The Rising Trend of Early-Onset Colorectal Cancer in Younger Individuals
Colorectal cancer, once considered a disease of the elderly, is increasingly affecting younger individuals. This CME article explores the alarming trend of early-onset colorectal cancer.
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Colorectal cancer used to be a disease of the aged. A recent dramatic increase in colon cancer incidence in younger individuals has become a notable problem. This article will review this increasing trend in a younger age group and will provide possible explanations for this increase.
Increasing Incidence
In the United States (US) an annual 2% increase of early onset colorectal cancer (EOCRC) was noted between 2011 and 2016.[1] Based on current trend, by 2030 the incidence of colon and rectal cancer compared to 2010 will increase by 90% for patients 20 to 34 years of age and by 27.7% for patients 35 to 49 years of age.[2] In contrast, the incidence of colorectal cancer in the elderly has been decreasing, and is thought to be due to screening colonoscopies which in the past were recommended for people over the age of 50.[2] However, in 2021, the U.S. Preventive Services Task Force recommended that colorectal cancer screening either by stool screening or direct observation should start at age 45.[3] It is thought that up to 30% of EOCRCs are hereditary in nature but the remainder may be due to lifestyle or environmental factors.[4]
Why is Early Onset Colon Cancer Increasing
The increasing incidence of EOCRC may be attributed to behavioral factors such as obesity, physical inactivity, and diet. Other possible causes are ingestion or inhalation of toxic substances. Some of these factors are directly toxic and some are thought to cause dysbiosis (an imbalance of the microorganisms in the gut which can lead to chronic inflammation), possibly leading to cancer development.[5,6]
Obesity
The prevalence of obesity has increased markedly in the United States over time and is a major risk factor for EOCRC.[2] It is thought that body fat releases inflammatory cytokines and adipokines as well as increasing insulin levels and growth factors that may predispose to the development of cancers at an earlier age.[7] The increased risk of colorectal cancer from obesity varies from study to study, depending on geographic location, gender, and body mass index (BMI), with a range of about an 8% to 50% increase in the risk of colorectal cancer in obese individuals.[8,9]
Lack of exercise
Lack of exercise may also be a precipitant of EOCRC. In one study prolonged sedentary television time, a marker of inactive lifestyle, was found to correlate with an increased risk of colorectal cancer. In that study, watching 7-to-14 hours of television per week increased risk of colorectal cancer 12% and watching more than 14 hours a week increased the risk by 69%.[10] Moderate physical activity has been demonstrated to reduce the risk of both colon and rectal cancers.[2,11] In other studies vigorous exercise reduced the risk of rectal cancer by 40%[11] and a meta-analysis reported that the risk of colon cancer was reduced 19% in those who regularly exercised.[12]
Diet
The Western diet which consists of significant amounts of processed meats, red meat, fast food, and low levels of vegetables and fruits is also associated with an increased risk of colon cancer[2]. One study found that subjects eating the Western diet had approximately twice the risk of developing colon cancer compared with those who ate a diet consisting of more vegetables, fruits, fish, and poultry and less red meat and sugar than the Western diet[13]
Ultra-processed foods including ready-to-eat or ready-to-heat formulations contribute about 57% of the calories consumed by American adults, and has been increasing for the past two decades. These foods are typically high in sugar, oils/fats, and refined starch, and have been found to alter gut microbiota composition unfavorably, which is a known cause of intestinal inflammation. Heating may also cause migration of carcinogenic chemicals from the ultra-processed foods as well as from the packaging. Ultra-processed foods can also contribute to an increased risk of obesity, which is another risk factor for colorectal cancer.[14]
Ultra-processed foods frequently contain food additives such as dietary emulsifiers and artificial sweeteners, some of which may also increase the pro-inflammatory potential of an imbalanced gut microbiome.[2] Food emulsifiers are chemically similar to detergents and are added to processed foods to improve texture or extend their shelf life. Scientists reported that mice fed low levels of common dietary emulsifiers developed altered gut microbiota and had a thinning of the mucus barrier protecting the intestinal lining. The mice also developed low-grade intestinal inflammation and metabolic syndrome. In a second experiment mice were either fed plain drinking water or water containing a 1% concentration of two common food emulsifiers. Mice fed the emulsifiers developed chronic low-grade intestinal inflammation and impaired glucose metabolism. These mice were then given a cancer-causing agent and the emulsifier-fed mice developed more intestinal inflammation and cancer development than the mice who were fed plain water.[15]
A longitudinal study of over 200,000 health professionals reported that men in the top fifth of ultra-processed food consumption had a 29% higher risk of developing colorectal cancer than men in the lowest fifth. No association between ultra-processed food consumption in women in that study was detected, with one possible explanation being a protective effect from estrogen.[14]
Alcohol
Alcohol has been found to be a risk factor in EOCRC. One study of over five million subjects reported that compared to light drinkers, moderate drinkers had a 9% increased risk and heavy drinkers a 20% increased risk of EOCRC. Compared to non-drinkers there was a dose-related response with a 7% increased risk of EOCRC for subjects that drank one-to-two days per week, 14% increased risk for those who drank three-to-four days per week and a 27% increased risk of EOCRC for those who drank five or more days per week. Suggested causes for this include a DNA damaging effect of acetaldehyde (an ethanol metabolite), tissue injury by oxidative stress, and alcohol-induced intestinal biome changes. Heavy drinkers are also known to frequently have a poor diet low in folate and fiber which may be synergistic with other cancer-causing properties of alcohol.[4] The U.S. Surgeon General has recently suggested that alcohol warning labels should include a statement about the heightened risk of cancer from drinking alcohol.[16]
Microplastics
Microplastics which are microscopic particles shed from plastic have been detected in soil, ground water, and many food products Microplastics have been found both in human stool and embedded in human intestinal specimens. One theory is that microplastics adherent to the intestinal mucus layer may release some of the carcinogenic chemicals used in the manufacturing of plastic into the intestinal wall. Microplastics adherent to the intestinal wall may also facilitate the development of biofilm which can change the intestinal microbiome and lead to chronic inflammation.[17] One study found microplastics in infant stool at higher levels per gram than adult stool, indicating possible lifelong exposure to intestinal microplastics.[18] A definitive connection between human exposure to microplastics and colorectal cancer has not been proven, but research is ongoing.
Chemicals
A meta-analysis reviewed 33 studies for any correlation between herbicide and insecticide exposure and colon cancer and found that significant herbicide and pesticide exposure increased colon cancer risk by 20% to 32%.[19]
“Forever chemicals” such as perfluoroalkyl and polyfluoroalkyl substances (PFAS) that are in the air, soil and food chain have been investigated as a possible cause of EOCRC. Perfluorooctanesulfonic acid (PFOS) is one of the most commonly detected PFAS, frequently found in drinking water samples with an estimated elimination half-life of 3.4-to-4.8 years in humans. In one experiment, mice were either fed a normal diet or a diet containing PFOS. They reported that the PFOS eating mice had downregulation of their HMGCS2 gene in their intestines. (HMGCS2 controls an enzyme for ketogenesis, a metabolic pathway that provides lipid-derived energy for various organs during times of carbohydrate deprivation.) In the study, reduced HMGCS2 activity resulted in enhanced proliferation of lipids and lipid accumulation. PFOS exposure induced changes in a number of other genes and increased levels of proteins associated with carcinogenesis in the intestinal tissues of mice. The authors also reported that a review of human specimens and cancer databases found decreased intestinal expression of HMGCS2 is associated with colon cancer as well as a decreased survival time in those who develop colon cancer.[20]
Toxic Metals
Toxic metals can accumulate in the body over time and are known to disrupt cellular homeostasis, trigger oxidative stress, and induce DNA damage, which can potentially lead to carcinogenesis.[21] There are some data about toxic metals and human colorectal cancer but these are not definitive.
In one study, higher lead levels in female factory workers were associated with an increased risk of death from colorectal cancer, but it was only based on three workers who had developed colorectal cancer. There was no significant difference in colon cancer death rates in male factory workers based on blood lead levels.[22]
Another study calculated mercury ingestion based on the subjects’ dietary intake of fish and shellfish products. It was reported that higher levels of mercury ingestion via seafoods resulted in greater than a three times increased risk of colorectal cancer compared to controls who ate much less seafood and theoretically had lower mercury exposure.[23]
One study reported increased levels of lead, chromium and mercury in human colon cancer samples that were absent in normal tissue.[24] However, a second study did not find any statistically significant difference between chromium levels of cancerous colonic tissue versus normal tissue.[25]
While aluminum, chromium and cadmium are known to potentially induce inflammatory changes, a definitive connection to colorectal cancer has not been established.[21] Arsenic is present in the food supply chain, and has been shown to have multiple toxic effects.[26] However, no association to colorectal cancer has been demonstrated as of yet.[21]
Thus, while there is some indirect and weak evidence that ingestion of some toxic metals may increase the risk of developing colorectal cancer, more research and better studies are needed.
Diabetes
In a number of studies type 2 diabetes has been shown to increase the risk of colorectal cancer to as high as 47% compared to non-diabetics. This increased risk appears to be more definitively demonstrated in men. In women with type 2 diabetes some studies have shown lesser increases in colorectal cancer risk compared to men, while others reported risk increases equivalent to men. Insulin supplies growth factors for colonic epithelial cells and higher than normal insulin levels, as seen in type 2 diabetes, may increase the cellular growth of tumors. Hyperglycemia may decrease the effectiveness of the immune system, which is theorized as another possible mechanism for development of cancer.[27,28,29,30]
Cigarette Smoking
Cigarette smoking is known to increase the risk of colon cancer. Subjects in one study who smoked for 12 or more years before the age of 30 were reported to have a 37% increased risk of developing colorectal cancer compared to non-smokers. The actual mechanism of how cigarette smoking increases EOCRC is not known but one theory is that smoking cigarettes in early adulthood may be associated with molecular changes in the colon that may increase the risk of colorectal cancer.[31]
Circadian Rhythm Disruption
It is known that circadian rhythm disturbances can cause gut dysbiosis where the normal balance of microorganisms in the intestines is negatively affected which can lead to chronic inflammation which is thought to be a possible precursor to EOCRC. In a mouse model, induced circadian rhythm disturbances cause increased amounts of bacteria known to cause inflammation, and increased gut barrier defects. The gut barrier is a multilayered system that allows nutrients to pass though the intestinal wall, but prevents pathogens from entering. It was also reported that circadian rhythm disturbances increased the incidence of cancer found in genetically modified mice. [32,33]
However, findings in humans have not been as clear. A longitudinal study of over 78,000 nurses reported that nurses who rotated on night shifts more than three times a month for over 15 years had a 35% increased risk of colorectal cancers compared to nurses that did not work nights. However, a study by some of the same authors 15 years later using many more subjects, as well as the original database, found no significant differences between rotating night nurses and day shift nurses with respect to colorectal cancer rates.[34,35] A meta-analysis of 57 studies reviewed this issue and found no increase in colorectal cancers in rotating or fixed night shift workers compared to day shift workers.[36] Thus while circadian rhythm disruption in the animal model has demonstrated negative changes to the gut environment, and an initial study with nurses was suggestive of a correlation, further studies have not confirmed the connection of night shift work and colorectal cancer.
Summary
It is clear from the scientific data that the incidence of EOCRC is increasing. As was discussed in this article there are many possible causes. These include food additives, microplastics, cancer-causing chemicals from plastics, herbicides, pesticides, forever chemicals, toxic metals, obesity, lack of exercise, alcohol use and cigarette smoking. Risk factors such as alcohol use and cigarette smoking, while contributory to EOCRC, are probably not the cause of its recent increase in incidence as they have been present and used in the population for generations. Generally, it takes decades to develop colorectal cancer, but there is evidence that some of these substances, such as microplastics in the intestine are now being ingested from infancy. Some causes may have a direct carcinogenic effect and some may increase cancer incidence by changing the microbiome of the intestine leading to chronic inflammation. The etiology of the increases in EOCRC appears to be multifactorial. It may be possible that in the future recommending the first colorectal cancer screening at an earlier age than 45 might need to be considered. It is impossible for individuals in modern societies to avoid all possible precipitating factors, but exposure can be limited and the risk of EOCRC decreased. Simple modifications of lifestyle such as increasing exercise, stopping cigarette smoking, or dietary changes may significantly reduce risk.
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References
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