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Young-Onset Colorectal Cancer: Current State of Knowledge and Future Perspectives

Oncology
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Epidemiology and Recent Trends

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related mortality worldwide[1]. The incidence of CRC varies across geographical regions, with New Zealand having the highest reported incidence and Africa and South-Central Asia having the lowest. Several factors may contribute to these variations, including socioeconomic status, diet, genetic predisposition, environmental exposures, and screening protocols [2].
CRC is most often reported in elderly individuals and is traditionally considered a malignancy of older individuals, with the median age of diagnosis being 66 years in men and 69 years in women [3].
Although CRC incidence in high-income countries has remained stable or decreased over the last several decades, the incidence of young-onset CRC (also known as early-onset CRC) has been increasing worldwide[4]. In the literature, young-onset CRC generally refers to individuals diagnosed under the age of 50 years. This specific age threshold is not based on pathophysiological or biological factors as much as corresponding to the initiation age of average-risk screening recommendations [5,6]. In the US, the dramatic rise in young-onset CRC has actually shifted the median age of diagnosis from 72 years to 66 years [7].
The reasons underlying the uptrend of young-onset CRC are poorly understood. Currently, young-onset CRC accounts for approximately 10% of all new CRC diagnoses[8]. A study that included seven high-income countries estimated that young-onset CRC will comprise 25% of rectal cancers and 12% of colon cancers by the year 2030 [9]. Chang et al. reported that over the last two decades, the incidence of CRC has increased in every age group between 20 to 54 [10].
The age-adjusted incidence of young-onset CRC in the US increased from 7.9 to 12.9 cases per 100,000 people.  A similar uptrend of young-onset CRC incidence has been seen worldwide, especially among developed countries. Most of the increase has been observed among non-Hispanic whites for reasons that remain elusive [11,12]. Young-onset CRC is more likely to have a hereditary component than later-onset CRC; however, over 80% of cases lack a germline mutation, [13] and most patients have sporadic CRC with no identifiable underlying cause.

Risk factors

Multiple studies in the literature have investigated potential risk factors for young-onset CRC, focusing on the known inherited and environmental factors that are associated with overall CRC risk. Some of these risk factors include genetic variants predisposing to cancer syndromes such as Lynch syndrome and Familial Adenomatous Polyposis, family history of CRC, inflammatory bowel disease, processed meat intake, and alcohol use. On the contrary, diets high in vegetables and fruit; aspirin use; increased intake of folate, vitamin C, vitamin E, and vitamin D; and physical activity are known to be protective against CRC risk [2,14].
Initial studies point toward an association between some of these same diet and lifestyle risk factors with increased incidence of young-onset CRC specifically. Over the last few decades, energy imbalance with a sedentary lifestyle and excessive caloric intake caused a surge in obesity development, which has seemingly paralleled the rise in young-onset CRC, and multiple studies have subsequently reported a close link between obesity and young-onset CRC [15,16].
The underlying mechanism is thought to be obesity-related dysregulation in adiponectin and leptin concentrations leading to energy imbalance, which may promote tumor progression and recurrence of CRC [17]. Several dietary habits have also been reported to be linked to young-onset CRC development. A prospective cohort study from the Nurses’ Health Study II reported an increased risk of young-onset high-risk colorectal adenomas with increased consumption of a Western-style high-caloric diet [18].
In the same study, the risk of young-onset CRC was increased by 32% in young adult women who consumed two or more daily servings of sugar-sweetened beverages.
Also, a sedentary lifestyle was evaluated in the prospective Nurses’ Health Study II cohort. Independent of exercise and obesity, a sedentary lifestyle was associated with an increased risk of young-onset CRC [16].
A recent study prospectively evaluated the association between total vitamin D intake and risks of young-onset CRC. The study reported that higher total vitamin D intake was significantly associated with a reduced risk of young-onset CRC [19]. Socioeconomic factors, including race/ethnicity, household income, education levels, and urban vs. rural residence, have also been shown to be associated with overall CRC incidence and mortality [20]. Although African Americans have higher CRC mortality rates than whites, the increase in the incidence of young-onset CRC is steepest among non-Hispanic whites [12].
Early-life exposures are likely contributing to the pathogenesis of young-onset CRC [15]. Current literature suggests an association between exposure to diet, chemicals, and environmental factors with epigenetic and genetic alterations [21]. Certain early-life exposures and conditions, including ionizing radiation, high BMI, physical inactivity, cigarette smoking, pesticides, and benzene, have been associated with lower long-interspersed nucleotide elements-1 (LINE-1) methylation levels, which has a potential role in the development of young-onset CRC [22].
Multiple studies evaluated childhood diet and reported an association with overall CRC development [23–25]. In contrast, childhood and adolescent energy restriction were related to a lower incidence of CRC [26]. Further larger-scale prospective studies from adolescence to adulthood should be conducted to investigate whether these factors are also contributing to young-onset CRC specifically.
The gut microbiota is another factor that potentially contributes to the increasing incidence of young-onset CRC. The interaction between the gut microbiome and the host immune system affects the anti-tumor immune response and can lead to cytokine production [27]. The gut microbiota can enhance the pro-inflammatory environment that may eventually increase the risk of CRC development [28,29].
Also, the direct effects of microorganism-related metabolites and virulence factors may potentially lead to the development of young-onset CRC.
Among patients matched by age and region, Ghosh et al. reported reduced bacterial diversity in CRC and indicated that Firmicutes, Bacteroidetes, enterotoxigenic Bacteroides fragilis, and the oral anaerobe Fusobacterium nucleatum are enriched in CRC compared to healthy individuals [30]. Jin et al. recently reported increased Fusobacterium spp in young-onset CRC patients’ gut microbiota [31].
Another study examining 1069 patients with CRC reported that those with tumors harboring high Fusobacterium nucleatum had a mortality hazard ratio of 1·58 (95% CI 1·04–2·39) compared to those without F. nucleatum [32]. Also, various animal models showed the potential relation of these microorganisms’ toxins with CRC development [33,34].
Specifically, colibactin, a genotoxin that can adduct to DNA and induce double-strand DNA breaks, is produced by some Escherichia coli strains. These bacterial toxins have garnered attention due to their ability to promote colorectal carcinogenesis in animal models.
A recent study described a distinct colibactin-related mutational signature in human CRC resulting directly from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island [35].

Clinical and Pathological Features

Overall, the incidence of young-onset CRC is higher among men than women, although the relative risk of developing CRC is similar. Young-onset CRCs are most commonly detected in the rectum, followed by the distal and proximal colon [36].
Up to 70% of young-onset CRC has left colon involvement at presentation with more aggressive histopathology [37].
Patients with young-onset CRC have a more advanced TNM stage of disease at diagnosis [38,39]. This finding is likely related to more aggressive tumor biology and delayed diagnosis. Previous studies indicated that young-onset CRC patients have a longer time to diagnosis (7 to 9 months) and more prolonged symptom duration compared to their older counterparts [40].
There is lower awareness of CRC and a lack of screening among young patients, likely contributing to the delayed diagnosis. Also, younger patients are more prone to underappreciate their symptoms [41]. The most common presenting symptoms among young-onset CRC patients are rectal bleeding (41%), abdominal pain and bloating (37%), change in bowel habits (23%), and weight loss (7%) [37].
Young-onset CRC has been associated with poor tumor differentiation and signet-ring cell formation, particularly among patients <40 years [42].
Signet-ring histology was observed in 2 to 13% of young-onset CRCs versus only 1.0-1.6% of later-onset CRCs. Nearly 30% of signet-ring cell formation in young-onset CRC was poorly differentiated [39].

Genomics

Young-onset CRCs are pathologically, genetically, and molecularly heterogeneous diseases that are also affected by endogenous and exogenous factors [43,44]. Previous studies reported distinct genetic and epigenetic alterations in young-onset CRC patients [45].
For example, young-onset CRC is less likely to have BRAF c.1799T>A (p.V600E) mutations and more likely to have lack of methylation and chromosomal instability compared to older-onset CRC. Nearly 30% of young-onset CRC patients have a family history of CRC [46].
Population-based data show a 3-5% overall prevalence of hereditary CRC [47], but this is higher at approximately 20% among patients with young-onset CRC, most commonly due to Lynch syndrome [48].
The prevalence of MSI-high tumors was higher in patients with young-onset CRC than in older patients (10-30% vs. 15%) [44,48]. Testing of all newly diagnosed CRC for mismatch repair (MMR) and MSI status is universally recommended by guidelines [49].
As another well-known familial hereditary cancer syndrome, Familial Adenomatous Polyposis (FAP), is an autosomal dominant disease caused by mutations in the Adenomatous Polyposis Coli (APC) gene. A study with advanced CRC patients reported a higher prevalence of APC and KRAS mutations in the MSI-high group of young-onset CRC compared to later-onset CRC [45]. Another study reported fewer V600E and mitogen-activated protein kinase (MAPK) signaling pathway mutations [50].
A large study from Cercek et al. reported no statistically significant difference at the gene or pathway level after multivariate adjustment for tumor sidedness [37]. In terms of epigenetic changes, young-onset CRC has been associated with tumor hypomethylation of LINE-1 and, inversely, with high-level CpG island methylator phenotype (CIMP) [22,51], both of which are typically associated with worse survival in patients with CRC.
There is a considerable need for further studies to adequately evaluate the role of these genetic/epigenetic changes and environmental interactions in the etiology of young-onset CRC.

Treatment and Prognosis

According to the American Cancer Society’s colorectal cancer facts and figures 2020–22 report, in the United States, nearly 37% of CRC patients present with early-stage disease, followed by 35% locoregional and 21% metastatic disease. The prognosis worsens dramatically as the disease progresses. The 5-year survival rate is approximately 14% for surgically unresectable metastatic disease, while the expected survival is 90% in early-stage disease.
To date, the data are conflicting about whether patients with young-onset CRC have improved survival compared to those with older-onset CRC. Many studies suggest a better prognosis while others found a similar or worse prognosis [38,52–56].
The unique clinical, genetic, and epigenetic features that differentiate young-onset CRC from late-onset CRC could potentially influence the survival rates [6,57]. However, a large clinical trial with 2326 metastatic CRC patients showed no significant survival difference between young-onset and later-onset CRC, despite young-onset patients experiencing higher dose intensity of treatment and fewer side effects compared to the older population [58].
Adjuvant treatment recommendations do not currently differ between young-onset CRC and late-onset CRC. However, the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) study showed a significantly higher relapse rate and worse outcomes among young-onset CRC patients with high-risk (T4 and/or N2) stage III disease compared to their older counterparts [59].
Treatment recommendations also do not currently differ for young-onset CRC versus older-onset CRC patients with metastatic disease. Biomarker testing has a crucial role in tailoring therapy and should be obtained as part of standard of care for all patients, with the most important genomic alterations that drive treatment decisions being MSI status, KRAS and NRAS mutations, HER2 amplification, V600E mutations, and NTRK fusions. Because patients with young-onset CRC often have left-sided primary tumors and fewer RAS mutations, anti-EGFR therapy may be used more frequently in younger patients in the first-line setting [45].
MSI-H CRC is also more commonly found among young-onset CRC patients, therefore those with metastatic MSI-H CRC may receive immune checkpoint inhibitors more often than older-onset CRC patients [60]. Better prognostic features and biomarkers for tailoring treatment in young-onset CRC are an active research area under heavy investigation.
Although there is currently no difference in the standard treatment paradigm for young-onset versus older-onset patients, more aggressive treatment is utilized in young patients [38,55,61,62]. However, studies have found that these aggressive treatment strategies, including combination chemotherapy, radiation, and surgery, do not confer any additional survival benefit in this group.
Although medical treatments are not different in younger versus older patients, some of the challenges faced by young patients diagnosed with cancer are very different than those of older patients. For example, fertility preservation is often a paramount concern and priority for young individuals, and counseling should be performed prior to treatment initiation.
Rates of psychosocial distress are also often higher in the younger adult population, therefore clinicians should provide resources for social work support, educational and career counseling, financial guidance, spiritual and existential concerns, and physical and mental well-being. Because young-onset patients tend to have advanced stage disease, education about palliative care is also critically important. Shared decision-making is therefore critical for patients with young-onset CRC.

Screening and Prevention

Given the poor prognosis of patients with young-onset CRC, preventing the development of cancer is extremely important, particularly given the high life expectancy in that group of patients. First, lifestyle modifications and avoiding known risk factors are among the most effective preventive methods. Proper lifestyle education likely needs to start in early childhood if early-life exposures are believed to be a major contributor to the risk of young-onset CRC. Also, patients with high MSI status should be encouraged to undergo germline MMR gene sequencing to identify Lynch syndrome [63].
It is well known that screening decreases the incidence and mortality of CRC [64]. The screening methods and recommended age to start screening vary among different countries worldwide. Due to the recent increase in young-onset CRC, multiple modeling studies estimate a higher number of predicted life-years gained when the screening age was lowered to 45 years [65,66]. In 2018, the American Cancer Society therefore lowered the recommended age to begin CRC screening from 50 years to 45 years.
Numerous professional societies, including US Preventive Services Task Force, have also updated their CRC screening recommendations in average-risk patients to begin at age 45 [66–69]. Most US guidelines recommend screening between ages 45 and 75 with the individualized decision for people older than 75. The vast majority of international guidelines, including The European Screening Guidelines Working Group and The Asia Pacific Working Group, still recommend screening between 50 and 75 years [70,71].
Although the most invasive option, colonoscopy (every 10 years), remains the gold standard for CRC screening, there are multiple alternative screening methods available for average-risk patients, including flexible sigmoidoscopy (every 5 years), guaiac-based fecal occult blood test (every year), fecal immunochemical test (FIT; every 1–2 years), or multi-targeted stool DNA (every 1–3 years) [69,72]. 
Most countries outside of the US use stool-based tests as the predominant screening modality. An individualized shared decision-making approach is recommended for selecting the optimal screening method.
Finally, although lowering the screening age to 45 years will likely detect more cancers at an earlier stage in young people and remove pre-cancerous polyps, this new guideline will not apply to the increasing number of patients who are being diagnosed with CRC in their 20s, 30s, and early 40s. Consequently, there is an urgent need to conduct research to better understand the underlying etiology of young-onset CRC so that high-risk young people can be accurately identified and targeted for earlier screening.

Conclusion and Future Expectations

In conclusion, the incidence of young-onset CRC is rising worldwide, and the underlying causes are unknown. It is expected that the incidence of young-onset CRC will double by 2030. This uptrend in incidence is likely due to changing environmental factors, but the exact etiology remains elusive.
To date, no targeted treatment or screening strategies have been implemented for young-onset CRC patients. Presenting in advanced disease stage and delayed diagnosis underscore the need for greater awareness of young-onset CRC.
Patient and provider education is key in symptom awareness, promoting the benefits of screening, and increasing adherence to the screening guidelines. A thorough individualized discussion is essential to obtain detailed family history data and personalized risk factors so that more tailored preventive strategies can be implemented. Germline genetic testing is recommended in all young-onset CRC patients to increase the detection of hereditary cancer syndromes.
There is a great need for large-scale etiological research to identify the biological and epidemiologic risk factors of young-onset CRC so that novel strategies for prevention, early detection, and treatment can be developed. Public health initiatives are needed to encourage healthy dietary and lifestyle habits, decrease obesity, and increase physical activity. Also, there is a huge need to identify the early-life exposures that my be contributing so that primary prevention tactics can be adopted early. Ongoing large prospective cohorts and international consortia can be utilized to accomplish these research priorities.

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