Colorectal Cancer: Epidemiology, Risk Factors, and Public Health Strategies

Colorectal cancer (CRC) is a major global health concern, ranking as the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths [1]. Countries with high human development index (HDI) values report the highest incidence rates, largely due to dietary patterns and lifestyle factors, including high consumption of red and processed meats, sugary beverages, and obesity. Conversely, countries with low to middle HDI values are experiencing rising CRC incidence driven by urbanization, westernized diets, and aging populations, compounded by limited access to healthcare services. Japan’s CRC epidemiology illustrates a shift from traditionally lower rates associated with a traditional diet to higher rates influenced by Western dietary habits. Despite advances in screening and treatment, CRC-related mortality remains a significant concern. Understanding the risk factors, including genetic predispositions and lifestyle factors, is essential for developing effective prevention strategies. This review provides a comprehensive analysis of CRC incidence, mortality, and risk factors to inform public health policies aimed at reducing the global CRC burden.

CRC is the third most commonly diagnosed cancer worldwide, with an estimated 1.93 million new cases in 2020, accounting for approximately 10% of all cancer diagnoses globally [1]. Countries with high HDI values, such as those in Europe, North America, and Australia, report some of the highest age-standardized incidence rates (ASIRs), exceeding 40 cases per 100,000 individuals. In these countries, comprehensive screening programs have significantly contributed to the early detection of CRC, resulting in higher survival rates. For example, in the USA, the introduction of screening colonoscopy has led to a substantial decrease in CRC incidence and mortality. However, the effectiveness of these programs depends on widespread participation, which can be influenced by public awareness, healthcare access, and socioeconomic factors [2]. In Asia, CRC incidence rates are rapidly rising, primarily due to increasing urbanization and the adoption of Western dietary habits. Countries like Japan, China, and South Korea have reported significant increases in CRC cases over the past few decades. Japan’s CRC incidence rate has been steadily increasing, reaching an ASIR of 45.5 per 100,000 for men and 28.5 per 100,000 for women, according to the latest reports (Table 1). When comparing CRC trends across Asian countries, significant variations are evident. Japan, South Korea, and Singapore exhibit high incidence rates comparable to those of Western nations, while developing countries like India and Indonesia report relatively lower rates. However, these nations are witnessing rapid increases in CRC incidence as they undergo economic transitions. Among the BRICS nations (Brazil, Russia, India, China, and South Africa), China has experienced the most dramatic rise in CRC incidence, with rates nearly doubling over the past 2 decades. Russia also demonstrates high and increasing rates, whereas India, despite its lower incidence, is seeing a rapid upward trend, particularly in urban areas. Brazil and South Africa display intermediate rates, albeit with significant urban-rural disparities.

CRC is a leading cause of cancer-related deaths worldwide, with an estimated 935,000 deaths in 2020, making it the second leading cause of cancer mortality after lung cancer [1]. The global age-standardized mortality rate (ASMR) for CRC is approximately 8.9 per 100,000 individuals. Mortality rates are highest in Eastern Europe and Eastern Asia, reflecting both high incidence rates and challenges in accessing effective treatment and early detection methods. For instance, countries like Russia, Romania, and Poland report mortality rates exceeding 15 per 100,000 individuals [2]. The study by Guida et al. [3] highlights the significant impact of CRC mortality, not only on the patients but also on their families and broader communities. The mortality burden extends beyond the loss of life, affecting economic stability and quality of life for surviving family members. In regions with limited healthcare infrastructure, such as parts of Africa and Southeast Asia, mortality rates are exacerbated by late-stage diagnosis and limited treatment options.

Japan presents a unique case in the epidemiology of CRC. Until 2015, the number of cancer cases in Japan was estimated from prefectural cancer registries, but since 2016, data has been captured and published through the national cancer registry. According to the latest statistics, there were 147,725 cases of CRC (82,809 men and 64,915 women, with some gender unspecified), accounting for 15.6% of all cancer cases (15.5% for men and 15.8% for women). When divided into colon cancer and rectal cancer, colon cancer accounted for 66.5% of cases (62.5% in men and 71.6% in women) [4]. The number and rate of CRC incidences by age group increased from the age of 40 for both men and women, with higher rates observed in older age groups. Notably, CRC incidence rates in Japan show significant regional variations. The top five prefectures with the highest CRC incidence rates are Aomori, Okinawa, Akita, Iwate, and Tochigi. Among these, Aomori Prefecture exhibits particularly high incidence rates for both men and women. These regional differences in incidence may be influenced by variations in dietary habits, alcohol consumption, and other lifestyle factors, though further research is needed to elucidate the precise causes. Annual trends can be observed using data from Yamagata, Fukui, and Nagasaki prefectures, which have high-accuracy cancer registries for the period from 1985 to 2012, and from the data of all 47 prefectures from 2014 onwards. Combining these data, the ASIR of CRC (per 100,000 population) for both men and women shows an increasing trend for colon cancer and rectal cancer until the late 1990s, followed by a decreasing trend. The increase was more pronounced for colon cancer than for rectal cancer [5].

According to the latest statistics, the number of deaths from CRC was 53,088 (28,099 men and 24,989 women), accounting for 13.7% of all cancer deaths (12.6% for men and 15.4% for women) [4]. When divided into colon cancer and rectal cancer, colon cancer accounted for 70.1% (64.8% in men and 76.1% in women). The number and rate of CRC deaths by age group increased from the age of 50 for both men and women, with higher rates observed in older age groups. Regional variations in CRC mortality rates also exist across Japan. The prefectures with the highest age-adjusted mortality rates are Aomori, Okinawa, Akita, Hokkaido, and Kyoto. Aomori Prefecture, in particular, ranks highest in both incidence and mortality rates, highlighting the significant regional disparities. Examining the annual trends of ASMR (per 100,000 population) from 1979 to 2022, colon cancer in both men and women increased until the late 1990s but has been declining since then, while rectal cancer shows a gradual decreasing trend [4]. By age group, there has been little change in ASMR for those under 60 years of age in both men and women. For men aged 60 and above, there was an increase until the 1990s followed by a gradual decrease, while for women aged 60–74, there was little change until around 2000, after which there was a gradual decrease. For those aged 75 and above, there was an increase until the late 1990s followed by no significant change.

Advancements in CRC screening and treatment have significantly improved stage-specific survival rates. The 5-year relative survival rate for early stage CRC (stage I) is approximately 90%, compared to about 14% for advanced-stage (stage IV) cancer [6]. These improvements are largely attributed to early detection through screening programs and advancements in surgical and adjuvant therapies. In Japan, survival rates are reported through cancer registry data, with separate reports for colon and rectal cancer. The reported 5-year relative survival rates for CRC cases diagnosed from 1993 to 2011 show notable improvements. For colon cancer diagnosed between 1993 and 1996, the 5-year relative survival rate was 71.3% for men and 66.1% for women, improving to 72.8% for men and 69.4% for women for cases diagnosed between 2009 and 2011. By clinical stage, from 1993–96 to 2009–11, the 5-year relative survival rate for localized colon cancer improved from 96.6% to 98.2%, and for rectal cancer from 93.0% to 95.7%. For regional cases with lymph node metastasis or adjacent organ invasion, colon cancer survival improved from 64.8% to 76.0%, and rectal cancer from 55.3% to 74.0%. For distant metastasis cases, survival for colon cancer improved from 8.2% to 16.2%, and for rectal cancer from 8.1% to 19.7%, showing improvement across all stages [7, 8].

Genetic factors play a crucial role in the development of CRC. Hereditary CRC syndromes, such as Lynch syndrome and familial adenomatous polyposis (FAP), significantly increase the risk of CRC. Lynch syndrome is the most common hereditary CRC syndrome, accounting for about 3% of all CRC cases. It is characterized by mutations in mismatch repair (MMR) genes, leading to microsatellite instability and an increased risk of cancer. Individuals with Lynch syndrome have a 50–80% lifetime risk of developing CRC. FAP, on the other hand, is caused by mutations in the APC gene, leading to the formation of numerous adenomatous polyps in the colon and rectum. If untreated, nearly all individuals with FAP will develop CRC, usually before the age of 40 (Table 2). In recent years, the adoption of cancer gene panel testing has been expanding in Japan, providing new opportunities for genetic diagnosis. This comprehensive approach not only aids in identifying hereditary cancer syndromes but also frequently results in secondary findings that lead to a diagnosis of Lynch syndrome. These advancements highlight the growing importance of genetic testing in clinical practice, enabling earlier detection and personalized management strategies for individuals at high risk of CRC. Such developments underscore the need for heightened awareness of genetic counseling and regular screening for individuals with a family history of CRC [9].

Consumption of processed foods, high-sugar beverages, and obesity are associated with an increased risk of CRC. Processed meats have been classified as Group 1 carcinogens by the International Agency for Research on Cancer (IARC) due to strong evidence linking them to CRC. A comprehensive review concluded that high consumption of processed meats increases the risk of CRC by 17% (relative risk [RR] = 1.17, 95% CI: 1.11–1.22) per 50 grams per day [10]. Similarly, the intake of sugary beverages has been linked to a higher risk of CRC. Research has shown that daily consumption of sugar-sweetened beverages is associated with a 16% increased risk of early onset CRC among women (HR = 1.16, 95% CI: 1.01–1.34) [11]. Furthermore, obesity significantly contributes to the risk of developing CRC, with a relative risk of 1.05 (95% CI: 1.03–1.07) for every 5 kg/m² increase in body mass index [12]. While Japan has been increasingly adopting Westernized dietary habits, including higher consumption of processed foods and sugary beverages, and obesity rates have risen over time, these levels remain lower compared to those in the USA. Paradoxically, despite these differences, Japan’s CRC incidence rate is higher than that of the USA. This discrepancy suggests that other factors beyond processed food intake, sugary beverages, and obesity may contribute to CRC risk in Japan. Potential explanations include differences in genetic predisposition, environmental exposures, gut microbiota, and screening practices, which may lead to earlier detection and diagnosis in Japan. According to the Japan Public Health Center-based Prospective (JPHC) Study, a high intake of red meat significantly increases the risk of colon cancer among Japanese women, while a high intake of total meat is associated with a higher risk of colon cancer in Japanese men. However, no significant association was observed between processed meat consumption and CRC risk in either men or women [24]. Similarly, the JPHC study found no significant association between sugary drink consumption and overall CRC risk in both men and women. However, a higher intake of sugary drinks was associated with an increased risk of colon cancer, particularly proximal colon cancer, among Japanese women [25]. These findings highlight the multifactorial nature of CRC risk, where dietary factors, along with genetic, environmental, and healthcare system differences, may contribute to population-specific CRC incidence rates.

Alcohol consumption is a well-established risk factor for CRC. Meta-analyses have demonstrated a dose-response relationship between alcohol intake and CRC risk. For instance, one meta-analysis found that individuals who consume 50 grams or more of alcohol per day have a 52% increased risk of CRC compared to nondrinkers (RR = 1.52, 95% CI: 1.27–1.81) [13]. Another study reported that moderate drinkers (12.5–50 grams/day) have a 17% increased risk (RR = 1.17, 95% CI: 1.11–1.24), while heavy drinkers (>50 grams/day) have a 44% increased risk (RR = 1.44, 95% CI: 1.25–1.65) [14]. These findings underscore the importance of limiting alcohol consumption as part of CRC prevention strategies. Results from a pooled analysis of Japanese cohort studies estimate that for both men and women, the risk of CRC increases by approximately 10% with each additional 15 grams of daily alcohol consumption. This trend is observed for both colon and rectal cancers [26]. When comparing these findings with reports from Western countries, it was confirmed that the association between alcohol consumption and CRC is stronger in Japanese people than in Western populations. Further research is needed to clarify whether this difference is due to genetic polymorphisms or environmental factors, including lifestyle habits.

Recent studies provide strong evidence linking smoking to increased CRC risk and mortality. A meta-analysis by Botteri et al. [15] found smoking increased overall CRC risk by 14–17%, with stronger associations for specific molecular subtypes. Large prospective cohort studies in Japan [16] and the USA [17] corroborated these findings, showing significantly higher CRC risk and mortality rates among smokers. The risk was dose-dependent, increasing with smoking duration and intensity, while decreasing after cessation. These studies collectively emphasize the importance of smoking prevention and cessation in CRC risk reduction strategies.

Certain vitamins and minerals have been shown to have protective effects against CRC, with vitamin D and calcium being particularly noteworthy. A meta-analysis demonstrated that higher vitamin D intake is associated with a significantly reduced risk of CRC. Specifically, elevated vitamin D intake and blood 25-hydroxyvitamin D [25(OH)D] levels were linked to a 12% and 33% reduction in CRC risk, respectively. Additionally, a 10 ng/mL increase in blood 25(OH)D levels was associated with a 26% lower risk of CRC [18]. Similarly, calcium intake has been inversely associated with CRC risk. A meta-analysis found that for every 300 mg/day increase in calcium intake, the risk of CRC decreased by 8% (RR = 0.92, 95% CI: 0.89–0.95) [12]. These findings suggest that adequate intake of vitamin D and calcium should be considered in CRC prevention strategies. The results of the JPHC study in Japan showed no statistically significant association between vitamin D intake and CRC risk in either men or women. However, among men, when vitamin D and calcium intake were divided into three groups (low, medium, and high), the group with high intake of both nutrients was found to have a lower risk of CRC. Fermented foods are also gaining attention for their potential protective effects against CRC [27]. Fermented foods, such as yogurt and kefir, contain beneficial bacteria that can modulate gut microbiota and improve gut health. A systematic review and meta-analysis of cohort studies on dairy products and CRC risk found that a higher intake of fermented dairy products is associated with a lower risk of CRC. Specifically, those who consumed the most fermented dairy had a 19% reduced risk of CRC (RR = 0.81, 95% CI: 0.74–0.90) compared to those with the lowest intake [19].

A meta-analysis of population-based cohort studies assessed the risk of CRC in patients with ulcerative colitis (UC), revealing a pooled standardized incidence ratio (SIR) of 2.4 (95% CI: 2.1–2.7). This indicates a 2.4-fold increased risk of CRC in UC patients compared to the general population, with approximately 1.6% of UC patients being diagnosed with CRC during an average follow-up of 14 years. The analysis further found that male UC patients have a higher risk (SIR 2.6) compared to females (SIR 1.9), and those with extensive colitis face an even greater risk (SIR 4.8), highlighting the importance of targeted surveillance in high-risk UC populations [20]. Complementing this, Birch et al. [28] examined the epidemiology of CRC in 5,141 patients with inflammatory bowel disease (IBD) and compared them to 385,473 non-IBD CRC patients. They found that IBD patients tend to develop CRC at a younger median age (66 vs. 72 years), are more likely to have right-sided tumors, be diagnosed in an emergency setting (25.1% vs. 16.7%), and experience higher rates of synchronous (3.2% vs. 1.6%) and metachronous tumors (1.7% vs. 0.9%). The 2-year survival rates for IBD-CRC were significantly lower, with 15% for stage I and 70.7% for stage III, compared to non-IBD patients. Additionally, Porter et al. [29] discuss the role of chronic inflammation, genetic mutations such as early TP53 mutations, and immune dysregulation, particularly involving pathways like nuclear factor kappa-light-chain-enhancer of activated B cells and the IL-6/STAT3 (signal transducer and activator of transcription 3) pathway, as crucial factors in the development of CRC in IBD patients. These factors drive the progression from inflammation to dysplasia and carcinoma, forming a distinct sequence that differs from the pathogenesis of sporadic CRC [29].

The association between type 2 diabetes, insulin resistance, and an increased risk of CRC has been well-documented, particularly in Western countries. A meta-analysis by Larsson et al. [21] which included over 2.5 million participants from 15 studies, revealed that diabetes is associated with a 30% increased risk of CRC (RR = 1.30, 95% CI: 1.20–1.40). This elevated risk was observed across both sexes and various subsites within the colorectum. Additionally, diabetes was associated with a 26% higher risk of CRC-related mortality (RR = 1.26, 95% CI: 1.05–1.50), highlighting the significant impact of diabetes on CRC outcomes [21]. Supporting these findings, a recent 20-year cohort study from England, involving 137,804 individuals with type 2 diabetes, reported a standardized mortality ratio of 2.40 (95% CI: 2.26–2.54) for CRC, indicating more than a twofold increased risk of CRC mortality compared to the general population, particularly among older adults [22]. Further evidence from the JPHC Study Group also supports the role of hyperinsulinemia in CRC development. This study found that higher plasma C-peptide levels were significantly associated with an increased risk of CRC in men, with odds ratios of 2.3, 2.8, and 3.2 for ascending quartiles of C-peptide. Notably, this association was stronger for colon cancer than rectal cancer, emphasizing the importance of addressing hyperinsulinemia in CRC prevention, particularly in male populations [23].

Socioeconomic factors, including income, education level, and healthcare access, play a critical role in CRC risk and outcomes [2, 6]. Individuals with lower income and education levels often face limited access to preventive healthcare, leading to delayed diagnosis and treatment. Furthermore, disparities in dietary habits and lifestyle factors associated with socioeconomic status contribute to regional differences in CRC incidence and mortality within Japan. Addressing these inequalities through targeted public health initiatives and improved healthcare access is essential for reducing CRC disparities.

Public health and research initiatives are crucial to the prevention and early detection of CRC. Effective public health strategies, such as raising awareness, removing barriers to access, and ensuring equitable distribution of resources, are essential for increasing CRC screening rates. Educational campaigns and community outreach, particularly those tailored to cultural needs and supported by community health workers, have proven successful in improving screening uptake among underserved populations [30]. For example, Japan’s population-based CRC screening program has significantly enhanced early detection and reduced mortality, although further efforts are needed to integrate screening data with the national cancer registry for more comprehensive surveillance [31]. While CRC screening programs have significantly improved early detection and reduced mortality, challenges remain. In Japan, key issues include suboptimal participation rates in fecal immunochemical test (FIT) screening, limited follow-up for individuals with positive results, and regional disparities in program implementation. Enhancing participation through targeted educational campaigns and integrating innovative technologies, such as smartphone-based reminders and artificial intelligence for quality assurance in colonoscopy, could address these gaps. Additionally, ensuring equitable access to screening and follow-up care is essential to improve outcomes across diverse populations. Future research should focus on evaluating the cost-effectiveness and long-term impact of these interventions to further optimize CRC screening strategies. Simultaneously, ongoing research plays a critical role in advancing CRC screening methods by improving their accuracy, affordability, and acceptability. Collaborative efforts between academia, healthcare providers, and industry, such as the Cancer Moonshot initiative in the USA, are driving significant advancements in early detection and precision medicine [32]. The integration of big data and machine learning is beginning to offer new avenues for understanding CRC epidemiology and risk factors, with the potential for more targeted and personalized interventions [33]. For instance, while still in early stages, efforts to use machine learning algorithms to analyze health records are showing promise in predicting CRC risk and identifying patients who might benefit most from targeted screening efforts.

CRC remains a significant global health challenge, influenced by genetic, lifestyle, and environmental factors. The rising incidence, especially in regions like Japan where westernized lifestyles are becoming more common, underscores the need for effective public health strategies. Enhancing screening, early detection, and preventive measures is essential to reducing CRC-related mortality. Continued research and collaboration are critical for developing targeted interventions that can address this growing burden and improve outcomes worldwide.

Prof. Takahisa Matsuda was a member of the journal’s Editorial Board at the time of submission.

This study was not supported by any sponsor or funder.

T.M. was the primary author of the manuscript. A.F. and Y.I. conducted the literature search and performed the proofreading of the manuscript.