecal immunochemical test; OR: odds ratio; SD: standard deviation.

BMI, diabetes, smoking and alcohol intake and risk of CRC

Data on the prevalence and multivariate analysis of CRC are listed in Table 4. Smoking (OR 1.5; 95% CI 1.10–2.04.) was associated with the presence of CRC and the association remained strong when considering colon cancer alone (OR 1.43; 95% CI 1.01–2.02). No association was found between smoking and rectal cancer (OR 1.58; 95% CI 0.86–2.90). Alcohol was also statistically associated with the presence of CRC (OR 2.29; 95% CI 1.15–4.58) and colon cancer alone (OR 3.09; 95% CI 1.53–6.23). A borderline significant association was observed for obese patients and colon cancer (OR 1.50; 95% CI 0.98–2.29; p = 0.06). A borderline inverse association with obese patients was observed for rectal cancer, but these data were hampered by the small number of patients (n = 4). Positivity at first round of FIT was significantly associated with CRC (OR 1.74; 95% CI 1.29–2.36), colon (OR 1.68; 95% CI 1.20–2.36) and rectal cancer (OR 1.89; 95% CI 1.01–3.54). No association was found between diabetes and colon and rectal cancers either combined or separately.

Table 4.

Characteristics of participants with CRC in comparison with those with no lesions.

	NO LESIONS (n = 1751)	CRC (n = 224)		COLON CANCER (n = 174)		RECTAL CANCER (n = 49)
	n (%)	n (%)	OR (95% CI)	n (%)	OR (95% CI)	n (%)	OR (95% CI)
Age (years)
Mean (SD)	60.8 (6.1)	62.9 (6.0)	1.06 (1.04–1.09)	63.1 (6.0)	1.07 (1.04–1.1)	62.5(5.9)	1.06 (1.01–1.11)
Sex
Female	988 (56.4)	101 (43.1)	1.0	82 (47.1)	1.0	19 (38.8)	1.0
Male	763 (43.6)	123 (54.9)	1.53 (1.14–2.05)	92 (52.9)	1.38 (1.0–1.91)	30(61.2)	2.13 (1.17–3.89)
BMI
Underweight	12 (0.7)	1 (0.4)	0.57 (0.07–4.60)	1 (0.6)	0.81 (0.1–6.51)	0	–
Normoweight	738 (42.2)	89 (39.7)	1.0	61 (35.1)	1.0	27 (55.1)	1.0
Overweight	694 (39.7)	85 (37.9)	0.89 (0.64–1.24)	67 (38.5)	1.03 (0.71–1.49)	18 (36.7)	0.62 (0.33–1.15)
Obesity	306 (17.5)	49 (21.9)	1.14 (0.77–1.68)	45 (25.9)	1.50 (0.98–2.29)	4 (8.2)	0.33 (0.11–0.96)
Ever smoking
No	1300 (74.2)	148 (66.1)	1.0	116 (66.7)	1.0	31 (65.3)	1.0
Yes	451 (25.8)	76 (33.9)	1.5 (1.10–2.04.)	58 (33.3)	1.43 (1.01–2.02)	17 (34.7)	1.58 (0.86–2.90)
Alcohol
No	1717 (98.1)	211 (94.2)	1.0	161 (92.5)	1.0	49 (100)	1.0
Yes	34 (1.9)	13 (5.8)	2.29 (1.15–4.58)	13 (7.5)	3.09 (1.53–6.23)	0	–
Diabetes^a
No	1627 (93)	196 (87.9)	1.0	151 (87.8)	1.0	44 (91.7)	1.0
Yes	123 (7)	27 (11.1)	1.38 (0.88–2.17)	23 (13.2)	1.57 (0.95–2.58)	4 (8.3)	1.15 (0.39–3.33)
FIT + at first round^b
No	755 (43.3)	72 (32.1)	1.0	57 (32.8)	1.0	15(30.6)
Yes	988 (56.7)	152 (67.9)	1.74 (1.29–2.36)	117 (67.2)	1.68 (1.20–2.36)	34 (69.4)	1.89 (1.01–3.54)

The site of cancer in one individual was missing.

Two participants, one with no lesions and one with cancer, had diabetes type 1.

Eight missing (no lesions: 8).

BMI: body mass index; CI: confidence interval; CRC: colorectal cancer; FIT: fecal immunochemical test; OR: odds ratio; SD: standard deviation.

Discussion

We retrospectively reviewed our CRC screening cohort of FIT + patients and evaluated whether lifestyle habits could be associated with increased risk for colorectal lesions at index colonoscopy. Our data show that obesity and smoking are also significantly associated with an increased risk of high-risk adenomas in this FIT + population. Importantly, smoking and alcohol intake are associated with the risk of CRC, while a borderline association was found for obesity and colon cancer. No associations were found between diabetes and any type of colonic lesions.

Based on epidemiological data from the general population, a strong association between increased BMI and CRC is well documented;^8–10 however, only very few studies have been conducted on CRC screening patients, with conflicting results. In 2010 Stein et al. retrospectively evaluated 600 asymptomatic individuals who underwent screening colonoscopy and found an association between BMI > 30 kg/m² and colonic advanced lesions (adenoma/serrated polyps >10 mm and CRC).¹¹ Conversely, Lieberman et al. evaluated a cohort of 1770 asymptomatic individuals aged 50–75 years who underwent screening colonoscopy, and failed to demonstrate a significant association between BMI and colonic advanced lesions (adenoma >10 mm or more in diameter or a villous adenoma or an adenoma with high-grade dysplasia and invasive cancer).¹² Different from our data, both studies were not based on FIT screening and had a smaller sample size.

In the present study, we found that obesity (OR 1.29; 95% CI 1.05–1.60) was significantly associated with the presence of high-risk adenomas and borderline-associated with colon cancer. Several complex mechanisms have been proposed to explain the link between obesity and colorectal carcinogenesis, including inflammation and unbalanced levels of adipokines.^4,13

Furthermore, in line with a previous report,¹² we found the strongest association was between heavy alcohol consumption and CRC.

In our cohort, we did not find any association with diabetes. Numerous studies have shown an association between diabetes and risk for CRC in the general population.¹⁴ It is reasonable to speculate that the differences found in our study could be related to an underestimation of individuals affected by diabetes because of the bias related to self-reported information during interviews.

Cigarette smoking is a well-established major risk factor for CRC.^15–17 In our study, cigarette smoking was associated with the risk of carrying high-risk adenomas or cancer. Two colonoscopy-based previous studies found, similar to our results, an association between smoking and adenomatous polyps as well as advanced neoplasia (high-risk adenomas and invasive cancer).^12,18

Our study features two important strengths. First, it is based on a large database with nearly 4000 consecutive participants who underwent colonoscopy, allowing enough power to obtain stable estimates. Second, our study population is highly selected and homogeneous, as all the participants are asymptomatic FIT+, 50- to 69-year-old individuals.

We also acknowledge several limitations. First, our cohort is a selected sample of the general population as it includes only FIT + individuals from the community who agreed to participate in colon cancer screening. Therefore, we lack information on those who did not agree to undergo colonoscopy. Thus, we may have introduced some selection biases that may have affected our results.

Second, BMI was calculated on self-reported weight and height: Misclassification varies with age (increases in older individuals) and relative BMI (increases with increasing BMI).¹⁹ Importantly, we have only static physiological information; available epidemiological studies have evidenced that life weight change may be more strongly predictive of CRC risk than overall obesity calculated by BMI.^20,21 Third, we lack information about physical activity, which, as we know, is associated with a lower risk of CRC.^22,23

We also found that the median age of patients with high-risk adenomas and cancer was 61.5 years. Recent studies emphasize the hypothesis to consider starting age-based CRC screening programs at younger than 50 years of age, as the incidence of early-onset CRC during decades across the age group 20–49 years is increasing,²⁴ highlighting a possible contribution from obesity.²⁵ Our results are in contrast with this hypothesis and confirm the standardized age of screening at 50 years, highlighting a possible need for calculating obesity trajectories (early onset + long-standing) in future studies in order to estimate possible different target populations based on age.

To our knowledge this is the first study that estimates the association of BMI, smoking and alcohol use with the risk of high-risk adenomas or CRC at index colonoscopy in consecutive FIT + individuals belonging to a population-based CRC screening program.

Many countries have now adopted FIT for population-based CRC screening programs, since it is a nonexpensive, noninvasive test that allows high participation rates among populations.²⁶ Our data could help improve future screening strategies among FIT + individuals by identifying true tumor carriers through the employment of clinical algorithms based on lifestyle changes/comorbidities. Furthermore, since the FIT-based screening programs are associated with a reduction in CRC mortality,²⁷ but are experiencing problems in reaching satisfactory participation rates,²⁸ our data highlight the need to increase awareness in high-risk groups for undergoing FIT screening.

Footnotes

Acknowledgements

Author contributions are as follows: DC: data collection, data analysis and drafting of the manuscript; MF: data collection, data analysis and drafting of the manuscript; RMZ: statistical analysis, data interpretation and drafting of the manuscript; AM: data collection; FB: data interpretation and drafting of the manuscript; LR: study supervision, data collection, data interpretation and drafting of the manuscript.

Declaration of conflicting interests

None declared.

Funding

LR is supported by the Italian Association for Cancer Research (AIRC) IG Investigator (grant number 14281) and the European Commission Seventh Framework Program FP7/2007–2013 (KBBE) under grant agreement 311876, Pathway-27.

Informed consent

As outlined in the ethical submission, for the retrospective analysis of our screening population, the written informed consent for the specific analysis was not taken for different reasons, including the wide number of subjects, the large time lapse (11 years) when the informations were started to be collected, and the exclusion of a high number of subjects from statistical analysis that we could not contact, that would have caused a high statistical bias for the study results. So relying on the general use for the treatment of personal data for scientific research purposes, the treatment of the personal data of the patients was authorized after approval of the study by the ethical review board. All the data collected and analyzed were in anonymous form and the subjects were included as a progressive number.

Ethics approval

This study was approved by the institutional review board of the Sant'Orsola-Malpighi University Hospital, Bologna, Italy.

References

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality wordwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136(5): E359–86.

NCD Risk Factor Collaboration (NCD-RisC). Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants. Lancet 2016; 387: 1377–1396.

Bardou

Barkun

Martel

et al.

Obesity and colorectal cancer. Gut 2013; 62: 933–947.

Alemán

Eusebi

Ricciardiello

et al.

Mechanisms of obesity-induced gastrointestinal neoplasia. Gastroenterology 2014; 146: 357–373.

Wang

Yang

Chen

et al.

Associations of body mass index with cancer incidence among populations, genders, and menopausal status: a systematic review and meta-analysis. Cancer Epidemiol 2016; 42: 1–8.

Lee

Myung

Cho

et al.

Adiposity and the risk of colorectal adenomatous polyps: A meta-analysis. Cancer Causes Control 2011; 22: 1021–1035.

Snover DC, Ahnen DJ, Burt RW, et al. Serrated polyps of the colon and rectum and serrated polyposis. In: Bosman FT, WHO, International Agency for Research on Cancer (IARC) (eds) WHO classification of tumours of the digestive system. 4th ed. Lyon: IARC Press, 2010, pp.160–165.

Larsson

Wolk

. Obesity and colon and rectal cancer risk: a meta-analysis of prospective studies. Am J Clin Nutr 2007; 86: 556–565.

Dai

Niu

. Obesity and colorectal cancer risk: a meta-analysis of cohort studies. World J Gastroenterol 2007; 13: 4199–4206.

10.

Otani

Iwasaki

Inoue

. Body mass index, body height, and subsequent risk of colorectal cancer in middle-aged and elderly Japanese men and women: Japan public health center-based prospective study. Cancer Causes Control 2005; 16: 839–850.

11.

Stein

Anderson

Rajapakse

et al.

Body mass index as a predictor of colorectal neoplasia in ethnically diverse screening population. Dig Dis Sci 2010; 55: 2945–2952.

12.

Lieberman

Prindiville

Weiss

et al.

Risk factors for advanced colonic neoplasia and hyperplastic polyps in asymptomatic individuals. JAMA 2003; 290: 2959–2967.

13.

Giovannucci

. Nutrition, insulin, insulin-like growth factors and cancer. Horm Metab Res 2003; 35: 694–704.

14.

González

Prieto

Del Puerto-Nevado

et al.

2017 Update on the relationship between diabetes and colorectal cancer: epidemiology, potential molecular mechanisms and therapeutic implications. Oncotarget 2017; 8: 18456–18485.

15.

Giovannucci

. An updated review of the epidemiological evidence that cigarette smoking increases risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev 2001; 10: 725–731.

16.

Giovannucci

Rimm

Stampfer

et al.

A prospective study of cigarette smoking and risk of colorectal adenoma and colorectal cancer in U.S. men. J Natl Cancer Inst 1994; 86: 183–191.

17.

Heineman

Zahm

McLaughlin

et al.

Increased risk of colorectal cancer among smokers: Results of a 26-year follow-up of US veterans and a review. Int J Cancer 1994; 59: 728–738.

18.

Anderson

Attam

Alpern

et al.

Prevalence of colorectal neoplasia in smokers. Am J Gastroenterol 2003; 98: 2777–2783.

19.

Kuczmarski

Najjar

. Effects of age on validity of self-reported height, weight, and body mass index: findings from the Third National Health and Nutrition Examination Survey, 1988–1994. J Am Diet Assoc 2001; 101: 28–34.

20.

Chen

Wang

Yang

et al.

Association between adult weight gain and colorectal cancer: a dose-response meta-analysis of observational studies. Int J Cancer 2015; 136: 2880–2889.

21.

Renehan

Flood

Adams

et al.

Body mass index at different adult ages, weight change, and colorectal cancer risk in the National Institutes of Health-AARP cohort. Am J Epidemiol 2012; 176: 1130–1140.

22.

Giovannucci

Ascherio

Rimm

et al.

Physical activity, obesity, and risk for colon cancer and adenoma in men. Ann Intern Med 1995; 122: 327–334.

23.

Giovannucci

Colditz

Stampfer

et al.

Physical activity obesity and risk of colorectal adenoma in women (United States). Cancer Causes Control 1996; 7: 253–263.

24.

Davis

Marcet

Frattini

et al.

Is it time to lower the recommended screening age for colorectal cancer?. J Am Coll Surg 2011; 213: 352–361.

25.

Rex

Johnson

Anderson

et al.

American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am J Gastroenterol 2009; 104: 739–750.

26.

Inadomi

Vijan

Janz

et al.

Adherence to colorectal cancer screening: a randomized clinical trial of competing strategies. Arch Intern Med 2012; 172: 575–582.

27.

Zorzi

Fedeli

Schievano

et al.

Impact on colorectal cancer mortality of screening programmes based on the faecal immunochemical test. Gut 2015; 64: 784–790.

28.

Buron

Auge

Sala

et al.

Association between socioeconomic deprivation and colorectal cancer screening outcomes: low uptake rates among the most and least deprived people. PLoS One 2017; 12: e0179864.