Meat subtypes and colorectal cancer risk: A pooled analysis of 6 cohort studies in Japan

Abstract

1. INTRODUCTION

Meat is one of the staple foods of the human diet, containing a good source of protein and several vitamins and minerals, and is a supplier of fat.¹ Although meat contains a high biological value of protein and essential micronutrients for a well‐balanced diet,¹ high intake of meat, especially red and processed meat, has received increasing attention as a risk factor of CRC,² which is the third most common cancer worldwide.³, ⁴ In 2015, the IARC classified processed meat as carcinogenic to humans (Group 1) and red meat as probably carcinogenic to humans (Group 2A).⁵ Although the panel of IARC concluded that red meat is a probable cause and processed meat is a convincing cause of colon cancer, no conclusion was drawn for rectal cancer.

Epidemiological evidence is, however, not entirely consistent. According to the systematic reviews and meta‐analyses, some observed a significant positive association,⁶, ⁷, ⁸, ⁹ whereas others failed to confirm the associations of CRC with intake of red meat¹⁰, ¹¹, ¹² and processed meat.¹³ Given that the fat content and the total amount of heme iron, which is a potent carcinogenic agent,¹⁴ vary according to red meat subtypes,¹⁵, ¹⁶ the risk of CRC and its subsites could vary across red meat subtypes. Epidemiological evidence on this issue is limited and conflicting. Specifically, a meta‐analysis of 5 prospective studies found an increased risk for CRC or colon cancer with the intake of beef, but not of pork.¹⁷ In contrast, a recent prospective study in the Swedish population reported that pork intake was associated with an increased risk of colon cancer, whereas beef intake was associated with a decreased risk of colon cancer.¹⁸ Additionally, few studies examined meat‐CRC risk association by subsites of the colon.¹⁹, ²⁰

In Japan, CRC is the third most common cancer type in men and the second in women.²¹ In spite of westernization of lifestyle and diet,²² the amount of red meat intake is still much lower than that of populations in Europe and America.²³, ²⁴ Based on a systematic review, we previously reported a positive association of high intake of red and processed meat with the moderate increased risk of CRC among Japanese individuals.⁸ That study, however, did not use uniform classification and/or categorization of meat intake and did not control uniformly for potentially important confounding factors across the participating cohorts.

Here, we report a pooled analysis of the relationship between intake of meat and its subtypes with cancer risk of the colorectum and its subsites among 356 038 participants of 6 large population‐based cohort studies in Japan, by using the same exposure category and adjusting for the same set of covariates across the studies. We hypothesized that higher intake of red meat and its subtypes (beef or pork) and processed meat is associated with increased risk of colon cancer.

2. MATERIALS AND METHODS

3. RESULTS

Analysis based on frequency of meat intake included 5 cohort studies comprising 232 403 participants and 5694 CRC cases for 1 815 617 person‐years (average) of follow‐up, whereas analysis based on quantity of meat intake included 2 cohort studies comprising 123 635 participants and 3550 CRC cases for 903 087 person‐years (average) of follow‐up (Table 1).

In the analyses of frequency of meat intake, we found no statistically significant associations of any type of meat with cancer risk of colorectum and its subsites in men (Table 2 and Table S1). In women (Table 3), processed red meat was significantly associated with an increased risk of CRC: the multivariable‐adjusted HR for “almost every day” vs “<1 time/wk” was 1.33 (95% CI, 1.001‐1.76; P trend = .12). The association was somewhat strengthened after excluding cases diagnosed within 3 years of the baseline (HR, 1.42; 95% CI, 1.04‐1.96; P trend = .18) (Table S2). This association was observed only for colon cancer: multivariable‐adjusted HR for “almost every day” vs “<1 time/wk” was 1.39 (95% CI, 0.97‐2.00; P trend = .04) but not for rectal cancer. By combining the category of “3‐4 times/wk” and “almost every day” in the colon subsite analysis, beef intake was associated with increased risk of DCC in the age‐ and area‐adjusted model: pooled HR for “3‐4 times/wk or more” vs “<1 time/wk” was 1.48 (95% CI, 1.03‐2.11). This association was attenuated and became statistically nonsignificant after adjusting for all the potential confounding factors. Frequent pork intake was associated with an increased risk of DCC: the multivariable‐adjusted HR for “3‐4 times/wk or more” vs “<1 time/wk” was 1.44 (95% CI, 1.10‐1.87; P trend = .07). Additionally, a weak, albeit not significant, positive association was found for processed red meat and DCC risk: the multivariable‐adjusted HR for “3‐4 times/wk or more” vs “<1 time/wk” was 1.30 (95% CI, 0.99‐1.71). We also noticed that, after excluding cases diagnosed within 3 years of the baseline, chicken intake was associated with a decreased risk of CRC (pooled HR for “almost every day” vs “<1 time/wk” was 1.04 [95% CI, 0.66‐1.63; P trend = .03]) or PCC (pooled HR for “3‐4 times/wk or more” vs “<1 time/wk” was 0.71 [95% CI, 0.55‐0.91; P trend = .01]) (Table S2).

As regards quantity‐based analysis in men (Table 4), beef intake was significantly and positively associated with risk of DCC in men: the multivariable‐adjusted HR in the highest vs lowest quartile of beef intake was 1.30 (95% CI, 1.05‐1.61; P‐trend = .02). The result was virtually unchanged after excluding cases diagnosed within 3 years of the baseline (HR, 1.29; 95% CI, 1.03‐1.61; P trend = .04) (Table S3). In women (Tables 5 and S4), colon cancer was significantly and positively associated with beef intake: the multivariable‐adjusted HR for the highest vs lowest quartile of beef intake was 1.20 (95% CI, 1.01‐1.44; P‐trend = .11). A similar association was found for colon cancer when beef intake was treated as a continuous variable: the multivariable‐adjusted HR for 100‐g increase of beef intake was 1.60 (95% CI, 1.04‐2.46). However, no association was observed for PCC and DCC with any type of meat intake. We undertook a sensitivity analysis after excluding the TAKAYAMA study, in which Cox proportional hazards assumption was violated in women for the association of beef intake with CRC and colon cancer, and found a similar association (the multivariable‐adjusted HR for the highest vs lowest quartile of beef intake was 1.11 [95% CI, 0.93‐1.33] for CRC and 1.23 [95% CI, 1.00‐1.52] for colon cancer).

4. DISCUSSION

In this pooled analysis involving 356 038 participants and 9244 incident cases of CRC from 6 large‐scale population‐based cohort studies in Japan, higher intake of total red meat was not significantly associated with an increased risk of CRC and its subsites in both men and women. In the analysis for each subtype of red meat, we found a significant positive association between beef intake (quantity) and risk for colon cancer among women and risk for DCC among men and pork intake (frequency) and risk for DCC in women. We observed that the frequent intake of processed red meat was associated with an increased risk for CRC or colon cancer among women. There was no association for chicken.

Contrary to our prior expectation, total intake of red meat was not appreciably associated with CRC and its subsites. In an analysis by specific meat based on quantitative intake estimate, we found a significantly increased risk of cancer of the colon (women) and distal colon (men) associated with high beef intake, and results based on frequency of meat intake were also suggestive of the beef‐colon cancer association in women. As regards pork intake, there was a significantly increased risk of DCC associated with its frequent intake (“3‐4 times/wk or more”) in women, whereas no such elevation was observed in the highest quartile of meat intake in both sexes. This seemingly more consistent association with beef than with pork agrees with the results of a meta‐analysis,¹⁷ showing an increased risk of colon cancer associated with high intake of beef, but not with pork. Accumulating evidence from experimental studies indicates that heme iron plays a crucial role in colon carcinogenesis.¹⁴, ³⁷, ³⁸ The heme iron stimulates endogenous formation of NOCs,³⁷ which increases the proliferation of the colonic epithelium and the production of cytotoxic aldehydes by the process of lipid peroxidation.³⁷, ³⁸ A meta‐analysis of prospective studies also provided data to support a role of heme iron in colon carcinogenesis.³⁹ The higher amount of heme iron in beef compared with other meat¹⁵ could partly account for the more consistent association between beef intake and colon cancer risk.

In the analyses by colon subsite, we observed an increased risk of cancer associated with red meat type (beef intake in men and pork intake in women) for DCC but not for PCC. This differential association by colon subsite agrees with findings of a meta‐analysis of 7 prospective studies, which reported a stronger association of DCC than PCC with red meat intake.⁴⁰ Such differential association by colon subsite has been ascribed to different exposure levels to potential carcinogens. Specifically, the concentrations of bile acid metabolites are higher in the right than in the left side of the colon, whereas those of a marker of exposure to potentially carcinogenic NOCs are higher in the distal than in the proximal colonic DNA of CRC patients.⁴¹, ⁴² Animal studies show that endogenous N‐nitrosation in the colon is dependent on the gut flora⁴³ and is most efficient at neutral pH.⁴⁴ Given the higher proportion of bacteria and pH in the distal colon than in the proximal colon,⁴⁵ the production of NOCs might be higher in the distal colon.

We found an increased risk of CRC or colon cancer with the frequent intake (almost every day) of processed red meat and risk in women but not in men. Accumulating evidence from meta‐analyses consistently reported an increased risk of CRC with higher intake of processed red meat,⁷, ¹⁹, ⁴⁶ although these studies did not present the association by sex. Our findings were also compatible with a recent meta‐analysis of 2 large cohorts (the Nurses’ Health Study and Health Professional Follow‐Up Study), which reported an increased risk of CRC associated with higher intake of processed red meat (>5 vs ≤1 serving/wk).²⁰ Nitrate or nitrite in processed meat could be the underlying reason for this association.⁴⁷ During the smoking and curing process of meat, nitrite and nitrogen oxides interact with the secondary amines and N‐alkyl amides of red meat and enhance the formation of NOCs.⁴⁸, ⁴⁹ The NOCs, including nitrosamines and nitroso‐amides, are carcinogenic in laboratory animals.⁵⁰

In our analysis by colon subsite in women, there was a suggestion of increased risk for DCC associated with frequent consumption of processed red meat (pooled HR of 1.30 for “3 times/wk or more” vs “<1 time/wk category”; 95% CI, 0.99‐1.71) but not for PCC. This finding is compatible with those of meta‐analyses of prospective studies¹⁹, ⁴⁶ and one recent pooled analysis of 2 large prospective studies.²⁰ We should note that very few women in the present Japanese cohort (2.4%) consumed processed red meat “almost every day” (the level of which was associated with an increased risk of CRC) during the 1990s and that there was no association in the analysis based on quantitative meat intake. This suggests little public health impact of decreasing intake of processed meat in the prevention of CRC in Japanese individuals.

We found no significant association of chicken intake with cancer risk in the colorectum, colon, and rectum either in men or in women, a finding consistent with the previous meta‐analyses of prospective studies.¹⁷, ⁵¹ In an analysis by colon subsite in women, we found a significantly lower risk of PCC, but not DCC, associated with frequent chicken intake (“≥3 times/wk”) (Table S2). This could be solely due to chance; however, a prospective study among 148 610 US adults reported chicken intake was inversely associated with the risk of both PCC and DCC.⁵² Due to limited and inconsistent data regarding chicken and cancer risk of colon subsites, further studies are needed to clarify the association.

Several mechanisms have been suggested to explain the association between red meat and processed red meat and the risk of CRC. Red and processed meat could increase the risk of CRC by the formation of heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons when cooking meat at high temperature or on open flame, which are potent carcinogens.⁵³ Moreover, HCAs are also in the group 2 category in the IARC classification.⁵ These types of meat might also increase the risk of CRC or colon cancer by the fat peroxidation pathway. The major endogenous genotoxic aldehyde product of this pathway is malondialdehyde,⁵⁴ which is mutagenic in human cells.⁵⁵ Secondary bile acids produced by anaerobic bacteria in the large bowl from primary bile acids, which are essential to the digestion of animal fat, are thought to be colonic irritants and to have hyperproliferative effects.⁵⁶ Furthermore, high red meat intake could increase the risk of CRC or colon cancer by enhancing the endogenous formation of NOCs,⁵⁷ most of which are known carcinogens.³⁷ Human experimental studies also reported that the intake of red meat but not white meat significantly increases the fecal levels of NOCs in a dose‐dependent manner.⁵⁸

The present study has several strengths. First, we undertook a meta‐analysis of data of the major cohort studies in Japan using a validated dietary questionnaire and used identical categories for meat intake across our incorporated studies. Second, each study was controlled for a common set of variables that are known or suggested to be associated with CRC. Finally, with a large number of participants and incident cases of CRC, we were able to examine the effect of meat with reasonable statistical power.

Our study also has limitations that need to be mentioned. First, of 6 cohorts participating in the present pooled analysis, only 2 used a detailed dietary questionnaire that can provide quantitative estimates of meat intake, whereas others assessed the intake frequency of each meat type using a single question. Such a large difference in the dietary questionnaire does not allow us to obtain summary estimates for all cohorts. Together with analyses by sex and subsite of the colorectum, this has led to numerous statistical test results, inflating the chance of significant associations. Therefore, we mainly discussed findings of the preplanned associations (red meat and colon cancer). Second, we used only baseline information on meat intake and did not consider lifetime intake or changes of intake during follow‐up. Third, statistical power might not be sufficient in site‐specific analyses. Fourth, although each study was adjusted for important factors associated with CRC, we cannot exclude the possibility of residual confounding factors. Fifth, the style of the questions on meat intake differed by each study, which might lead to a misclassification of meat intake. However, the test for heterogeneity across studies was not statistically significant in most analyses. Sixth, the validity of estimated meat intake used in each participating cohort was low to moderate and tended to be lower in men than in women (red meat, r = 0.21‐0.43 in men and r = 0.38‐0.53 in women). The measurement error of meat intake might result in biased associations towards the null. The null or weaker association between red meat subtype and colon cancer in men of the present study may be partly due to the gender difference of validity of meat intake. Finally, due to a lack of information on cooking methods, we were unable to examine the association of intake of well‐done red meat, which could contain higher levels of HCAs, with CRC risk.

In the present pooled analysis using data from large prospective studies in Japanese men and women, who consume much less meat compared to western population, higher beef intake was associated with an increased risk of cancer of the colon (women) and distal colon (men). Frequent pork intake was also associated with DCC in women, but the association with pork intake seems less consistent than that of beef. Frequent intake of processed red meat was associated with an increased risk of CRC and colon cancer in women, but not in men. Further investigation is required to elucidate the mechanisms underlying the differential association by meat subtype, subsite of the colorectum, and sex.

DISCLOSURE

The authors declare that they have no competing interests.

Supporting information

ACKNOWLEDGMENTS

Notes

Islam Z, Akter S, Kashino I, et al. Meat subtypes and colorectal cancer risk: A pooled analysis of 6 cohort studies in Japan. Cancer Sci. 2019;110:3603–3614. 10.1111/cas.14188 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Members of the Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan: Manami Inoue (principal investigator); Motoki Iwasaki, Michihiro Muto, Eiko Saito, Norie Sawada, Taichi Shimazu, Shoichiro Tsugane, Taiki Yamaji, and Hadrien Charvat (until 2017); Tetsuya Otani (until 2006); Shizuka Sasazuki (until 2017) (National Cancer Center, Tokyo); Akiko Tamakoshi (until 2018) (Hokkaido University, Sapporo); Yumi Sugawara, Ichiro Tsuji, and Yoshikazu Nishino (until 2006); Yoshitaka Tsubono (until 2003) (Tohoku University, Sendai); Tetsuya Mizoue (National Center for Global Health and Medicine, Tokyo); Shuhei Nomura (University of Tokyo, Tokyo); Hidekazu Suzuki (Keio University, Tokyo); Hidemi Ito, Keitaro Matsuo, and Isao Oze (Aichi Cancer Center, Nagoya); Kenji Wakai (until 2017) (Nagoya University, Nagoya); Yingsong Lin (Aichi Medical University, Aichi); Chisato Nagata and Keiko Wada (Gifu University, Gifu); Yuri Kitamura (Osaka University, Osaka); Tomio Nakayama (until 2017) (Osaka International Cancer Institute, Osaka); Mariko Naito (Hiroshima University, Hiroshima); Kotaro Ozasa, Atsuko Sadakane, and Mai Utada (Radiation Effects Research Foundation, Hiroshima); and Keitaro Tanaka (Saga University, Saga) .

Contributor Information

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REFERENCES