Colon and Rectal Cancer Is Increasing at Younger Ages – Causes, Characteristics and Differences

Large-bowel (colon and rectum = colorectal) cancer, worldwide, is the third most common cancer. It is also the second leading cause of cancer-related death.

What Is Early-Onset Colorectal Cancer?

Early-onset colorectal cancer is defined as a diagnosis before the age of 50. Cases of colorectal cancer at younger ages are increasing at an alarming rate in the US and other high-income countries (Figure-1).

Of all newly diagnosed colorectal cancer cases, approximately 10% occur at younger ages. In addition, colorectal cancer-related mortality (death) rates are increasing among young patients. In contrast, diagnoses of colorectal cancer at older ages and related mortality have steadily decreased over the past twenty years in the US and other high-income countries.

The median age at colorectal cancer diagnosis, which was 72 in the 2000s, has now fallen to 66.

The relationship between increasing diagnoses at younger ages and the associated decrease in diagnoses at older ages is attributed to increased cancer screening, advances in treatment and subsequent follow-up. Over the next 10 years, 25% of rectal cancer cases and 10-12% of colon cancer cases are projected to be diagnosed before the age of 50.

Patients with early-onset colorectal cancer are more likely to have a hereditary syndrome than those diagnosed at older ages, but most cases are still sporadic and have no identifiable cause.

NOTE: Sporadic cancers arise from environmental causes (such as obesity, diet, smoking and alcohol) and  aging and account for approximately 80 percent of all cancers. In other words, they are cancers caused by DNA damage that accumulates over time for various reasons.

No specific somatic mutation profile has been identified for early-onset colorectal cancers. No targetable genetic alterations have been established that would improve our understanding of how these cancers arise at the cellular level or guide their treatment. Therefore, there are not yet "different" targeted drugs (directed at molecular targets) for early- and late-onset colorectal cancers. 

Figure-1: Trends in colorectal cancer incidence (1995-2016) and mortality (1970-2017) in the US by age and sex. "Incidence" refers to the number of new cancer cases occurring annually per 100 thousand people. "Mortality" refers to the death rate.

Clinical Characteristics of Colon and Rectal Cancers at Younger Ages

The clinical characteristics of early-onset colorectal cancer differ from those of disease that develops at older ages. Early-onset colorectal cancers are more often detected in the rectum, followed by the distal/end (near the rectum) colon; more than 70% of early-onset colorectal cancers occur in the left colon. By contrast, colorectal cancers that develop at older ages (in people older than 50) occur with similar frequency in the right and left colon.

Overall, colorectal cancer rates are 30% higher in men than in women; however, the difference between the sexes is more pronounced for rectal cancer than for colon cancer.

Studies have suggested that earlier-onset colorectal cancers (in patients younger than 40) are more likely to be poorly differentiated and to have signet-ring cells. However, most of these studies lacked data on tumors with hypermutation resulting from DNA mismatch repair deficiency (dMMR), leading to high microsatellite instability (MSI-H). More recent studies have shown that early-onset colorectal cancers are more likely to exhibit MSI-H, which is associated with poor tumor differentiation. MSI-H tumors are caused less often by MLH1 gene epigenetic inactivation than by inherited mutations in MMR genes.

In addition, early-onset colorectal cancers have generally been shown to be diagnosed at more advanced stages.

However, the question here is whether this is a result of tumors arising at younger ages being more aggressive or of a delayed diagnosis.

Why Is Early-Onset Colorectal Cancer Increasing?

Age-adjusted reports from the US state that between 1988 and 2015, 7.9 out of every 100,000 people developed early-onset colorectal cancer, and that this number has now risen to 12.9, representing a 63% increase.

This growing rate is generally observed in developed countries, suggesting that people in these geographical regions may have been exposed to similar risk factors. In addition, a marked increase has generally been observed in non-Hispanic White people, while a small increase that could be described as relatively stable has been observed in Black people.

Among the factors that may contribute to developing early-onset colorectal cancer, diet is also thought to play a role. A study conducted by Nurses' Health (1991-2015) reported that a Western diet was associated particularly with the development of colon and rectal cancers at younger ages. Consequently, consumption of processed meat and refined grain products has increased over the past 50 years, bringing with it an increase in early-onset colorectal cancer cases. In contrast, whole-grain foods are known to offer protection against colorectal cancer.

Likewise, artificially or naturally sweetened beverages, which are widely consumed particularly among adolescents and young people, are also risk factors. In the same Nurses’ Health study, each additional daily serving among adolescents aged 13-18 who consumed these products was associated with a 32% increase in colorectal cancer risk.

Obesity was examined in another study, which showed that its prevalence rose from 30.5% in 1999 to 42.4% in 2017.

Fortunately, factors such as a Western diet, overweight and obesity can be changed, thereby preventing early cases. In addition, smoking is another risk factor that can be controlled.

Metabolic syndrome and type 2 diabetes are also becoming more common among young adults, and this has been associated with an increase in early-onset colorectal cancer. 

In conclusion, no single primary or dominant factor has been fully identified to explain the worldwide increase in early-onset colorectal cancer. However, multiple factors, including changes in the gut microbiome and environmental factors, are responsible for this increase (Figure 2).

Figure-2: Factors affecting colorectal cancer risk

A study focusing particularly on a Western diet suggested that excessive amounts of sulfur-metabolizing bacteria detected in stool were responsible for this increase. These bacteria produce genotoxic hydrogen sulfide, which causes inflammation and DNA damage. This in turn increases cancer risk. In addition, antibiotics are also known to alter the gut microbiome, meaning that their long-term use also poses a risk.

Genetic Predisposition to Early-Onset Colorectal Cancer

Approximately 30% of patients with early-onset colorectal cancer have at least one first-degree relative with a history of the same cancer.

Population-based data show that hereditary colorectal cancers have an overall frequency of 3-5% in the population, with Lynch syndrome being the most common. Lynch syndrome results from an inherited mutation in MMR genes (MLH1, MSH2, MSH6, PMS2 or EPCAM) that leads to dMMR and MSI-H.

Multigene panel testing (25 genes) of 450 people with early-onset colorectal cancer registered at 51 hospitals in Ohio found that 16% had germline (inherited) mutations, with approximately half of these having Lynch syndrome. Another similar study reported that 25% of 315 patients younger than 50 had a hereditary colorectal cancer syndrome.

Half of the patients with a pathogenic inherited genetic alteration reported a first-degree relative with a history of colorectal cancer. Given this finding and the limited sensitivity of clinical criteria, the Collaborative Group of the Americas on Gastrointestinal Cancer recommended genetic testing by next-generation sequencing using a hereditary multigene panel for all colorectal cancer patients younger than 50. Similarly, the National Comprehensive Cancer Network (NCCN) recommended genetic risk counseling for all individuals at risk of early-onset colorectal cancer.

Figure-3: Frequency of pathogenic germline (inherited) alterations in patients who develop early-onset colorectal cancer

What Are the Molecular Differences Between Late- and Early-Onset Colorectal Cancers?

Colorectal cancers are molecularly heterogeneous tumors (with mixed biology). Although colorectal tumors developing at younger or older ages are relatively similar, some differences have been identified.

An MSI-H frequency of 17% was reported among a group of patients with early-onset colorectal cancer. While most MSI-H colorectal cancers in young patients result from Lynch syndrome, cases beginning at older ages more often include sporadic MSI-H tumors due to MLH1 hypermethylation and frequent BRAF V600E mutations. 

In a study of 18,218 colorectal cancer cases, patients were divided into three age groups and genomic alterations were compared; molecular alterations in microsatellite-stable (MSS) cancers were similar across age groups. However, APC, KRAS and BRAF mutations were more common in patients aged 50 and older. Alterations in TP53 and CTNNB1 were more common in patients younger than 40.

Disease Course in Early- and Late-Onset Colorectal Cancer

Early-onset colorectal cancers tend to become apparent at advanced stages, when the risk of death from the disease is also higher. These patients have more metastatic regional lymph nodes, but are also more likely to receive more effective/high-dose treatment. In addition, young patients are more likely to receive adjuvant chemotherapy (after surgery to reduce the risk of cancer recurrence) and multidrug regimens.

In one study, survival after adjuvant chemotherapy in patients with stage II and III colon cancer was similar to that of colorectal cancers beginning at older ages. Another study also found no difference in survival between early- and late-onset cases after adjustment for MMR, KRAS and BRAF V600E.

Finally, there was no significant difference in survival between patients with early- and late-onset metastatic colorectal cancer. Taken together, these data suggest that the main determinant of disease course is the cancer's stage at diagnosis.

Cancer Screening

Early diagnosis significantly reduces mortality. Although the importance of colorectal cancer screening in people aged 50 and older is known, only 68.8% of those who should be screened in the US undergo screening (this rate is lower in Turkey). Factors influencing this include insufficient information about screening, gaps in access to healthcare or reluctance. Low income is another contributing factor.

There are many screening options for people at risk of colorectal cancer, including the fecal immunohistochemical test (FIT), multitarget stool DNA testing, colonoscopy, sigmoidoscopy alone or with FIT, and the guaiac test. Nevertheless, the most standard of these tests is colonoscopy, which also offers benefits such as removing polyps before they become cancerous (see 7 alternatives to colonoscopy for early diagnosis of colon and rectal cancer).

Until recently, the recommended screening age for people at risk of colorectal cancer in the US and many other countries was 50. However, in view of the increasing incidence of early-onset colorectal cancer, the US Preventive Services Task Force updated its guidance in 2016 and lowered the recommended screening age to 45. Similarly, in 2018, the American Cancer Society emphasized age 45 for colorectal cancer screening.

In addition:

• People with a first-degree relative diagnosed with colorectal cancer or an advanced adenoma (colon polyp) before the age of 60, or
• with two first-degree relatives diagnosed with these conditions at any age, are advised to begin screening (colonoscopy) before the age of 40 or 10 years younger than the age at which their youngest affected relative was diagnosed.

Strategies to Reduce Early-Onset Colorectal Cancer Incidence

Difficulties and barriers to colorectal cancer screening should be addressed for all age groups at risk (both younger than 50 and older than 50).

In addition, the main factor motivating people to undergo screening is a doctor's recommendation. Raising awareness, providing information and encouraging approaches that reflect patients' preferences will have a positive effect.

Updating data on individuals with a family history and identifying those at high risk are also important.

Another strategy is a new screening method that involves assessing circulating tumor DNA in the blood to detect early-stage colorectal cancer. If this approach is successful in clinical practice, it is thought that the number of people undergoing screening could increase.

Conclusion

• The number of people developing early-onset colorectal cancer is expected to keep rising until 2030 and to double compared with today.
• The diagnosis of young patients at advanced stages underlines the need for public health authorities and physicians to raise greater awareness.
• There is also a need to develop more specific prevention and screening strategies for risk profiling. Since hereditary syndromes account for 25% of early-onset colorectal cancer cases, with Lynch syndrome being the most common, both hereditary and sporadic disease should be addressed carefully and separately.
• While multigene panels for hereditary cancer genes help detect hereditary syndromes, research continues to identify the specific causes underlying early-onset colorectal cancer. Environmental exposures at younger ages, including a Western diet that can alter the gut flora, are a focus of these studies. Health measures to prevent poor dietary habits, obesity and physical inactivity are needed, particularly for adolescents.
• Finally, psychosocial difficulties and reduced health-related quality of life are also issues that need to be addressed in early-onset colorectal cancer.