Colorectal cancer (CRC) is the third most common cancer worldwide and the second most common cause of cancer-related death (1). In recent decades, the number of cases of early-onset colorectal cancer (EOCRC), defined as CRC diagnosed before age 50 (2), has increased dramatically in the United States (3), Japan, Australia (4), Canada (5), China, the United Kingdom, and other countries (6). According to the current data, it is estimated that in the next ten years, the incidence rates of rectal cancer and colon cancer in adults aged 20-34 will increase by 90% and 124% respectively, while the incidence rate in adults aged 35-49 will increase by 27% and 46% respectively (7). Moreover, most young CRC patients have a later stage of disease at diagnosis, a higher risk of metastasis, and a poorer prognosis than elderly CRC patients, which highlights the need for the public and medical personnel to enhance their understanding of the disease (8).

Multiple risk factors have been identified, such as a family history of CRC, inflammatory bowel disease (IBD), sedentary behaviors, smoking, elevated body mass index (BMI), diabetes, and poor diet (9). However, the conclusions of different studies remain controversial, such as obesity, data from a prospective cohort study (10) and an observational study (11) showed that obesity during adolescence was associated with an increased incidence and mortality of EOCRC. A cross-sectional study (12) of local Songjiang District community residents in the city of Shanghai, east of China also found that obesity was an independent risk factor for early colorectal neoplasm. In contrast, Low et al. (13) found that obesity or overweight was a protective factor for EOCRC. The risk factors for EOCRC remain unclear. Identifying risk factors for EOCRC can inform primary prevention programs and targeted screening approaches for high-risk individuals.

To the best of our knowledge, O’Sullivan et al. (14) conducted a meta-analysis of risk factors for EOCRC and showed that smoking was not significantly associated with EOCRC. However, we found that some potentially important studies were not included in this study, such as a study (15) involving 8,873,080 people, which compared patients with EOCRC with healthy individuals under 50 and illustrated that smoking was significantly associated with the incidence rate of EOCRC (adjusted OR=2.675; P<0.001), which may affect the results. In addition, there were few studies included in the above meta-analysis, and the results may be biased. Carroll et al. (16) and Li et al. (17) only evaluated a single factor in their systematic reviews, and could not determine all the risk factors related to EOCRC. With the in-depth study of EOCRC in recent years, it is very important to identify the risk factors that may increase EOCRC through a comprehensive literature search.

To improve knowledge based on existing evidence and to address the limitations of previous reviews, we conducted a systematic review and meta-analysis to investigate risk factors for EOCRC. Our goal was to synthesize previous studies, which we hypothesized would be highly heterogeneous, under a uniform framework that can provide insights into development of new, evidence-based identification of risk factors associated with EOCRC, exploration of more effective prevention methods, and improved screening of high-risk populations.

The protocol was registered with PROSPERO (CRD42022371340). We conducted this systematic review and meta-analysis according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (18) and Meta-analysis of Observational Studies in Epidemiology recommendations (19).

Initial searches identified 4137 studies, and 16 additional studies were identified from references. Subsequently, 2038 studies were obtained after removing duplicate literature, and 1060 were excluded after screening titles and abstracts. After full-text review, a total of 36 studies examining at least one risk factor for EOCRC were retained, and 30 of these studies were included in the meta-analysis ( Figure 1 ).

Among the 36 studies (13, 15, 21–54), 19 were cohort studies and 17 were case-control studies, with 66312 participants. The year of publication ranged from 1989 to 2022, and studies in the last three years accounted for 56.76% ( Table 1 ).

CRC is a global public health problem that seriously threatens human health. Although the overall incidence and mortality of CRC have tended to stabilize or decline in recent years, the incidence and mortality of EOCRC have shown an increasing trend, and EOCRC is usually diagnosed at later stages with a poor prognosis. Identifying risk factors for EOCRC is essential to reduce the growing burden of this disease.

In this systematic review and meta-analysis, we identified risk factors associated with demographics (male, Caucasian, family history), chronic conditions (IBD, obesity, overweight, abdominal obesity, hypertension, triglycerides, metabolic syndrome), and lifestyle or environmental factors (smoking, alcohol consumption, sedentary behaviors, sugar-sweetened beverages, red meat, processed meat, and Western dietary patterns). Although some of the factors (hyperlipidemia, diabetes) were statistically non-significant, they were suggestive and non-negligible risk factors. The study also found that vitamin D was a protective factor for EOCRC. Other potential risk factors included a family history of cancer, a low education level, chronic kidney disease, primary breast tumors, abdominal pain, intestinal function changes, iron-deficiency anemia, hematochezia, weight loss, exposure to dust, and diet-related factors.

Male sex, Caucasian race, and a family history of CRC were risk factors for EOCRC. The results were the same as those exhibited by O’Sullivan et al. (14). Individuals with a family history or CRC had a higher risk of CRC than the general population. Screening based on a family history of CRC has become an important screening strategy for early detection and prevention of EOCRC. Previous research also showed that people with a family history of other cancers had a higher risk of developing EOCRC. Therefore, future research also needs to examine whether a family history of other cancers before the age of 50 is related to an increased risk of EOCRC (28). Research on a family history of other cancers may guide more precise targeted screening strategies.

This study compared the effects of different degrees of obesity on EOCRC. We found that weight gain in young adults was associated with the risk of EOCRC. The results of this study were consistent with those of Li et al. (17). Since Glover et al. (15) did not define obesity and Kwak et al. (21) only compared individuals with BMI≥25 kg/m² with the general population, these 2 studies were not included for the analysis in this study. Glover et al. (15) found that obesity was a risk factor for EOCRC (OR=1.82; 95% CI, 1.62-2.04), but Kwak et al. (21) suggested that obesity was not related to EOCRC. Liu et al. concluded that the risk of CRC increased by 20% for every 5 units of BMI increase. The results of this study also demonstrated that obese individuals had a higher risk of CRC than overweight individuals. The reason why obesity was related to EOCRC may be that obesity is involved in the occurrence and development of CRC by affecting metabolism and inflammatory factors, including insulin and insulin-like growth factors, sex hormones, and adipokines. Further research has found that obesity can promote the occurrence of CRC by affecting DNA methylation. In young mice, obesity can promote oxidation of long-chain fatty acids to increase the number of stem cells or stem cell-like cells in intestinal tissues (57). These findings also provide new clues to explain the mechanism by which obesity promotes EORC. Therefore, interventions to prevent obesity and strengthen obesity management in adolescents and young people are crucial to reduce the incidence of EOCRC.

No statistically significant difference was found between diabetes and hyperlipidemia and EOCRC in the present study, but this result was contrary to that reported by Breau et al. (55). Breau et al. assessed cross-sectional studies, while our study investigated case-control studies and cohort studies, and differences in the included literature may have influenced the results. In a Swedish national cohort study (56), more than 100,000 patients diagnosed with diabetes before the age of 50 were included. Diabetes was shown to be associated with a 1.9-fold increased risk of EOCRC. However, some studies found that diabetes was not associated with EOCRC (24). Given the increasing prevalence of diabetes in young people and the potential impact of CRC screening guidelines, more studies are required to confirm this relationship. Hyperlipidemia and hypertension are both associated with the development of CRC, but there is insufficient research on the relationship with EOCRC. More studies are needed in the future to assess whether hyperlipidemia is associated with the development of EOCRC, and to include triglyceride and cholesterol levels in the analysis at the same time, thereby identifying individuals at a high risk of EOCRC and benefiting from earlier screening.

Poor lifestyles were associated with EOCRC. Smoking has always been recognized as a risk factor for EOCRC, but the results of O’Sullivan et al. (14) suggested that smoking was not associated with the development of EOCRC, which was contrary to the results of this study. On the one hand, O’Sullivan et al. (14) comprehensively analyzed the results of cross-sectional studies, case-control studies, and cohort studies; on the other hand, only 5 studies were included for the meta-analysis, which may have a certain impact on the results of the study. Nicotine, an alkaloid in tobacco, can induce and promote the proliferation of colon cancer cells and the formation of tumor blood vessels (58). Diet is an important factor affecting EOCRC. The Western diet, which is high in saturated fat, rich in red meat, and low in fiber, has become a well-known risk factor for CRC. Adherence to a healthier diet, such as the Mediterranean diet, can help prevent CRC (59). Nguyen et al. (34) suggested that a high-sulfur microbial diet would increase the incidence of EOCRC (OR=1.13; 95% CI, 1.10-1.56). Microbes can metabolize sulfur in the diet to produce hydrogen sulfide, which is a gastrointestinal carcinogen. A healthy diet allows a more beneficial intestinal microbiota and may reduce the risk of CRC. Therefore, it is necessary to take public health measures against the unhealthy lifestyles and eating habits of young people to reduce the incidence of EOCRC.

Low et al. (13) found that aspirin had a protective effect on EOCRC, while McDowell et al. (24) reported that aspirin was not associated with the development of EOCRC. Considering the chemical protective potential of aspirin against CRC, the relationship between aspirin and EOCRC needs to be further evaluated. Studies on whether antibiotics play a role in EOCRC have varied. McDowell et al. (24) analyzed the effects of antibiotics on colon and rectal cancers separately and concluded that antibiotics only increased the risk of colon cancer. The correlation between different antibiotic types, different tumor sites and different ages needs further analysis. However, due to the limited number of studies included, whether these factors are related to the development of EOCRC remains to be further studied.

1) Most of the included studies used data from databases, with Danial et al. (28), Syed et al. (45), and Glover et al. (15) using the Explorys database, and Kim et al. (30), Zheng et al. (31), Yue et al. (32), Nguyen et al. (34), Joh et al. (35), Hur et al. (37), Liu et al. (44) using the Nurses’ Health Study II database, which made it possible for some data to be calculated multiple times. In addition, using the same database would lead to a decrease in the diversity of the population. 2) We only included studies published in English and may have omitted non-English studies. 3) We only searched for peer-reviewed journal studies and may have overlooked unpublished data. 4) Risk estimates for most risk factors were highly heterogeneous across studies. 5) Confounding factors were not controlled in some research results, which may lead to bias in the results. 6) Some of the results may have a publication bias.

Smoking, drinking, sedentary behaviors, red meat, processed meat, sugary drinks, and Western dietary patterns were modifiable risk factors for EOCRC. IBD, obesity, high triglycerides, and hypertension were risk factors that are difficult to be changed by interventions. Although our study identified risk factors for EOCRC, further research is needed for validation and explore other aspects of EOCRC etiology to inform primary and secondary prevention measures. At the same time, our study provides the basis for the future construction of EOCRC risk prediction models to identify high-risk individuals and develop more targeted screening strategies, which in turn can better allocate resources to those most in need to cope with the global growth of EOCRC.

All the authors contributed to the study design. QJ and XX screened abstracts and full-text articles for inclusion. QJ and PS appraised study quality. Any disagreements or uncertainties during the screening and quality appraisal process were referred to HH. QJ drafted the manuscript, which was reviewed, edited, and approved by HH. All authors contributed to the article and approved the submitted version.