Why does smoking cause colorectal cancer

New study results strengthen the evidence that people who smoke cigarettes over a long period of time have an increased risk for developing colorectal cancer, even after adjusting for other risk factors. Thun, M. Thun and colleagues tested the association between long-term cigarette smoking and colorectal cancer after adjusting for multiple other factors that are generally associated with risk, including screening.

From through the researchers followed almost , participants aged 50 to 74 years old; participants described their behaviors and medical conditions. Participants who smoked cigarettes for 40 or more years, or who did not quit before age 40, had a 30 percent to 50 percent increased risk of developing colon or rectal cancer during the follow-up, even in analyses that adjusted for 13 other potential risk factors, according to Thun.

After 13 years of follow-up, the researchers identified 1, cases of invasive colorectal cancer. While previous large studies conducted in long-term smokers showed similar results, Thun stated that this study is the first to control for screening and all of the suspected risk factors for colorectal cancer, such as alcohol consumption, physical inactivity and consumption of red or processed meat.

Smoking was established as a causal factor for CRC almost 10 years ago 8 , 9. The majority of the studies reviewed considered CRC as a single disease and did not examine possible sex differences. Neither of the 2 expert reports commented on possible sex differences in the relationship between smoking and the 3 anatomical subsites right proximal or ascending colon, left distal or descending colon, and rectum of CRC 8 , 9.

In the United States, the prevalence of smoking during the 20th century differed for men and women. In , the prevalence of smoking was In , Giovannucci et al. In the last century, the smoking epidemic in women lagged 10—20 years behind that in men 9 , 10 , 12 , and consequently the smoking-related increase in CRC for women should have been expected to emerge 1 or 2 decades later than that in men. The purpose of this study was to examine whether the increased risk of CRC due to cigarette smoking differed by tumor anatomical subsite or sex in the Multiethnic Cohort MEC Study.

The MEC consists of more than , men and women who were aged 45—75 years and living in Los Angeles County, California, and the state of Hawaii at the time of cohort recruitment. Briefly, between and , participants born between and enrolled in the study by completing a page mailed questionnaire asking for detailed information on demographic factors, dietary habits, other lifestyle factors, prior medical conditions, and family history of common cancers.

The institutional review boards of the University of Hawaii and the University of Southern California approved the study protocol. The cohort has been previously described in detail At baseline, participants reported whether they had ever smoked at least 20 packs of cigarettes in their lifetime, the number of years they had smoked cigarettes, the average number of cigarettes smoked per day during the period when they smoked, and, if they had quit smoking, the number of years since they had quit.

We calculated pack-years as number of cigarettes smoked per day divided by 20 and multiplied by the duration of smoking in years. Dietary intake during the previous year was assessed at baseline using a self-administered quantitative food frequency questionnaire with over food items, including alcoholic beverages We calculated mean alcohol intake in grams per day based on the alcohol content of different beverages and usual portion sizes.

We calculated daily intakes of nutrients from the questionnaire using a food composition table that was developed and is maintained by the University of Hawaii Cancer Center for the MEC Study.

We identified incident invasive adenocarcinoma of the colon and rectum through linkage with Surveillance, Epidemiology, and End Results Program cancer registries covering Hawaii and California. We identified deaths through linkage with death certificate files in Hawaii and California and with the National Death Index. Ascertainment of CRC cases and deaths was complete through December 31, We calculated person-years from cohort entry to the date of CRC diagnosis, death, or the end of follow-up December 31, , whichever occurred first.

Cases with tumors at more than 1 subsite were not included in subsite-specific analyses. We calculated sex-specific CRC incidence rates per , person-years, truncated to ages 45—85 years and age-adjusted to the US standard population Subsequently, we calculated corresponding incidence rates for the 3 anatomical subsites.

For each sex, we used Cox proportional hazards regression to model time to CRC, with age as the underlying time scale. We repeated the analyses for colon cancer overall and for the 3 subsites. We modeled the dietary intake variables in the multivariate Cox models as continuous variables. Participants with missing data on covariates tended to be older We present the results from the complete-case analyses throughout this paper.

The proportional hazards assumption was tested using Schoenfeld residuals and was found to hold 15 , We conducted tests for linear trends by including an ordinal exposure variable with equally spaced scores in the models, using never smokers as the first category. We assessed heterogeneity in the CRC-smoking association by sex on the basis of Wald statistics for cross-product terms between sex and smoking trend variables.

We calculated CRC-smoking associations with adjustment for MHT which was set to 0 in men and other covariates using sex as a covariate. We performed the analyses using SAS, version 9. For men and women, the annual age-adjusted incidence rates of CRC were For men, the distribution of cases by anatomical subsite was The corresponding numbers for women were At enrollment, Table 1 shows that, for both sexes, age at diagnosis was lower for ever smokers than for never smokers.

The right colon was the subsite at which cancer was most frequently diagnosed among both ever smokers and never smokers of both sexes. Except for left colon cancer among women, ever smokers had higher sex-specific incidence rates than never smokers for all subsites.

Among never smokers, men had higher incidence rates than women for right colon cancer and rectal cancer and a similar incidence rate as women for left colon cancer. Compared with female smokers, male smokers had smoked for more years, smoked more cigarettes per day, and, consequently, had more pack-years of smoking.

Web Table 2 shows that among postmenopausal women, both ever and never users of MHT had statistically significantly higher smoking-related multivariate-adjusted risks of right colon cancer. Among MHT ever users, several of the corresponding risk estimates for left colon cancer were above unity but not statistically significant. Figure 1 displays multivariate-adjusted risks of cancer at the 3 anatomical subsites according to pack-years of smoking, by sex. The figure shows that the association differs by sex for left and right colon cancer and that the association between smoking and rectal cancer is stronger for women than for men.

Multivariate-adjusted risks of right and left colon cancer and rectal cancer according to pack-years of smoking, by sex, Multiethnic Cohort Study, — The reference group was never smokers. Black markers show results for men and white markers results for women. In the present prospective study, although women were smoking less than men, we found that the smoking-related increased risks for CRC and for colon cancer overall were similar for both sexes.

However, we observed that this increase in colon cancer risk for men was confined to the left colon, and for women to the right colon. Additionally, among postmenopausal women, for both ever and never users of MHT, we found a smoking-related increase in the risk of right colon cancer. Furthermore, while the association between smoking and rectal cancer was present for both men and women, it was stronger for women. We had previously examined the sex-specific associations between smoking and colon 17 and rectal 18 cancer in a large Norwegian cohort including , men and women.

The results from these studies suggested that female smokers may be more susceptible to colon cancer 17 but not rectal cancer 18 in comparison with male smokers.

Male former smokers had a higher risk of left colon cancer In the MEC, we observed that both current and former male smokers had a higher risk of left colon cancer. As we pointed out in the Introduction, women in the United States took up smoking in large numbers more recently than men 9 , 10 , The present study included the birth cohorts of men and women that have had the highest smoking prevalences in US history.

In the MEC, we find that men have a higher incidence rate of CRC, smoke more, and have a smaller proportion of never smokers compared with women. These findings are all in accordance with population reports from both the United States 10 , 19 and Norway 20 , Differences in incidence patterns for lung cancer, a cancer driven largely by smoking behavior, between the United States and Norway provides insight into the distinct results observed by country.

As a result of reductions in smoking prevalence that began decades earlier 9 , 10 , 12 , lung cancer incidence rates began declining in the United States in the mids in men and in the mids in women In Norway, not until did the lung cancer incidence among men start to decline, while it was still increasing among women We argue that the 2 main reasons for the stronger and more consistent sex differences for CRC risk in the MEC as compared with the Norwegian cohort are 1 the lag time in the decline in the smoking epidemic in Norway compared with the United States and 2 the fact that follow-up in the Norwegian cohort extended only to , as compared with in the MEC.

In further support of this notion are the results from one meta-analysis including older cohorts 22 and those of another including more recent cohorts 5. In the latter study, the smoking-related increases in risk for both overall colon cancer and rectal cancer were quite similar for male and female smokers. The remaining cohort studies included only women 23—27 or did not report results by sex 28 , In the most recent report from the European Prospective Investigation into Cancer and Nutrition, with more than 1, left colon cancer cases, Murphy et al.

Smoking cigarettes causes exposure to a mixture of more than 7, toxic chemicals, including at least 70 known carcinogens that can affect nearly every organ system in the human body Carcinogens in cigarette smoke, such as nitrosamines, heterocyclic amines, benzene, and polycyclic aromatic hydrocarbons, may reach the colorectal mucosa through direct ingestion or through the bloodstream and may have a direct oncogenic effect on both the colon and the rectum 5.

The evidence suggests that smoking probably plays a role in early carcinogenesis in both the colon and the rectum, as reflected by its association with colorectal adenomas. The temporal pattern of the effects of smoking, with a continuing increase in risk, particularly for rectal cancer, suggests that smoking may also act in the later stages of CRC carcinogenesis 9.

Several reports have described biological mechanisms by which smoking may cause CRC 5 , 6 , 8 , 9 , 28 , 31— These results were later confirmed in a meta-analysis examining correlations between smoking history and molecular pathways in sporadic CRC 6. Differences in genetic makeup and lifestyle, including smoking and dietary habits, are thought to cause the differences between right- and left-sided colon cancer 2.

Our findings that smoking increases the risks of right- and left-sided colon cancer among women and men, respectively, fit with the overall sex-specific site predominance for colon cancer. In the United States, males have had a higher incidence of lung cancer than of CRC for many decades, while females had higher CRC incidence than lung cancer incidence until the early s.

For males, the decrease in CRC incidence also started in the early s and paralleled that of lung cancer incidence. For females, CRC incidence rates have also been decreasing steadily since the mids, while the decrease for lung cancer started later The changes in CRC incidence result from changes in risk factor prevalences and levels and CRC screening practices It is based on a large prospective cohort population from Norway comprising both men and women, with a long and virtually complete follow-up.

The long follow-up period resulted in a large number of cases, and gave us more stable risk estimates and results that are less prone to chance. We were able to stratify all the analyses according to different measures of smoking exposure and were able to conduct all analyses separately by gender. Also, smoking histories were obtained at enrollment and, therefore, are not subject to recall bias.

We have a high proportion of men and women ever smokers. In addition, we focused our analyses on the comparison between ever versus never smokers. Thus, it is only never smokers that could have possibly changed their smoking status during follow-up. As very few Norwegians start to smoke after the age of 30 and the mean age at enrollment for our study is more than 40 years, we are confident that possible changes in smoking status among never smokers during follow-up did not influence our risk estimates.

We had information on, and were able to control for, established risk factors for rectal cancer, many of which varied according to smoking status. Rectal cancer screening was not in place in Norway during our study period, thus reducing detection bias. Also, two previous reports confirmed the internal validity of the association between smoking exposure and the risk of breast [ 14 ] and colon cancer [ 2 ].

Our study has also several limitations. We lacked information on family history of rectal cancer and on dietary factors, such as alcohol and red meat consumption, which are established risk factors for rectal cancer.

Increased consumption of alcohol and red meat are factors that may partly explain the steep increase in rectal cancer incidence for both genders. Alcohol consumption is higher among men than women in Norway [ 31 ]. Thus, the lack of adjustment for alcohol consumption in our main analyses is likely to have inflated the estimates among men more than women, thereby, biasing a potential gender difference.

However, in the subcohort analyses, the risk estimates were similar for men ever smokers with and without adjustment for alcohol consumption. This was also the case for women. This indicates that our results may be noteworthy in spite of the lack of data on alcohol consumption for the majority of the subjects in the main analyses.

Rectal cancer has a long induction period [ 30 ] and the interpretation of our sensitivity analyses should be done with caution, as they included fewer cases and younger participants with less follow-up time compared to the main cohort. If Norwegian men consumed more red meat than women, this would bias a potential gender difference in the same direction as alcohol consumption. However, we cannot rule out that alcohol and red meat consumption may have stronger effects in women than men.

Similarly, information on the use of COX inhibitors, such as aspirin, which has preventive effects on rectal cancer development [ 32 ] was not available. The lack of molecular data is another limitation. We also lacked detailed information on occasional and passive smoking.

We believe that some occasional smokers may have been excluded due to insufficient smoking information, whereas others may have been included in the reference group, together with women exposed to passive smoking, which would have attenuated the associations between smoking and rectal cancer. As current smokers have an increased risk of dying from any major cause during follow-up and rectal cancer is assumed to take many years, competing causes of death may decrease the impact of smoking more among current than former smokers, and make the association with rectal cancer more similar for current and former smokers.

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