Association of High Body Mass Index in Early Life With the Development of Colorectal Cancer

Abstract

Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive tract. In recent years, the age at which CRC is diagnosed has been trending younger on a global scale. Obesity, as a worldwide epidemic, is on the rise in most countries due to changes in dietary habits and lifestyles. Concurrently, with increased screening efforts and growing public awareness of health, the incidence of CRC in older adults is gradually declining, while the incidence in younger and middle-aged individuals is steadily increasing. This seems to indicate a strong association between overweight and obesity and a younger age of colorectal cancer diagnosis. Currently, with advancements in research on the relationship between early life (childhood and adolescence) body weight and CRC, new insights have been gained regarding the role of high BMI (overweight and obesity) in the occurrence and development of CRC, as well as its impact at different early life stages. Adolescence appears to be a particularly critical period. Therefore, this review will summarize the relationship between early life high BMI and CRC, aiming to provide a reference for clinical and basic research as well as CRC prevention.

Significance

This study on the relationship between early life high BMI and the development of CRC reveals the role of high BMI during childhood and adolescence in the occurrence and progression of CRC. It suggests the importance of restoring normal weight or reducing weight in individuals with high BMI early in life for the prevention of colorectal cancer.

Introduction

According to the World Health Organization’s 2020 report, colorectal cancer (CRC) ranks third in cancer incidence worldwide. ¹ Among these, the incidence of late-onset CRC is gradually decreasing. However, in contrast, the incidence of early-onset CRC is rising sharply.^2,3 Recently, a study from the United Kingdom clearly demonstrated that high BMI is one of the most important modifiable risk factors for cancer incidence, second only to smoking among all cancer risk factors. ⁴ Unfortunately, little is known about the most critical periods when high Body Mass Index (BMI) increases the risk of CRC. ⁵ A mathematical model based on the dynamics of intestinal crypt stem cells and progenitor cells suggests that CRC typically takes 40-50 years to develop. ⁶ Due to the long latency period of CRC, some researchers believe that the risk factors for its occurrence may appear early in life. ⁷ Cé lind et al posited that the onset of weight-related CRC occurs in childhood, with adolescent weight acting as a mediator between childhood weight and CRC. ⁸ Additionally, several studies have reported that after adjusting for childhood and/or adolescent weight, there is no correlation between adult weight and increased CRC risk.^9–11 Therefore, some studies suggest that although adult BMI is a risk factor for CRC, it has little to do with the etiology of CRC. ⁷ In recent decades, the number of children and adolescents who are overweight or obese has risen dramatically, as Westernized diets and sedentary lifestyles have become increasingly prevalent. Early life high BMI, as a modifiable risk factor for CRC, combined with the nearly parallel increase in high BMI and CRC incidence, indicates that high BMI in early life plays a crucial role in the occurrence and development of CRC. This paper reviews the role of high BMI in early life in the development of CRC.

The Relationship Between High Body Mass Index and Colorectal Cancer

As an established modifiable risk factor for colorectal cancer, high BMI can be divided into direct and indirect effects according to its role in the occurrence and development of CRC through different mechanisms or pathways.

The Direct Effect of High Body Mass Index on Colorectal Cancer

Compared to individuals with normal weight, those with high BMI have more adipose tissue. As an endocrine organ, adipose tissue plays an irreplaceable role in the connection between high BMI and CRC.^1,12,13 Adipose tissue promotes an increase in most inflammatory factors by secreting adipokines (such as leptin). ¹⁴ This increase in inflammatory factors leads to insulin resistance in obese patients, which in turn results in chronic hyperinsulinemia and elevated levels of insulin-like growth factors. ¹⁵ This promotes the proliferation and differentiation of tumor cells in obese individuals, ultimately leading to the formation of malignant tumors. ¹⁶ Furthermore, chronic intestinal inflammation is a recognized significant risk factor for CRC. ¹⁶ In patients with high BMI, increased inflammatory mediators and decreased adiponectin levels place the intestines in a pro-inflammatory state. ¹⁴ Prolonged inflammation in the intestines can further develop into CRC. The study of Naujoks and Quandt et al found that Natural killer (NK) cells in patients with high BMI had a decreased ability to kill cancer cells, which in turn increased the number of cancer cells in patients, greatly increasing the probability of developing into CRC. ¹⁷ Additionally, studies by Scheurlen et al ¹⁵ suggest that high BMI can cause systemic inflammation through oxidative stress mediated by nuclear factor erythroid 2-related factor 2 (NRF2), leading to the development of CRC in these patients. Inflammation induced by high BMI may also be involved in the DNA methylation regulation of oncogenes (such as NANOG) in differentiated colonic cells, making them more susceptible to subsequent cancerous changes. ¹⁸ Changes in DNA methylation could also lead to dysregulation of insulin signaling pathways, ¹⁹ increasing uncontrolled cell proliferation and malignant transformation, making individuals with high BMI more prone to developing intestinal malignancies compared to those with normal weight.

Indirect Effects of High Body Mass Index on Colorectal Cancer

High BMI is a well-established risk factor for type 2 diabetes and its related complications. ²⁰ Studies have reported that high BMI and type 2 diabetes are among the most significant risk factors for CRC, ²¹ with the association between type 2 diabetes and CRC being comparable to that of individuals with a family history of CRC. Patients with type 2 diabetes develop insulin resistance, ²² resulting in elevated insulin levels, hyperinsulinemia, and increased levels of insulin-like growth factors, which promote tumor occurrence and growth, leading to CRC. Additionally, metabolic syndrome is also a definitive risk factor for CRC. ²³ Metabolic syndrome refers to a cluster of conditions that include three or more of the following: diabetes, hypertension, abdominal obesity, hypertriglyceridemia, or low-density lipoprotein (LDL) cholesterol. ²⁴ High BMI increases the risk of diabetes, heart disease, hypertension, and hypercholesterolemia. ²⁵ Therefore, obesity can increase the prevalence of metabolic syndrome, which in turn raises the incidence of CRC. Numerous studies suggest a gender difference in the association between high BMI and CRC.^1,26 High BMI is an independent risk factor for CRC in men, but there is no significant association between high BMI and CRC in women. ²⁷ This may be because estrogen lowers serum levels of insulin-like growth factor (IGF), thereby exerting a protective effect via the insulin/IGF-1 axis. ²⁸ Furthermore, adipose tissue can produce a certain amount of estrogen, ²⁹ which may play a preventive role in the development of CRC in premenopausal and postmenopausal women with high BMI. Additionally, estrogen replacement therapy has been consistently associated with reduced CRC mortality, further supporting this notion. ³⁰ Beyond these factors, obesity is also related to the nature and alteration of gut microbiota, which in turn may play a significant role in the development of obesity.^31,32 Gut microbiota not only affect metabolic disorders but also have a critical relationship with the occurrence and development of intestinal inflammation. Cani et al ³³ proposed that lipopolysaccharides (a component of the outer membrane of Gram-negative bacteria) are triggers for the early development of intestinal inflammation and metabolic diseases. Moreover, changes in gut microbial metabolites, ³⁴ such as deoxycholic acid (a secondary bile acid produced by Gram-positive bacteria), can lead to DNA damage. Hence, obesity can promote the development of CRC through its effects on gut microbiota. Obesity may also serve as a proxy for other established CRC risk factors. For example, increased consumption of red meat and prolonged sedentary behavior are associated with weight gain. ³² Red meat and processed meat contain preservatives such as heterocyclic amines, polycyclic aromatic hydrocarbons, and N-nitroso compounds (NOCs) derived from nitrates/nitrites, which can cause epithelial injury and proliferation in the intestine, potentially leading to DNA damage and CRC. ³² Additionally, the heme iron in red meat can catalyze the formation of NOCs and lipid peroxidation, further exacerbating the formation of CRC. ³²

The Role of High Body Mass Index at Different Early Life Stages in the Development of Colorectal Cancer

The Role of High Body Mass Index in Childhood in the Development of Colorectal Cancer

Obesity as a modifiable risk factor for CRC has been confirmed in middle-aged and older populations. ³⁵ However, CRC has a long latency period, typically requiring 40-50 years to develop. Therefore, considering the timeline of CRC and the current prevalence of high BMI among children, it is meaningful to explore the potential link between childhood body size and CRC. ⁷

Weihe and colleagues ⁴ suggest that inflammation induced by obesity begins as early as childhood and continues to influence metabolic regulation and immune responses to non-metabolic stimuli throughout life as the prevalence of obesity increases across all age groups. Additionally, the NK cells in obese children are activated, ⁴ leading to metabolic stress and functional defects. This indicates that the negative impact of obesity on anti-tumor immunity manifests early in life and may exist long before the development of malignancies. Furthermore, childhood obesity could lead to lifelong insulin exposure because obesity in childhood often persists into adulthood. ¹¹ Since adolescence is a sensitive period for reduced insulin sensitivity, obesity before and during adolescence may be associated with higher insulin levels. Childhood growth is primarily driven by growth hormone, and obesity reduces insulin sensitivity. Accordingly, some studies ⁷ suggest that childhood may be a critical window for the metabolic programming of CRC risk factors, with growth factors playing a significant mediating role in the link between childhood BMI and CRC by catalyzing early pathophysiological steps of CRC through related metabolic processes. The study ⁷ also posits that childhood BMI is a determinant of adult CRC risk, finding a significant positive correlation between higher-than-average childhood BMI and adult colorectal cancer. Additionally, a compelling study indicates that early-life obesity impacts the risk of CRC decades later. ³⁶

Nimptsch et al ¹¹ discovered a significant positive correlation between higher body fat at ages 5 and 10 and the risk of colorectal adenomas, but no such correlation was found with BMI at age 20. Another study ⁸ found that children who were overweight at age 8 had a significantly increased risk of developing colon cancer in adulthood, even after adjusting for birth cohort weight and physical activity. Similarly, research ³⁷ by Boyd-Orr et al found no association between BMI measured in early childhood (ages 2-8) and cancer later in life, but significant associations emerged when BMI was measured and elevated at ages above 8. Moreover, a Danish study ⁷ clearly indicated that the relationship between high BMI and colon and rectal cancer might begin between ages 7-13. Convincingly, data from two large prospective studies also demonstrated a significant association between childhood weight gain and increased CRC risk. ³⁶

The Role of High Body Mass Index During Adolescence in the Development and Progression of Colorectal Cancer

Adolescence is a period characterized by a significant reduction in insulin sensitivity. ³⁸ Additionally, the growth patterns during adolescence are markedly different from those in childhood. Therefore, compared to individuals with high BMI during childhood, those with high BMI during adolescence may have a relationship with CRC that is at a distinctly different stage from that of the childhood high BMI group.

Adolescence marks the transitional phase from childhood to adulthood, characterized by accelerated growth. ³⁹ Therefore, this period may be a critical window for the susceptibility of high BMI exposure in adolescents. ³⁹ Adolescent BMI and inflammation might be related to exposures in childhood and adulthood. It seems that the increased risk of CRC associated with high BMI or inflammation is due to the total duration of exposure rather than exposure during any specific life stage. ³⁹ Multiple studies^{5,9,10,16,39–51} have demonstrated a strong association between high BMI during adolescence and an increased risk of CRC, even after adjusting for potential confounding factors and across different regions. ¹⁶

To evaluate the temporal effect of high BMI on CRC, studies ⁵⁰ have categorized adolescents with high BMI into early and late entry periods based on study entry and cancer registry times. The results showed no association between CRC and early entry, but a significant association with late entry among adolescents with high BMI. This effectively validates the role of recent population weight gain in the increase of CRC cases. ⁵⁰ A study assessing BMI at age 18 found that BMI at this age is a better predictor of colon cancer risk than BMI in middle age. ⁴² Le and colleagues ⁴⁴ suggested that late adolescence might be a potentially important period in the etiology of CRC, and high BMI in early and late young adulthood appears to have an additive cumulative positive effect on the risk of sigmoid colon cancer in men, with late adolescence high BMI seeming to have a greater impact than midlife obesity. Some studies have reported that the relationship between BMI and CRC might be closer when considering the period from adolescence to adulthood compared to pre-adolescence to adulthood. ⁵² Additionally, other studies indicate that regardless of the mechanisms linking high BMI and CRC, an increase in high BMI during adolescence seems to lead to an increased incidence of CRC in adulthood, and the rise in adult CRC cases can be attributed to adolescent overweight. ¹⁰ This aligns with another study suggesting that overweight males in adolescence have an increased risk of developing colon cancer and gout, and adolescent overweight seems to be a better predictor of these diseases than adult overweight. ⁵³ Furer and colleagues ⁵⁰ found that starting at age 30, an increase in BMI since adolescence is associated with an increased incidence of cancer in both men and women, and among cancer patients, a history of high adolescent BMI is linked to higher mortality rates. Research has shown that compared to normal BMI groups, those with high BMI at ages 20, 30, and the decade before diagnosis or interview, have the strongest association between BMI at age 20 and CRC, further indicating the special relationship between late adolescent BMI and CRC. ⁴¹ Chute and colleagues ⁵⁴ discovered a weak association between obesity at age 18 and CRC, which was stronger than that between adult obesity and CRC. Additionally, two studies^54,55 concluded that BMI assessed at ages 21 and 18 is a better predictor of CRC risk than BMI assessed in contemporary middle-aged adults. However, several studies have shown no correlation between high adult BMI and CRC. In a cohort of Japanese men in Hawaii, Nomura and colleagues found no association between weight at age 25 and CRC incidence. ⁵⁶ Whittemore and colleagues, in a prospective study of male college students, found no link between weight during college or after graduation and CRC risk. ⁵⁵ Furthermore, a study on the relationship between female BMI at age 18 and CRC found no significant link between weight gain after age 18 and overall CRC risk after adjusting for BMI at age 18 ⁹ .

However, the aforementioned studies did not evaluate the association between childhood BMI and CRC. High BMI in childhood often persists into adolescence and adulthood, ¹⁶ making it crucial to assess the relationship between high BMI in childhood and CRC during adolescence, as well as the different roles of high BMI in childhood and adolescence in the development and progression of CRC. A study utilizing data from two large prospective studies found that weight gain during childhood and adolescence in females was significantly associated with an increased risk of CRC, whereas this association was not observed in adults. ³⁶ This study suggests that weight gain during childhood and adolescence may be a risk factor for CRC, independent of high BMI in adulthood. ³⁶ Cé lind and colleagues, ⁸ after evaluating the relationship between high BMI in childhood and adolescence and CRC within the same population, concluded that high BMI in childhood is a determining factor in the development of CRC, while high BMI in adolescence is a modulating factor. This study posits that the association between high weight in childhood and CRC is only evident if the individual’s weight remains above the median during adolescence. ⁸ If their weight is normal during adolescence, there is no association with CRC. The researchers also found that BMI at age 8 is associated with an increased risk of colon cancer, while changes in BMI during adolescence (the difference between BMI at age 20 and BMI at age 8) and BMI at age 20 were not significantly associated with an increased risk of colon cancer. ⁸ Despite the trend of increasing BMI, the risk of CRC in overweight boys at age 8 could be reduced if excessive BMI increase is avoided during adolescence. ⁸ Furthermore, a study on colorectal adenomas found a significant positive correlation between higher BMI at age 5 and the risk of colorectal adenomas, as well as a positive correlation between body size at age 10 and colorectal adenomas. ¹¹ However, there was no association between body weight at age 20 and colorectal adenomas, independent of birth weight, physical activity, and age at menarche. ¹¹ Interestingly, the study also found no association between BMI at age 18 and colorectal adenomas. ¹¹ Additionally, a Danish study reported that being overweight at ages 7 or 13 was associated with an increased risk of CRC in adulthood if the overweight status persisted throughout adolescence. ⁷ However, if the overweight status normalized by adulthood, there was no increased risk. ⁷

In summary, the relationship between high BMI and CRC may begin early in life. Childhood BMI appears to be a determining factor for BMIrelated CRC, while adolescence represents a critical period during which BMI changes might influence the incidence and even mortality of BMIrelated CRC. In other words, adolescence might be more crucial than childhood in the link between high BMI and CRC, even though childhood could be the determining factor. Therefore, it is reasonable to consider adolescence as the most critical period for CRC related to high BMI. In the future, adolescence could be the optimal time for targeted and effective preventive measures against BMI-related CRC.

The Relationship Between Early Life High Body Mass Index and Early-Onset Colorectal Cancer

According to the consensus of major gastroenterology and oncology societies, early-onset CRC is defined as CRC occurring in individuals under 50 years old. ⁵⁷ With the increased use of colonoscopy, the number of late-onset (≥50 years old) CRC cases is gradually declining, whereas earlyonset CRC (<50 years old) cases are steadily rising. In recent years, with the prevalence of Western dietary habits and sedentary lifestyles, the number of children and adolescents with high BMI has been continuously increasing. Studies have shown that the incidence of high BMI has surged dramatically since the last century, affecting 340 million children and 2 billion adults worldwide. Moreover, it is projected that the number of overweight and obese individuals will double in the next decade. ⁵⁸ At the same time, the incidence of early-onset CRC has also sharply increased. A retrospective study predicts that by 2030, the number of diagnosed colon cancer patients aged 20-34 will be 1.9 times the current number, and the number of diagnosed colon cancer patients aged 35-49 will be 1.28 times the current number. ⁵⁹ Therefore, there seems to be a parallel relationship between earlyonset CRC and high BMI in early life. Additionally, relevant studies suggest that obesity may surpass smoking as the primary risk factor for cancer. ⁵⁰ A study on the Body Mass Index (BMI) of Jewish males and females aged 16-19 found that the median age at CRC diagnosis was 49.4 years, with the median ages for colon cancer and rectal cancer being 49.5 years and 49.2 years, respectively. ⁴⁰ The study also suggested that CRC incidence significantly increases between 25-30 years of follow-up, indicating that individuals with high BMI early in life might see the highest CRC incidence between the ages of 41-49 ⁴⁰ . One study ⁴¹ indicated that participants with a BMI greater than 30 kg/m² at age 20 had a 2.56-fold higher risk of early-onset CRC compared to those with a BMI less than 25 kg/m². However, the risk of early-onset CRC for those with high BMI about 10 years prior to the interview was only 0.88 times higher than the general population. ⁴¹ This study also found that the association between BMI and early-onset CRC risk was particularly pronounced among participants who had not undergone colonoscopy, and was almost exclusively limited to these participants. ⁴¹ The study also found that overweight and obesity at age 20 had the strongest association with CRC compared to individuals with normal BMI. ⁴¹ Therefore, overweight and obesity at age 20 are closely associated with an increased risk of early-onset CRC. Based on these findings, the authors suggest that the rising prevalence of high BMI individuals in recent generations may be a significant factor contributing to the increased incidence of early-onset CRC in many countries. ⁴¹ Researchers found that the incidence of early-onset CRC in Europe is increasing most rapidly among the 20-39 age group. ⁶⁰ A study on the relationship between BMI at age 20 and CRC in individuals with and without germline mutation DNA mismatch repair genes showed that the average age of CRC diagnosis was 44 years for carriers and 42 years for non-carriers. ⁴⁷ Another study on the weight of 1.1 million Jewish males aged 16-19 and its relation to CRC found that the average age at CRC diagnosis was 43.2 years. ¹⁰ Interestingly, a separate study on BMI and middle-age cancer in 2.3 million Israeli adolescents revealed that the average age of cancer diagnosis in males was also 43.2 years. ⁵⁰ This study noted that when cancer was diagnosed at age 40 in males and before age 50 in females, the participants’ BMI was often high. ⁵⁰ Additionally, the study suggested a significant association between high BMI at adolescence and an increased risk of CRC in later life. ⁵⁰ A study involving 230,000 Norwegian adolescents on BMI and causespecific mortality indicated that the average age of death was 40 for males and 43 for females, with CRC being one of the major cancers contributing to these mortality rates. ⁵¹ This underscores the role of high BMI during adolescence in the risk of early-onset CRC.

Therefore, based on the above literature, a high BMI in early life may be strongly associated with early-onset colorectal cancer.

The Relationship Between High Body Mass Index in Early Life and the Location of Colorectal Cancer

In adults, body mass index (BMI) appears to be significantly related to the location of malignant colon tumors. Early-life BMI may also have a strong connection to colon cancer, but according to relevant articles, the colorectal tumors it causes seem to be mostly located in the distal colon.

Studies suggest that being overweight or obese during adolescence is associated with an increased risk of developing colon cancer later in life, while rectal cancer is only associated with obesity. ⁴⁰ Additionally, another study ³⁹ on the relationship between adolescent BMI and erythrocyte sedimentation rate (ESR) and CRC also indicates that obese adolescents have a significantly increased risk of both colon and rectal cancer, while overweight individuals are only at an increased risk of colon cancer. A meta-analysis by Hidayat and Yang et al on high BMI in early life and CRC suggests that higher early-life body fat is associated with an increased risk of CRC ⁵ ; however, the observed positive correlation seems to be limited to colon cancer. A study ¹¹ by Nimptsch and colleagues on the relationship between body fat during childhood and adolescence and colorectal adenomas shows that BMI at ages 5 and 10 is significantly associated with distal adenomas, but not with proximal colon or rectal adenomas. Research ³⁶ by Zhang et al also demonstrates a significant positive correlation between high childhood BMI and adult colon cancer, with a stronger association with sigmoid colon cancer than non-sigmoid colon cancer, and no association with rectal cancer. Additionally, a study examining the sigmoid colon in young men found a significant positive correlation between BMI and sigmoid colon cancer, but no correlation with other parts of the colon or rectum. A case-control analysis of different anatomical sites of the colon indicated that early-life body weight in men increases the risk of sigmoid colon cancer in a dosedependent manner. ⁴⁴ Le et al concluded that early-life obesity appears to have a cumulative effect on the risk of sigmoid colon cancer in men, providing further evidence for the link between obesity and male colon cancer, seemingly restricted to the sigmoid colon. ⁴⁴ Furthermore, some studies have found that individuals with a high BMI have a 50% increased risk of colon cancer and nearly double the risk of distal colon cancer. ⁹ Interestingly, studies not examining the relationship between early-life BMI and CRC found that CRC in middle-aged and older adults is more often located in the right side of the colon and rectum rather than the distal colon.^61–63 Therefore, it is suggested that right-sided colon cancer and rectal cancer may not be strongly associated with BMI and are likely influenced by factors other than BMI.

The Correlation Between High Early-Life Body Mass Index and Gender Differences in Colorectal Cancer Patients

It is well-known that adult body weight and CRC show gender differences. Specifically, adult male body weight is significantly correlated with CRC, whereas there seems to be no clear association between female body weight and CRC. ²³ However, several studies suggest that there appears to be no gender-related correlation between high early-life BMI and CRC.

A Danish study clearly indicates that there is no gender difference in the correlation between high BMI during childhood or adolescence and CRC. ⁷ Research by Nimptsch et al on high BMI during childhood and adolescence and colorectal adenomas found no observed gender difference between childhood BMI and adult CRC. ¹¹ A study involving 1.79 million Israeli male and female adolescents demonstrated that the interaction between gender and BMI had no significant impact on either colon cancer or rectal cancer. ⁴⁰ Similarly, Smith et al found no gender differences in a study investigating the relationship between birth weight and CRC. ⁶⁴ However, a study using BMI at age 18 as a baseline for body weight and CRC risk found that weight gain from late adolescence to middle age significantly impacted the risk of colon cancer, especially for men, with little impact on women. ⁴⁵ Campbell and colleagues ⁶⁵ also discovered that obesity in men is associated with an increased risk of both sporadic and Lynch syndrome-related colorectal cancer, but this association was not observed in women. In another study ⁴⁸ by Campbell et al, they found a positive correlation between BMI at age 20 and CRC risk in both men and women, but the correlation was not statistically significant for women. Additionally, a large case-control study on CRC found a positive correlation between BMI at different ages in men and CRC risk. ⁴⁶ Among women, although patients in adolescence had higher body weight than controls, there was no association between BMI in middle age and CRC diagnosis and risk. ⁴⁶ Furthermore, a case-control study on colorectal cancer cases following revised Bethesda or Amsterdam Lynch syndrome criteria and population controls indicated that increased BMI at age 20 in men was associated with increased CRC risk, but not in women. ⁶⁵ The reduced risk of CRC in females with high BMI during late adolescence may be due to the protective effects of estrogen precursors produced by adipose tissue, which counterbalance the increased risks associated with obesity. ⁶⁵ Additionally, adolescence can confound the relationship between BMI and CRC. For instance, heavier girls might reach menarche earlier than their thinner peers. ⁶⁶ High BMI might also be related to changes in the sex hormone profile, as adipose tissue converts androgens to estrogens. ⁶⁶ Obese women metabolize estrogen differently from women of normal weight, ⁶⁶ with lower levels of sex hormone-binding globulin, ⁶⁷ leading to higher levels of bioavailable hormones. Consequently, this population may benefit from greater estrogen protection, resulting in a lower incidence of CRC compared to males with high BMI.

In summary, we have reason to believe that the gender differences in CRC associated with high BMI emerge in late adolescence rather than in early life or adulthood. This phenomenon is likely influenced primarily by estrogen.

The Relationship Between Obesity Treatment and Colorectal Cancer Incidence and Mortality in Individuals with High Early-Life Body Mass Index

Currently, the main measures for treating obesity include physical activity, weight loss surgery, and dietary control. It has been proven that physical activity can reduce the risk of CRC in obese or overweight individuals. However, the critical age for preventing weight gain or promoting weight loss remains a crucial issue that needs to be addressed. The level of physical activity in individuals with high BMI during early life seems to have a significant connection with the occurrence and development of CRC.

Studies suggest that physical activity can prevent cancer by reducing fat storage and insulin resistance. ⁶⁸ Additionally, physical activity can prevent cancer by decreasing inflammatory markers, growth factors, oxidative stress, and DNA damage. ⁶⁸ Based on this and the relationship between adolescence and insulin, some research indicates that normalizing weight before puberty seems to be an important measure for reducing cancer risk in adulthood. ¹⁶ Moreover, Blü her et al believe that physical activity can reverse the activity of NK cells and the synthesis of NK cell-mediated cytokines in individuals with high BMI. ⁶⁹ Data also show that adolescents with high BMI can mitigate the pro-inflammatory state induced by obesity through weight loss or even weight stabilization, thereby reducing the incidence of CRC. ⁴ A study on the relationship between college students’ weight and colon cancer risk suggests that the risk of colon cancer may not increase among overweight individuals who are physically active. ⁴² Furthermore, increasing evidence shows that increasing physical activity can have a protective effect by enhancing insulin sensitivity.^70,71 Interestingly, a meta-analysis revealed that increased physical activity is associated with a reduced risk of colon cancer but not rectal cancer. ⁵ Additionally, this meta-analysis found that physical activity itself is associated with increased insulin sensitivity. ⁵ A meta-analysis on the incidence of CRC and weight loss surgery has shown that all types of weight loss surgery are associated with a reduced incidence of CRC. ⁷² This meta-analysis also found that the incidence of colorectal cancer was reduced by 54% in obese individuals who had undergone weight loss surgery compared to those who had not. ⁷² A study in the UK indicated that individuals with high BMI can lower the incidence of CRC through dietary and physical activity interventions. ⁷³ Similarly, a cancer prevention study found that 12% of CRC cases could be prevented by increasing physical activity, while 34% could be prevented by altering diet and alcohol intake. ⁷³ Furthermore, an exciting study from Japan on the recurrence rates of colorectal adenomas and weight relationship revealed that individuals who lost weight had significantly lower recurrence rates of colorectal adenomas compared to those who maintained or gained weight. ⁷⁴ Regarding the mortality rates of CRC patients, several studies indicate that certain obesity treatment measures taken before diagnosis can improve patient survival.^75,76 Kroenke and colleagues ⁷⁷ found a U-shaped relationship between CRC survival rates and weight, suggesting that both underweight and excessively overweight patients have higher mortality rates, whereas patients with high-normal weight and those who are moderately overweight have reduced mortality rates for colorectal cancer.

Therefore, in summary, we believe that measures to treat obesity, such as physical activity, dietary interventions, and weight loss surgery, can reduce the incidence of CRC and mortality before diagnosis. However, for patients already diagnosed with colorectal cancer, maintaining a high-normal weight and being moderately overweight is beneficial for their survival. Obesity treatment is not recommended unless the patient is extremely obese.

Relationship Between Early Life High Body Mass Index and Poor Prognostic Genetic Factors in Colorectal Cancer

CRC is a highly complex disease caused by the cumulative effects of somatic genetic and epigenetic changes, including microsatellite instability (MSI) and CpG island methylator phenotype (CIMP), which lead to alterations in gene function, including KRAS, BRAF, and PIK3CA ⁷⁸ Additionally, many molecular changes in colorectal tumors interact with high BMI, resulting in more aggressive colorectal tumors. ⁷⁸ These molecular changes include STMN1, ⁷⁹ p21 ⁸⁰ and p27. ⁸¹ The CpG island methylator phenotype is associated with the expression of p27 and p21, ⁷⁸ while STMN1 may influence cell cycle progression and cell migration. ⁷⁹ Some studies suggest that the activity of STMN1 is inhibited by p27.^82,83

Multiple studies have shown that patients with MSI-high tumors have a better prognosis compared to those with MSI-stable tumors.^78,84,85 Campbell and colleagues investigated the relationship between colorectal cancer patients and tumor molecular phenotypes, finding that high BMI may reduce the survival rate of MSI-high tumors. ⁸⁶ Additionally, related research indicates that high BMI may be associated with more aggressive MSI-stable tumors, but not with the risk of less aggressive MSI-high tumors. ⁸⁷ Patients with BRAF mutations have lower survival rates compared to those with wildtype BRAF^78,88 and high BMI can increase the likelihood of BRAF mutations, ⁸⁹ thereby exacerbating the negative effects associated with BRAF mutations. Amado et al ⁹⁰ suggested that the prognosis of KRAS-mutant tumors is worse than that of wild-type KRAS tumors, and high BMI is associated with an increased risk of KRAS-mutant colorectal cancer. Inamura and colleagues ⁹¹ also found that low levels of adiponectin (an obesity-related marker) are more strongly associated with KRAS-mutant CRC than with wild-type, indicating that high BMI can worsen the adverse effects of KRAS mutations. Ogino and colleagues ⁸¹ found that patients with nuclear-positive p27 have higher mortality rates compared to those with altered p27 (cytoplasmic localization of p27 along with loss of p27 expression), and obesity increases the mortality of nuclear-positive p27 patients, with no correlation to patients with altered p27. Ogino et al also discovered that tumors with p21 expression have lower survival rates compared to those with p21 loss, ⁸⁰ and this effect is exacerbated in obese individuals, indicating that obesity further reduces the survival rate of patients with p21-expressing tumors. ⁸⁰ Moreover, high BMI can worsen the outcomes associated with unfavorable factors and even negatively impact relatively favorable prognostic factors. For instance, STMN1-positive patients typically have higher survival rates, but high BMI reduces their survival rate. ⁷⁹

In summary, we believe that high BMI exacerbates the poor prognostic factors associated with cancer-related genetic causes and can even worsen the outcomes related to relatively favorable genetic factors.

Limitations

One limitation of our study is that we used BMI as the measure of obesity and overweight in relation to CRC. However, BMI might not be the best indicator, as a significant number of studies suggest that the best measures linking obesity and overweight to CRC are those related to central obesity, such as waist circumference and waist-to-hip ratio.^92,93 Another limitation is that only a few studies discussed the relationship between high BMI in childhood and adolescence with CRC. The reliability of the connection between high BMI in childhood and adolescence is relatively poor, and extensive research is needed in the future to further support the current findings. Additionally, we have not yet found studies on the treatment of colorectal cancer related to high BMI in early life. With the increasing prevalence of high BMI populations in recent years, further exploration is required.

Summary and Outlook

High BMI in early life plays a crucial role in the occurrence and development of CRC. High BMI in early life plays a crucial role in the development of CRC. Early-life high BMI is one of the major modifiable factors contributing to colorectal malignancy. The associated insulin resistance, gut inflammation, NK cell dysfunction, DNA damage, and complications play a significant role in this process. Additionally, childhood BMI appears to be a key factor in BMI-related CRC, with high BMI in adolescence acting as a modulating factor, whereas adult BMI seems unrelated to CRC. Early-life high BMI also impacts the age of CRC diagnosis, gender, and tumor location. Unfortunately, high BMI not only exacerbates poor prognostic factors related to cancer genetics but can also worsen relatively favorable prognostic factors. However, in the relationship between high BMI during childhood and adolescence and CRC, physical activity, dietary interventions, and weight loss surgery seem to reverse the negative impact of BMI on CRC. The critical role of early-life high BMI in CRC has been confirmed, but the optimal age for weight loss and the development of an effective weight loss plan remain unclear. Further exploration of these issues is needed to reduce CRC incidence and its associated burdens.