viernes, 30 de octubre de 2015
Molecular classification system for colorectal cancer
The International Consensus of Intrinsic Subtypes of Colorectal Cancer
The most robust molecular classification system currently available for colorectal cancer
Date: 29 Oct 2015
Topic: Genitourinary cancers / Translational research
The Colorectal Cancer Subtyping Consortium was formed to assess the presence or absence of core subtype patterns among existing gene expression–based colorectal cancer subtyping algorithms. The researchers also wanted to characterise the key biological features of the core subtypes, integrate and confront all other available data sources (mutation, copy number, methylation, microRNA and proteomics) and assess whether the subtype assignment correlated with patient outcome. Furthermore, their aim was to establish an important paradigm for collaborative, community-based cancer subtyping that will facilitate the translation of molecular subtypes into the clinic, not only for colorectal cancer, but for other malignancies as well.
The colorectal cancer subtypes are:
CMS1 (microsatellite instability immune, 14%), hypermutated, microsatellite unstable and strong immune activation;
CMS2 (canonical, 37%), epithelial, marked WNT and MYC signaling activation;
CMS3 (metabolic, 13%), epithelial and evident metabolic dysregulation; and
CMS4 (mesenchymal, 23%), prominent transforming growth factor–β activation, stromal invasion and angiogenesis.
Samples with mixed features (13%) possibly represent a transition phenotype or intratumoral heterogeneity.
Clinical and prognostic associations of the consensus molecular subtypes
The consortium also found important associations between the CMS groups and clinical variables. CMS1 tumours were frequently diagnosed in females with right-sided lesions and presented with higher histopathological grade.
Conversely, CMS2 tumours were mainly left-sided and, whereas CMS4 tumours tended to be diagnosed at more advanced stages (III and IV).
To determine whether the CMS groups differed in outcome, the researchers performed a Cox proportional hazards analysis on the combined data sets and separately in the subset of patients enrolled in a clinical trial with uniform follow-up (PETACC-3 clinical trial).
Irrespective of patient cohort, CMS4 tumours resulted in worse overall survival and worse relapse-free survival in both univariate and multivariate analyses, after adjustment for clinico-pathological features, MSI status and presence of BRAF or KRAS mutations.
The researchers also found superior survival rates after relapse in CMS2 patients, with a larger proportion of long-term survivors in this subset.
Notably, the CMS1 population had a very poor survival rate after relapse, in agreement with recent studies showing worse prognosis of patients with MSI and BRAF-mutated colorectal cancers that recur.
These differences in prognosis with unsupervised gene expression signatures confirm the clinical relevance of the intrinsic biological processes implicated in each CMS.
From a biological perspective, the consortium researchers were able to refine the number and interpretation of the 'non-MSI' subtypes, which represent nearly 85% of the primary colorectal cancer samples. They also described strong molecular associations, particularly for samples lacking a mesenchymal phenotype. From a clinical perspective, in colorectal cancer, as for many other cancer types, it remains unclear what features will provide the most relevant subclassification tool.
In colorectal cancer, few biomarkers (including RAS and BRAF mutations and MSI and CIMP status) have been translated to patient care. It is important to emphasize that although the CMS groups are enriched for some genomic and epigenomic markers, their associations described do not allow categorisation of gene expression subtypes, thus reinforcing the notion that transcriptional signatures allow refinement of disease subclassification beyond what can be achieved by currently validated biomarkers.
For example, although tumours with wild-type RAS are considered to be a homogeneous entity for the purpose of making therapeutic decisions in the setting of advanced cancer, they were found across distinct CMS groups with profound biological differences that are expected to translate into heterogeneous drug responses.
Thanks to the collaborative bioinformatics work on the largest collection of colorectal cancer cohorts with molecular annotation to date, and building upon previous efforts by the independent researchers, the analyses by members of the consortium resulted in a consensus molecular classification system that allows the categorisation of most tumours into one of four robust subtypes.
Marked differences in the intrinsic biological underpinnings of each subtype support the new taxonomy of this disease. The Consortium researchers believe that this new taxonomy will facilitate future research in the colorectal cancer field and should be adopted by the community for colorectal cancer stratification.
Reference
Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nature Medicine 2015; Published online 12 October. doi:10.1038/nm.3967
martes, 27 de octubre de 2015
Processed meat and colorectal cancer: a review
Nutr Cancer. Author manuscript; available in PMC 2009 Mar 27.
Published in final edited form as:
Nutr Cancer. 2008; 60(2): 131–144.
doi: 10.1080/01635580701684872
PMCID: PMC2661797
HALMS: HALMS334544
Processed meat and colorectal cancer: a review of epidemiologic and experimental evidence
Raphaëlle L. Santarelli,* Fabrice Pierre, and Denis E. Corpet
Abstract
Processed meat intake may be involved in the etiology of colorectal cancer, a major cause of death in affluent countries.
The epidemiologic studies published to date conclude that the excess risk in the highest category of processed meat-eaters is comprised between 20 and 50% compared with non-eaters.
In addition, the excess risk per gram of intake is clearly higher than that of fresh red meat. Several hypotheses, which are mainly based on studies carried out on red meat, may explain why processed meat intake is linked to cancer risk.
Those that have been tested experimentally are
(i) that high-fat diets could promote carcinogenesis via insulin resistance or fecal bile acids;
(ii) that cooking meat at a high temperature forms carcinogenic heterocyclic amines and polycyclic aromatic hydrocarbons;
(iii) that carcinogenic N-nitroso compounds are formed in meat and endogenously;
(iv) that heme iron in red meat can promote carcinogenesis because it increases cell proliferation in the mucosa, through lipoperoxidation and/or cytotoxicity of fecal water.
Nitrosation might increase the toxicity of heme in cured products. Solving this puzzle is a challenge that would permit to reduce cancer load by changing the processes rather than by banning processed meat.
Introduction
Colorectal cancer (CRC) is a major cause of cancer death in affluent countries, notably the United States and Western Europe.
Diet would strongly influence CRC risk, and changes in foods habits might reduce up to 70% of this cancer burden (1–3).
Epidemiologic studies suggest that meat intake is associated with CRC risk, although the association is not significant in most studies. Published in 1997, the World Cancer Research Fund authoritative expert report states: “evidence shows that red meat probably increases risk and processed meat possibly increases risk of CRC” (2).
Since 2000, three meta-analyses showed that total meat intake is not related to risk, but that red meat intake is a significant risk factor. In addition, as reported below, the association of CRC risk with processed red meat may be stronger than that with fresh red meat (4–6).
Several hypotheses could explain how processed meat could increase CRC risk, and experimental studies have been carried out accordingly. The major hypotheses that have been tested experimentally are
(i) that high-fat or high-protein diets could promote carcinogenesis;
(ii) that cooking meat at high temperature forms mutagenic and carcinogenic heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs);
(iii) that potentially carcinogenic N-nitroso compounds (NOCs) are formed in food and/or endogenously by nitrosation of amines and amides;
(iv) that heme iron in red meat can promote carcinogenesis because it increases cell proliferation in the colonic mucosa, through lipoperoxidation and/or cytotoxicity of fecal water.
Few experiments have been directly carried out on processed meats but the studies undertaken on red meats make it possible to propose the hypotheses cited above. There are no clearly demonstrated biologic mechanisms that could explain the risk difference between processed and unprocessed meat.
The aims of the present paper are
(i) to describe briefly the processed meat products
(ii) to review the epidemiologic evidence that processed meat increases CRC risk,
(iii) to review the experimental studies on the mechanisms explaining the effect of processed meat on colorectal carcinogenesis.
Processed Meat
Processed meat is made mostly from pork or beef meat that are preserved by methods other than freezing, and that undergo a treatment to improve the quality of cuts of carcasses, to increase preservation, and to change flavor.
There is a huge variety of processed meat products and it is not easy to sort them by categories, but parameters involved in the making of these foods are curing (adding salt and other additives), drying, smoking, cooking and packaging.
Processed meat includes bacon, ham (raw, smoked or cooked), heated sausages like hot-dogs (frankfurters), raw sausages (like salami), bologna, blood sausage (UK: black pudding), liver pâté (or liverwurst) and other pâtés and spread meat, luncheon meat and other cold cuts, canned meat, and corned beef (7, 8).
This list is not comprehensive, and many other specific products are made all over the world, using traditional recipes. Curing and smoking, two specific processes for meat, are described below as they might generate potential hazards.
Curing is the addition of a combination of salt, sugar and either nitrate or nitrite: salt improves the taste of meat and preserves it by stopping bacterial growth, because it diffuses inside the muscle and reduces the water activity.
Nitrite inhibits the germination of Clostridium botulinum spores, and gives the meat the desirable cured color by combining with heme iron. Nitrosylmyoglobin is responsible for the red color of raw cured meat. Cooking denatures globin which detaches from the heme, yielding a pink mononitrosylheme complex, the color of cooked cured meat (9, 10).
When saltpeter/nitrate is used, a previous step is needed so that bacteria reduce nitrate to nitrite. In many countries, the maximum permitted concentration of nitrite in processed meat is 200 ppm, and it is 150 ppm in the European Union. Curing can be done with dry salt, in a brine tank, or by injection:
Dry salting is the old way of meat curing. Cuts of meat are placed on heaps of salt and rubbed with salt or with a mix of salt, sugar and saltpeter (11).
This treatment is simple, but long, and its efficacy depends on the diffusion of salt into the meat.
A low temperature must be maintained until the center of the meat piece is salted enough to prevent internal spoilage.
Tank curing is faster than dry salting: meat pieces are placed in brine, water saturated with salt that may also contain sugar and nitrite.
Methods have been developed to accelerate the rate of diffusion of curing agents into meat either by the use of the arterial system by needle injections, or with multi-needle system.
Moreover, new additives have been used in brine to improve the color formation and stability with reducing agents like sodium ascorbate or erythorbate.
Smoking is the process of exposing meat to the smoke from incomplete wood pyrolysis. This gives meat a brown color, changes its flavor and helps its preservation because smoke contains phenols, aldehydes, acetic acid and other carboxylic acids. Wood pyrolysis may generate carcinogenic polycyclic aromatic hydrocarbon (PAH), and the process is hard to control.
A more controlled process is obtained by immersing meat pieces into a “smoke solution”, which gives smoke flavor without PAH contamination, and improves meat preservation because it contains acetic acid.
Among the many existing processed meat products, we chose to describe ham and sausages that contribute most to the overall processed meat intake (12). Ham is obtained by curing the upper quarter (thigh and sirloin) of a pig, and may be boiled (Jambon de Paris), dried (country ham), and/or smoked.
Sausages are prepared with chopped meat (pork usually, or a mix of pork and beef), lard, salt, and other additives (e.g., wine, saltpeter, garlic, herbs, spices). This preparation is usually packed in a casing (historically the intestines of the animal, though now often collagenic, cellulosic or polymeric).
Sausages may be dried (salami-type), cooked (hot-dog type), and/or smoked.
Blood sausage (UK black pudding) is prepared with blood (usually from pork), lard or suet, and a plant-based filling (bread, barley, onions), in three equal parts, with salt and spice. This preparation is packed in a pork bowel, and cooked until it becomes thick.
Processed meat intake makes one half to one fifth of total red meat intake. For instance, in 1999 French adults ate 38 and 63 g/d processed and fresh red meat, respectively (13).
In Europe, the intake of processed meat was 27 g/d [11–48] in women (median and range of 23 EPIC centers from ten European countries), and 48 g/d [19–88] in men (12). Fresh red meat intake was 36 g [25–52] in women, and 60 g/d [40–120] in European men (7). In the American CPSII Nutrition Cohort (median age 63 years) the median intake of processed and fresh red meat was estimated as 10 and 40 g/d, respectively (14).
In a Bethesda case-control study (median age 58 years) the mean intake of processed and red meat was 12 and 36 g/d (15, 16). These values may be underestimated, since they are based on food-frequency questionnaire data, and because subjects were older than the general population. Indeed, Norat et al. estimated that red meat intake in North America is 72 g/d per caput (5).
Epidemiologic Studies
International ecological studies show that countries where people eat more red meat are also countries where the risk of CRC is high (17). Analytical studies suggest that this association is also seen at the individual level, but the link is significant in only one study out of three (18).
Three meta-analyses have been published since 2000, and their quantitative risk estimate for fresh red meat and processed meat intake are summarized below and in Table 1.
Excess risk of CRC associated with the intake of fresh red meat and of processed meat in three dose-response meta-analyses of analytical studies Sandhu et al. (2001) made a meta-analysis gathering 13 cohort studies, selected from 17 studies, according to pre-established quality criteria (4).
All cohorts’ studies with relative risks between meat/processed meat intake and colon/colorectal cancer incidence or mortality were included up to 1999. Prospective studies that did not report the level of exposure (red meat/processed meat consumption) were excluded.
Norat et al. (2002) study derives 18 case-control and 6 cohort studies, selected from 48 (5). All studies published up to 1999, and providing association between total meat, red meat or processed meat intake and colon, rectal and colorectal incidence or mortality, were included.
Sandhu’s and Norat’s meta-analyses were not independent, since eleven studies were common to both articles.
Last, Larsson et al. published in 2006 a meta-analysis of 18 prospective studies, selected from 23, gathering a total of more than one million subjects. Norat’s and Larsson’s studies were quite independent, since only 15% of Norat’s subjects were counted again in Larsson’s study (6).
These three meta-analyses take all previous studies into account, and bring global and consistent conclusions on the effect of different types of meat: total meat, red meat, processed meat. Briefly:
Total intake of meat (including white and red meat from all sources) is not associated with CRC risk in Norat’s and in Larsson’s analyses. Sandhu’s study shows a significant moderate risk associated with total meat intake, but the authors did not include white meat (poultry) in total meat.
A high intake of red meat (usually including beef, veal, lamb, mutton, pork, and offal) is associated with a moderate and significant increased risk of CRC in the three studies:
In Sandhu’s study (4), the average relative risk (RR) of CRC for a 100 g portion of red meat is 1.17. The 95% confidence interval (CI) is 1.05–1.31. Processed meat was not included in red meat, we think, in this study (4).
In Norat’s study (5), CRC RR = 1.35 (CI: 1.21–1.51) for the highest quartile of consumption of red meat (including processed meat). A minor difference is observed between results from case-control and cohort studies (RR=1.36 and 1.27 respectively). The intake of 120 g/d of fresh (unprocessed) red meat is associated with a significant risk, but of lower magnitude than when processed meat is included (+ 19% compared with + 35%) (5).
In Larsson’s study (6), CRC RR = 1.28 (CI: 1.15–1.42) for the highest category of consumption of red meat (including processed meat). Fresh red meat intake (unprocessed meat) was reported in nine studies out of fifteen, and the associated RR was 1.22, a significant value. The risk excess associated with intake of 120 g/d of red meat was + 28%. Larsson’s article does not report the quantitative effect of fresh red meat, and no precision is given on the categories (6).
Processed meat intake (usually including sausages, meats burgers, ham, bacon, salami, nitrite-treated meat and meat products) is associated with CRC risk in all reports: Global RR are 1.49 (CI: 1.22–1.81), 1.31 (CI: 1.13–1.51) and 1.20 (CI: 1.11–1.31) in the three meta-analyses (4–6). In Norat’s analysis, a minor difference is observed between results from case-control and cohort studies (RR=1.29 and 1.39 respectively).
Thus the estimated excess risk associated with fresh red meat intake was 17%, 19% and 22%, and the risk associated with processed meat was 49%, 31% and 20%, in the three reviews, respectively.
The estimates of risk for fresh red meat are within a narrow range, but estimates of risk for processed meat are more dispersed. However, all RRs are significant, and none is larger than 1.5, which shows the consistency of the meta-analyses. As shown in Table 1, doses-response meta-analyses suggest that one gram of processed meat is eleven-times, six-times or twice more “promoting” than one gram of fresh red meat in the three meta-analyses, respectively (4–6).
It is not easy to explain why the processed/fresh meat ratio is higher in Sandhu’s study than in Larsson’s study. However, the three studies indicate that processed meat intake is associated with a higher CRC risk than the intake of other types of meat.
Four cohort study articles dealing with processed meat intake and CRC have been published after Larsson’s 2006 review (one new cohort, and three re-analyses, Table 2), and seven case-control studies shown in Table 3 were published after Norat’s 2002 review. Let us examine below if they strengthen or weaken the above-reported meta-analyses results.
Prospective studies published between 2003 and 2006, on the association between processed meat intake and colorectal cancer risk.
Case-control studies published between 2003 and 2007, on the relationship between processed meat intake and colorectal cancer risk.
A cohort of 30,000 men and women in Japan was studied by Oba et al. (2006), with 231 CRC cases.
Processed meats were ham, sausage, bacon, and yakibuta (Chinese roasted pork). In men, there was a positive association between CRC and the highest tertile of processed meat consumption (RR=1.98, CI: 1.24–3.16). No association was seen in women (RR=0.85, CI: 0.5–1.43) (19).
Three other articles made use of already published cohort studies, but they analyzed prospective data by dietary patterns, instead of type of foods. Fung et al. (2003) used data from the Nurses’ Health Study (20). The highest quintile of women eating a “western pattern”, defined by a high intake of red and processed meats, sweets and desserts, French fries, and refined grains, had a marginally significant increase in colon cancer risk, consistent with meta-analyses result (RR= 1.46, CI: 0.97–2.19).
No association was found with rectal cancer (20). Dixon et al. (2004) analyzed three prospective studies: the Alpha-Tocopherol Beta-Carotene Study (ATBC), the Netherlands Cohort (NLC), and the Swedish Mammography Cohort (SMC) (21).
Exploratory factor analysis identified a dietary pattern that includes processed meat in the three cohorts: the Processed meat, Pork, and Potatoes pattern. This pattern was associated with an increased risk of colon cancer in the SMC women (RR=1.62, CI: 1.12–2.34), and of rectal cancer in the ATBC men (RR=2.21, CI: 1.07–4.57), but not in the NLC study (RRs=0.9) (21). Kesse et al. (2006) studied food patterns in a French cohort of women, already reported in the EPIC study.
The “Western” diet pattern included: processed meat, potatoes, pizzas and pies, sandwiches, sweets, cakes, cheese, cereal products, eggs, and butter. The three other diets were: “Healthy” diet (vegetables, fruit, yogurt, sea products, and olive oil, “Drinker” diet (sandwiches, snacks, processed meat, and alcoholic beverages) and “Meat eaters” diet (meat, poultry, and margarine). “The” Western pattern increased adenoma risk, but not CRC risk (RR= 1.39, CI: 1.00–1.94 and RR = 1.09, CI: 0.60–2.00 respectively). “The” Drinker and the Meat eaters diets increased the adenoma risk and the CRC risk (see RRs on Table 3) (22).
To sum up these recent prospective studies, they bring some support to the conclusions of Larsson’s metaanalysis that processed meat intake is associated with increased risk, and the RR is in the range 1.5–2. However, the link was not found in all sub-groups (male/female, colon/rectum), and the risk associated with dietary patterns cannot be attributed to processed meat alone.
Seven case-control studies dealing with processed meat have been published after Norat’s meta-analysis. All studies report OR above 1.15, but only three studies out of six found a significant association between processed meat intake and CRC risk.
In Shangai, China, Chiu et al. (2003) found that a high intake of preserved foods (whether animal or plant source) was associated with an increased risk of colon cancer (OR= 2.0, CI: 1.5–2.9 in men, and OR=2.7, CI: 1.9–3.8 in women). Preserved vegetables was more strongly associated with cancer risk than preserved animal foods (23).
In the U.S.A., Chiu and Gapstur (2004) investigated the effect of dietary changes during adult life. They showed that risk was higher for people who did not reduce their consumption of red meat and processed meat after the age of 30 years, and risk was particularly high for pork chops/ham steaks eaters (OR= 3.7, CI: 1.6–8.7) (24).
In Canada, Nkondjock et al. established dietary patterns, as reported above for cohorts. The “pork and processed meat” pattern, characterized by a high consumption of processed meat, pork, and white bread, increased colon cancer risk nearly significantly (RR=1.6, CI: 0.9–2.8) (25).In Utah and Northern California, Murtaugh et al. (2004) found no association between processed meat intake and the risk of rectal cancer (RR=1.2, CI: 0.85–1.7) (26).
In Japan, Kimura et al. found that processed meat intake (and red meat intake) was not related to CRC risk (OR=1.15, CI: 0.83–1.60) (27). A Maryland case-control study of colorectal adenoma found a two-fold increased risk in the highest, compared to the lowest, quartile of processed meat intake (95% CI = 1.0–4.0). This OR was mostly explained by nitrate/nitrite intake, and marginally attenuated by MeIQx intake (a heterocyclic amine formed by cooking).
In addition, ham steak/pork chops, hot dogs/other sausages, and liverwurst intake each were associated with a two-fold risk of adenoma, while bacon, breakfast sausages, ham, bologna, salami, and other luncheon meats intake were not associated with the risk (16).
Lastly, In Canada, Hu et al. (28) found that consumption of processed meat increase risk of both proximal and distal colon cancer in men and women (all four OR were between 1.4 and 1.6, all CI:1.0–2.0, 2.2 or 2.4). Bacon intake was particularly associated with risk of colon cancer (proximal and distal) in women.
The estimation of cancer risk associated with meat may be influenced by other dietary factors, as shown clearly in the “dietary pattern” studies cited above (20–22). In those studies, the intake of processed meat was associated with intake of French fries (or potatoes), sweets, cakes, desserts, snacks and alcoholic beverages: These high glycemic index diets, and alcohol intake, may be risk factors for colorectal cancer.
In addition, high-meat diets have been negatively associated with food groups rich in antioxidants and fiber, components which have been associated with a reduced risk of colorectal cancer (4).
Thus, the effect of processed meat consumption on the risk of colorectal cancer may be confounded by other foods, as discussed further in the “Indirect mechanisms” section below. However, red meat intake is more consistently associated with risk than any other dietary factor, except the total energy intake (3, 29).
In summary,
the results of these meta-analyses support the hypothesis that high consumption of red and processed meat may increase the risk of CRC. The few studies published after the metaanalyses also support the evidence, although individual studies are seldom significant. In addition, the risk associated with consumption of one gram of processed meat was two to ten times higher than the risk associated with one gram of fresh red meat. It is thus likely that processed meat contains some components that are more potent than fresh red meat components.
Published in final edited form as:
Nutr Cancer. 2008; 60(2): 131–144.
doi: 10.1080/01635580701684872
PMCID: PMC2661797
HALMS: HALMS334544
Processed meat and colorectal cancer: a review of epidemiologic and experimental evidence
Raphaëlle L. Santarelli,* Fabrice Pierre, and Denis E. Corpet
Abstract
Processed meat intake may be involved in the etiology of colorectal cancer, a major cause of death in affluent countries.
The epidemiologic studies published to date conclude that the excess risk in the highest category of processed meat-eaters is comprised between 20 and 50% compared with non-eaters.
In addition, the excess risk per gram of intake is clearly higher than that of fresh red meat. Several hypotheses, which are mainly based on studies carried out on red meat, may explain why processed meat intake is linked to cancer risk.
Those that have been tested experimentally are
(i) that high-fat diets could promote carcinogenesis via insulin resistance or fecal bile acids;
(ii) that cooking meat at a high temperature forms carcinogenic heterocyclic amines and polycyclic aromatic hydrocarbons;
(iii) that carcinogenic N-nitroso compounds are formed in meat and endogenously;
(iv) that heme iron in red meat can promote carcinogenesis because it increases cell proliferation in the mucosa, through lipoperoxidation and/or cytotoxicity of fecal water.
Nitrosation might increase the toxicity of heme in cured products. Solving this puzzle is a challenge that would permit to reduce cancer load by changing the processes rather than by banning processed meat.
Introduction
Colorectal cancer (CRC) is a major cause of cancer death in affluent countries, notably the United States and Western Europe.
Diet would strongly influence CRC risk, and changes in foods habits might reduce up to 70% of this cancer burden (1–3).
Epidemiologic studies suggest that meat intake is associated with CRC risk, although the association is not significant in most studies. Published in 1997, the World Cancer Research Fund authoritative expert report states: “evidence shows that red meat probably increases risk and processed meat possibly increases risk of CRC” (2).
Since 2000, three meta-analyses showed that total meat intake is not related to risk, but that red meat intake is a significant risk factor. In addition, as reported below, the association of CRC risk with processed red meat may be stronger than that with fresh red meat (4–6).
Several hypotheses could explain how processed meat could increase CRC risk, and experimental studies have been carried out accordingly. The major hypotheses that have been tested experimentally are
(i) that high-fat or high-protein diets could promote carcinogenesis;
(ii) that cooking meat at high temperature forms mutagenic and carcinogenic heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs);
(iii) that potentially carcinogenic N-nitroso compounds (NOCs) are formed in food and/or endogenously by nitrosation of amines and amides;
(iv) that heme iron in red meat can promote carcinogenesis because it increases cell proliferation in the colonic mucosa, through lipoperoxidation and/or cytotoxicity of fecal water.
Few experiments have been directly carried out on processed meats but the studies undertaken on red meats make it possible to propose the hypotheses cited above. There are no clearly demonstrated biologic mechanisms that could explain the risk difference between processed and unprocessed meat.
The aims of the present paper are
(i) to describe briefly the processed meat products
(ii) to review the epidemiologic evidence that processed meat increases CRC risk,
(iii) to review the experimental studies on the mechanisms explaining the effect of processed meat on colorectal carcinogenesis.
Processed Meat
Processed meat is made mostly from pork or beef meat that are preserved by methods other than freezing, and that undergo a treatment to improve the quality of cuts of carcasses, to increase preservation, and to change flavor.
There is a huge variety of processed meat products and it is not easy to sort them by categories, but parameters involved in the making of these foods are curing (adding salt and other additives), drying, smoking, cooking and packaging.
Processed meat includes bacon, ham (raw, smoked or cooked), heated sausages like hot-dogs (frankfurters), raw sausages (like salami), bologna, blood sausage (UK: black pudding), liver pâté (or liverwurst) and other pâtés and spread meat, luncheon meat and other cold cuts, canned meat, and corned beef (7, 8).
This list is not comprehensive, and many other specific products are made all over the world, using traditional recipes. Curing and smoking, two specific processes for meat, are described below as they might generate potential hazards.
Curing is the addition of a combination of salt, sugar and either nitrate or nitrite: salt improves the taste of meat and preserves it by stopping bacterial growth, because it diffuses inside the muscle and reduces the water activity.
Nitrite inhibits the germination of Clostridium botulinum spores, and gives the meat the desirable cured color by combining with heme iron. Nitrosylmyoglobin is responsible for the red color of raw cured meat. Cooking denatures globin which detaches from the heme, yielding a pink mononitrosylheme complex, the color of cooked cured meat (9, 10).
When saltpeter/nitrate is used, a previous step is needed so that bacteria reduce nitrate to nitrite. In many countries, the maximum permitted concentration of nitrite in processed meat is 200 ppm, and it is 150 ppm in the European Union. Curing can be done with dry salt, in a brine tank, or by injection:
Dry salting is the old way of meat curing. Cuts of meat are placed on heaps of salt and rubbed with salt or with a mix of salt, sugar and saltpeter (11).
This treatment is simple, but long, and its efficacy depends on the diffusion of salt into the meat.
A low temperature must be maintained until the center of the meat piece is salted enough to prevent internal spoilage.
Tank curing is faster than dry salting: meat pieces are placed in brine, water saturated with salt that may also contain sugar and nitrite.
Methods have been developed to accelerate the rate of diffusion of curing agents into meat either by the use of the arterial system by needle injections, or with multi-needle system.
Moreover, new additives have been used in brine to improve the color formation and stability with reducing agents like sodium ascorbate or erythorbate.
Smoking is the process of exposing meat to the smoke from incomplete wood pyrolysis. This gives meat a brown color, changes its flavor and helps its preservation because smoke contains phenols, aldehydes, acetic acid and other carboxylic acids. Wood pyrolysis may generate carcinogenic polycyclic aromatic hydrocarbon (PAH), and the process is hard to control.
A more controlled process is obtained by immersing meat pieces into a “smoke solution”, which gives smoke flavor without PAH contamination, and improves meat preservation because it contains acetic acid.
Among the many existing processed meat products, we chose to describe ham and sausages that contribute most to the overall processed meat intake (12). Ham is obtained by curing the upper quarter (thigh and sirloin) of a pig, and may be boiled (Jambon de Paris), dried (country ham), and/or smoked.
Sausages are prepared with chopped meat (pork usually, or a mix of pork and beef), lard, salt, and other additives (e.g., wine, saltpeter, garlic, herbs, spices). This preparation is usually packed in a casing (historically the intestines of the animal, though now often collagenic, cellulosic or polymeric).
Sausages may be dried (salami-type), cooked (hot-dog type), and/or smoked.
Blood sausage (UK black pudding) is prepared with blood (usually from pork), lard or suet, and a plant-based filling (bread, barley, onions), in three equal parts, with salt and spice. This preparation is packed in a pork bowel, and cooked until it becomes thick.
Processed meat intake makes one half to one fifth of total red meat intake. For instance, in 1999 French adults ate 38 and 63 g/d processed and fresh red meat, respectively (13).
In Europe, the intake of processed meat was 27 g/d [11–48] in women (median and range of 23 EPIC centers from ten European countries), and 48 g/d [19–88] in men (12). Fresh red meat intake was 36 g [25–52] in women, and 60 g/d [40–120] in European men (7). In the American CPSII Nutrition Cohort (median age 63 years) the median intake of processed and fresh red meat was estimated as 10 and 40 g/d, respectively (14).
In a Bethesda case-control study (median age 58 years) the mean intake of processed and red meat was 12 and 36 g/d (15, 16). These values may be underestimated, since they are based on food-frequency questionnaire data, and because subjects were older than the general population. Indeed, Norat et al. estimated that red meat intake in North America is 72 g/d per caput (5).
Epidemiologic Studies
International ecological studies show that countries where people eat more red meat are also countries where the risk of CRC is high (17). Analytical studies suggest that this association is also seen at the individual level, but the link is significant in only one study out of three (18).
Three meta-analyses have been published since 2000, and their quantitative risk estimate for fresh red meat and processed meat intake are summarized below and in Table 1.
Excess risk of CRC associated with the intake of fresh red meat and of processed meat in three dose-response meta-analyses of analytical studies Sandhu et al. (2001) made a meta-analysis gathering 13 cohort studies, selected from 17 studies, according to pre-established quality criteria (4).
All cohorts’ studies with relative risks between meat/processed meat intake and colon/colorectal cancer incidence or mortality were included up to 1999. Prospective studies that did not report the level of exposure (red meat/processed meat consumption) were excluded.
Norat et al. (2002) study derives 18 case-control and 6 cohort studies, selected from 48 (5). All studies published up to 1999, and providing association between total meat, red meat or processed meat intake and colon, rectal and colorectal incidence or mortality, were included.
Sandhu’s and Norat’s meta-analyses were not independent, since eleven studies were common to both articles.
Last, Larsson et al. published in 2006 a meta-analysis of 18 prospective studies, selected from 23, gathering a total of more than one million subjects. Norat’s and Larsson’s studies were quite independent, since only 15% of Norat’s subjects were counted again in Larsson’s study (6).
These three meta-analyses take all previous studies into account, and bring global and consistent conclusions on the effect of different types of meat: total meat, red meat, processed meat. Briefly:
Total intake of meat (including white and red meat from all sources) is not associated with CRC risk in Norat’s and in Larsson’s analyses. Sandhu’s study shows a significant moderate risk associated with total meat intake, but the authors did not include white meat (poultry) in total meat.
A high intake of red meat (usually including beef, veal, lamb, mutton, pork, and offal) is associated with a moderate and significant increased risk of CRC in the three studies:
In Sandhu’s study (4), the average relative risk (RR) of CRC for a 100 g portion of red meat is 1.17. The 95% confidence interval (CI) is 1.05–1.31. Processed meat was not included in red meat, we think, in this study (4).
In Norat’s study (5), CRC RR = 1.35 (CI: 1.21–1.51) for the highest quartile of consumption of red meat (including processed meat). A minor difference is observed between results from case-control and cohort studies (RR=1.36 and 1.27 respectively). The intake of 120 g/d of fresh (unprocessed) red meat is associated with a significant risk, but of lower magnitude than when processed meat is included (+ 19% compared with + 35%) (5).
In Larsson’s study (6), CRC RR = 1.28 (CI: 1.15–1.42) for the highest category of consumption of red meat (including processed meat). Fresh red meat intake (unprocessed meat) was reported in nine studies out of fifteen, and the associated RR was 1.22, a significant value. The risk excess associated with intake of 120 g/d of red meat was + 28%. Larsson’s article does not report the quantitative effect of fresh red meat, and no precision is given on the categories (6).
Processed meat intake (usually including sausages, meats burgers, ham, bacon, salami, nitrite-treated meat and meat products) is associated with CRC risk in all reports: Global RR are 1.49 (CI: 1.22–1.81), 1.31 (CI: 1.13–1.51) and 1.20 (CI: 1.11–1.31) in the three meta-analyses (4–6). In Norat’s analysis, a minor difference is observed between results from case-control and cohort studies (RR=1.29 and 1.39 respectively).
Thus the estimated excess risk associated with fresh red meat intake was 17%, 19% and 22%, and the risk associated with processed meat was 49%, 31% and 20%, in the three reviews, respectively.
The estimates of risk for fresh red meat are within a narrow range, but estimates of risk for processed meat are more dispersed. However, all RRs are significant, and none is larger than 1.5, which shows the consistency of the meta-analyses. As shown in Table 1, doses-response meta-analyses suggest that one gram of processed meat is eleven-times, six-times or twice more “promoting” than one gram of fresh red meat in the three meta-analyses, respectively (4–6).
It is not easy to explain why the processed/fresh meat ratio is higher in Sandhu’s study than in Larsson’s study. However, the three studies indicate that processed meat intake is associated with a higher CRC risk than the intake of other types of meat.
Four cohort study articles dealing with processed meat intake and CRC have been published after Larsson’s 2006 review (one new cohort, and three re-analyses, Table 2), and seven case-control studies shown in Table 3 were published after Norat’s 2002 review. Let us examine below if they strengthen or weaken the above-reported meta-analyses results.
Prospective studies published between 2003 and 2006, on the association between processed meat intake and colorectal cancer risk.
Case-control studies published between 2003 and 2007, on the relationship between processed meat intake and colorectal cancer risk.
A cohort of 30,000 men and women in Japan was studied by Oba et al. (2006), with 231 CRC cases.
Processed meats were ham, sausage, bacon, and yakibuta (Chinese roasted pork). In men, there was a positive association between CRC and the highest tertile of processed meat consumption (RR=1.98, CI: 1.24–3.16). No association was seen in women (RR=0.85, CI: 0.5–1.43) (19).
Three other articles made use of already published cohort studies, but they analyzed prospective data by dietary patterns, instead of type of foods. Fung et al. (2003) used data from the Nurses’ Health Study (20). The highest quintile of women eating a “western pattern”, defined by a high intake of red and processed meats, sweets and desserts, French fries, and refined grains, had a marginally significant increase in colon cancer risk, consistent with meta-analyses result (RR= 1.46, CI: 0.97–2.19).
No association was found with rectal cancer (20). Dixon et al. (2004) analyzed three prospective studies: the Alpha-Tocopherol Beta-Carotene Study (ATBC), the Netherlands Cohort (NLC), and the Swedish Mammography Cohort (SMC) (21).
Exploratory factor analysis identified a dietary pattern that includes processed meat in the three cohorts: the Processed meat, Pork, and Potatoes pattern. This pattern was associated with an increased risk of colon cancer in the SMC women (RR=1.62, CI: 1.12–2.34), and of rectal cancer in the ATBC men (RR=2.21, CI: 1.07–4.57), but not in the NLC study (RRs=0.9) (21). Kesse et al. (2006) studied food patterns in a French cohort of women, already reported in the EPIC study.
The “Western” diet pattern included: processed meat, potatoes, pizzas and pies, sandwiches, sweets, cakes, cheese, cereal products, eggs, and butter. The three other diets were: “Healthy” diet (vegetables, fruit, yogurt, sea products, and olive oil, “Drinker” diet (sandwiches, snacks, processed meat, and alcoholic beverages) and “Meat eaters” diet (meat, poultry, and margarine). “The” Western pattern increased adenoma risk, but not CRC risk (RR= 1.39, CI: 1.00–1.94 and RR = 1.09, CI: 0.60–2.00 respectively). “The” Drinker and the Meat eaters diets increased the adenoma risk and the CRC risk (see RRs on Table 3) (22).
To sum up these recent prospective studies, they bring some support to the conclusions of Larsson’s metaanalysis that processed meat intake is associated with increased risk, and the RR is in the range 1.5–2. However, the link was not found in all sub-groups (male/female, colon/rectum), and the risk associated with dietary patterns cannot be attributed to processed meat alone.
Seven case-control studies dealing with processed meat have been published after Norat’s meta-analysis. All studies report OR above 1.15, but only three studies out of six found a significant association between processed meat intake and CRC risk.
In Shangai, China, Chiu et al. (2003) found that a high intake of preserved foods (whether animal or plant source) was associated with an increased risk of colon cancer (OR= 2.0, CI: 1.5–2.9 in men, and OR=2.7, CI: 1.9–3.8 in women). Preserved vegetables was more strongly associated with cancer risk than preserved animal foods (23).
In the U.S.A., Chiu and Gapstur (2004) investigated the effect of dietary changes during adult life. They showed that risk was higher for people who did not reduce their consumption of red meat and processed meat after the age of 30 years, and risk was particularly high for pork chops/ham steaks eaters (OR= 3.7, CI: 1.6–8.7) (24).
In Canada, Nkondjock et al. established dietary patterns, as reported above for cohorts. The “pork and processed meat” pattern, characterized by a high consumption of processed meat, pork, and white bread, increased colon cancer risk nearly significantly (RR=1.6, CI: 0.9–2.8) (25).In Utah and Northern California, Murtaugh et al. (2004) found no association between processed meat intake and the risk of rectal cancer (RR=1.2, CI: 0.85–1.7) (26).
In Japan, Kimura et al. found that processed meat intake (and red meat intake) was not related to CRC risk (OR=1.15, CI: 0.83–1.60) (27). A Maryland case-control study of colorectal adenoma found a two-fold increased risk in the highest, compared to the lowest, quartile of processed meat intake (95% CI = 1.0–4.0). This OR was mostly explained by nitrate/nitrite intake, and marginally attenuated by MeIQx intake (a heterocyclic amine formed by cooking).
In addition, ham steak/pork chops, hot dogs/other sausages, and liverwurst intake each were associated with a two-fold risk of adenoma, while bacon, breakfast sausages, ham, bologna, salami, and other luncheon meats intake were not associated with the risk (16).
Lastly, In Canada, Hu et al. (28) found that consumption of processed meat increase risk of both proximal and distal colon cancer in men and women (all four OR were between 1.4 and 1.6, all CI:1.0–2.0, 2.2 or 2.4). Bacon intake was particularly associated with risk of colon cancer (proximal and distal) in women.
The estimation of cancer risk associated with meat may be influenced by other dietary factors, as shown clearly in the “dietary pattern” studies cited above (20–22). In those studies, the intake of processed meat was associated with intake of French fries (or potatoes), sweets, cakes, desserts, snacks and alcoholic beverages: These high glycemic index diets, and alcohol intake, may be risk factors for colorectal cancer.
In addition, high-meat diets have been negatively associated with food groups rich in antioxidants and fiber, components which have been associated with a reduced risk of colorectal cancer (4).
Thus, the effect of processed meat consumption on the risk of colorectal cancer may be confounded by other foods, as discussed further in the “Indirect mechanisms” section below. However, red meat intake is more consistently associated with risk than any other dietary factor, except the total energy intake (3, 29).
In summary,
the results of these meta-analyses support the hypothesis that high consumption of red and processed meat may increase the risk of CRC. The few studies published after the metaanalyses also support the evidence, although individual studies are seldom significant. In addition, the risk associated with consumption of one gram of processed meat was two to ten times higher than the risk associated with one gram of fresh red meat. It is thus likely that processed meat contains some components that are more potent than fresh red meat components.
Processed Meat and Cancer AICR
Processed Meat and Cancer
This article appears in the August 7, 2014 issue of AICR's eNews.
Lunch meats bacon, ham, cold cuts – we get more questions about processed meats than any other type of food. It’s not surprising since the headlines can change with every new study. So we put together some answers to your most-asked questions.
What Are Processed Meats?
AICR/WCRF’s expert report and its updates define processed meat as “meat preserved by smoking, curing or salting, or addition of chemical preservatives.” Ham, bacon, sausages, hot dogs and yes, deli meats, are all considered processed meat.
How Does Processed Meat Affect Cancer Risk?
The latest analysis of the global research found that eating even small amounts of cold cuts or other processed meats on a regular basis increases the risk of colorectal cancer.
The report by AICR/WCRF also found that eating high amounts of red meat – over 18 ounces a week (501 gr.)– linked to increased risk of colorectal cancer.
In addition to its link to colorectal cancer, processed meat may also increase risk of heart disease.
How Much Processed Meat Is Safe to Eat?
Processed Meats
Sausage
Bacon
Deli meats
Hot dogs
Ham
Pepperoni
Salami
Corned beef
Research suggests that regularly eating even small amounts of cold cuts, bacon, sausage and hot dogs increase colorectal cancer risk, which is why AICR recommends avoiding these foods, except for special occasions.
The risk continues to rise as processed meat consumption increases. Studies show that compared to eating no processed meat, eating 3.5 ounces every day – a large hot dog – increases colorectal cancer risk by 36%.
Why Does Processed Meat Increase Cancer Risk?
It’s not yet clear exactly why processed meats increase risk for colorectal cancer. Researchers are currently exploring a few possible mechanisms, including:
Nitrates/Nitrites: These are added to processed meats to preserve color and prevent spoilage. In lab studies, these compounds form cancer-causing compounds, carcinogens.
Smoking: Smoked meats contain PAHs (Polycyclic Aromatic Hydrocarbons), substances that are formed at high-heat and considered carcinogenic.
Cooking at high temperatures: Meats cooked at high temperatures can also contain PAHs and heterocyclic amines (HCAs), which can damage DNA.
Heme iron: The heme iron found in red meat may damage the lining of the colon.
What about nitrate/nitrite-free turkey or other deli meats?
These products are relatively new. At this point, more research is needed to distinguish between nitrate/nitrite-free processed meats and the typical hot dogs and luncheon meats with added nitrates and nitrites. Sausage and other processed meat made from turkey or chicken is still smoked, salted, or cured so it is also included among the processed meats to carefully limit.
How to Reduce Overall Risk
When it comes to nutrition and cancer, it’s the healthy choices you make every day that matter most. The occasional hot dog at a baseball game or ham on a holiday is unlikely to increase cancer risk. To decrease your overall risk, try some of these simple swaps:
Replace packaged deli meats with fresh chicken or fish
Instead of bacon, chorizo or salami, try spicy vegetarian sausages.
Replace sausage in chili and sauces with beans like kidney beans, chickpeas and lentils.
Try out different sources of protein like eggs, cottage cheese and hummus.
Use herbs and spices like garlic, fennel seed and chili flakes to add flavor to your dish.
You May Also Like
What Is Processed Meat?
Learn More about Colorectal Cancer
Published on 2014-09-29 12:15:45.0
This article appears in the August 7, 2014 issue of AICR's eNews
This article appears in the August 7, 2014 issue of AICR's eNews.
Lunch meats bacon, ham, cold cuts – we get more questions about processed meats than any other type of food. It’s not surprising since the headlines can change with every new study. So we put together some answers to your most-asked questions.
What Are Processed Meats?
AICR/WCRF’s expert report and its updates define processed meat as “meat preserved by smoking, curing or salting, or addition of chemical preservatives.” Ham, bacon, sausages, hot dogs and yes, deli meats, are all considered processed meat.
How Does Processed Meat Affect Cancer Risk?
The latest analysis of the global research found that eating even small amounts of cold cuts or other processed meats on a regular basis increases the risk of colorectal cancer.
The report by AICR/WCRF also found that eating high amounts of red meat – over 18 ounces a week (501 gr.)– linked to increased risk of colorectal cancer.
In addition to its link to colorectal cancer, processed meat may also increase risk of heart disease.
How Much Processed Meat Is Safe to Eat?
Processed Meats
Sausage
Bacon
Deli meats
Hot dogs
Ham
Pepperoni
Salami
Corned beef
Research suggests that regularly eating even small amounts of cold cuts, bacon, sausage and hot dogs increase colorectal cancer risk, which is why AICR recommends avoiding these foods, except for special occasions.
The risk continues to rise as processed meat consumption increases. Studies show that compared to eating no processed meat, eating 3.5 ounces every day – a large hot dog – increases colorectal cancer risk by 36%.
Why Does Processed Meat Increase Cancer Risk?
It’s not yet clear exactly why processed meats increase risk for colorectal cancer. Researchers are currently exploring a few possible mechanisms, including:
Nitrates/Nitrites: These are added to processed meats to preserve color and prevent spoilage. In lab studies, these compounds form cancer-causing compounds, carcinogens.
Smoking: Smoked meats contain PAHs (Polycyclic Aromatic Hydrocarbons), substances that are formed at high-heat and considered carcinogenic.
Cooking at high temperatures: Meats cooked at high temperatures can also contain PAHs and heterocyclic amines (HCAs), which can damage DNA.
Heme iron: The heme iron found in red meat may damage the lining of the colon.
What about nitrate/nitrite-free turkey or other deli meats?
These products are relatively new. At this point, more research is needed to distinguish between nitrate/nitrite-free processed meats and the typical hot dogs and luncheon meats with added nitrates and nitrites. Sausage and other processed meat made from turkey or chicken is still smoked, salted, or cured so it is also included among the processed meats to carefully limit.
How to Reduce Overall Risk
When it comes to nutrition and cancer, it’s the healthy choices you make every day that matter most. The occasional hot dog at a baseball game or ham on a holiday is unlikely to increase cancer risk. To decrease your overall risk, try some of these simple swaps:
Replace packaged deli meats with fresh chicken or fish
Instead of bacon, chorizo or salami, try spicy vegetarian sausages.
Replace sausage in chili and sauces with beans like kidney beans, chickpeas and lentils.
Try out different sources of protein like eggs, cottage cheese and hummus.
Use herbs and spices like garlic, fennel seed and chili flakes to add flavor to your dish.
You May Also Like
What Is Processed Meat?
Learn More about Colorectal Cancer
Published on 2014-09-29 12:15:45.0
This article appears in the August 7, 2014 issue of AICR's eNews
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