What are the characteristics of the increasing number of early-onset colorectal cancer?

According to the latest global cancer burden data released by the World Health Organization's International Agency for Research on Cancer (IARC) in 2020, colorectal cancer (CRC) currently ranks third in the global incidence spectrum and second in the cause of death spectrum, accounting for 3% of the total cancer incidence and deaths, respectively.

Worldwide, the incidence of early-onset colorectal cancer (CRC diagnosed in individuals under the age of 50) is on the rise and has become a public health priority

Recently, a comprehensive review on early-onset colorectal cancer was published in The Lancet Gastroenterology & Hepatology, detailing early-onset colorectal cancer worldwide.

Screenshot source: The Lancet Gastroenterology & Hepatology

Epidemiology of early-onset colorectal cancer

The global incidence of early-onset colorectal cancer has increased over the past few decades

According to cancer registry data from 20 European countries:

The incidence of CRC among people aged 20-29 increased from 0.

The incidence rate increased from 2.

The incidence of early-onset colorectal cancer has also shown an increasing trend in several countries in North America, Oceania, and Asia

Regarding the mortality rate of early-onset colorectal cancer, the data trends are not completely consistent across regions

Across 20 European countries, there was no change in mortality among people aged 20-29

Risk factors for early-onset colorectal cancer

Data on risk factors for early-onset colorectal cancer are accumulating

Those with the most Western diets (ie, diets high in ultra-processed foods; 81%-100%) had a higher risk of developing early-onset advanced adenomas compared with those with the lowest Western diets (1%-20%)57 % (OR 1.

A variety of unhealthy diets are associated with an increased risk of early-onset colorectal cancer:

Drinking two or more sugar-sweetened beverages per day more than doubled the risk (RR 2.

Vegetables (50% risk reduction, OR 0.

Smoking of 20 packs or more per year (OR 4.

Increasing age (OR 1.

Reasons for rising incidence of early-onset colorectal cancer

Although the precise reasons for the rising incidence of early-onset colorectal cancer in high-income countries are unclear, epidemiological, clinical, and biological observations suggest that the incidence of early-onset colorectal cancer may be more likely in countries with a Western life>

The incidence of early-onset colorectal cancer varies regionally, with higher rates in the southern United States and Appalachia, and a decrease in Italy, which may reflect differences in diet and life>
.

Studies have shown that smoking is a risk factor for early-onset colorectal cancer, but considering the long induction period of CRC, it is unclear whether this factor is a predisposing factor for early-onset colorectal cancer
.

Clinical and pathological features of early-onset colorectal cancer

Early-onset colorectal cancer behaves differently from late-onset colorectal cancer
.
Most patients with early-onset colorectal cancer were symptomatic and were more likely to have blood in the stool (28.
8% vs 23.
2%, p<0.
01) and abdominal pain (41.
2% vs 27.
2%, p<0.
01).
Incidental diagnosis was more likely (14.
6% vs 5.
2%, p<0.
01)
.

In addition, early-onset colorectal cancer had a longer time to onset of symptoms (243 vs 154 days) and a longer delay from symptom onset to diagnosis (152-217 vs 29.
5-87 days)
.

Early-onset colorectal cancer is more likely to occur in the left colon and has a more aggressive histopathology
.
Patients with late-onset colorectal cancer were more likely to have right-sided cancer (31.
1% vs 20.
0%, p<0.
001)
.

In early-onset colorectal cancer, 10.
0%–14.
5% had mucinous histology, 2.
0%–13.
0% had signet ring histology, and up to 27.
9% of cancers were poorly differentiated or undifferentiated
.
Data from the US National Cancer Database showed that compared with late-onset colorectal cancer, early-onset disease was more likely to have mucinous or signet-ring histology (12.
6% vs 10.
8%, p<0.
01) and histology was differentiated Poor or no differentiation (20.
4% vs 18%, p<0.
01)
.

Compared with late-onset disease, early-onset colorectal cancer is more likely to be diagnosed at an advanced stage
.
Compared with older patients, younger patients had a 1.
37-fold relative risk (RR) for regional metastasis and a 1.
58-fold relative risk for distant metastasis
.
Although patients with early-onset disease are more advanced at diagnosis and have more aggressive histology, they have better survival
.

In the report, stage-adjusted 5-year cancer-specific survival was better in patients with early-onset colorectal cancer than in patients with late-onset disease (95.
1% vs 91.
9% for localized cancer, p<0.
001; 76% vs 70.
3% for regional cancer, p<0.
001) <0.
001; distant metastases 21.
3% vs 14.
1%, p<0.
001)
.

Genetic and epigenetic landscape

1.
Prevalence and profiles of germline-inherited pathogenic variants

Studies have shown that 14%-25% of individuals with early-onset disease have pathogenic germline variants associated with cancer risk
.
But there are no data to suggest that the incidence of these genetic variants is increasing in the general population
.
Thus, although genetic syndromes are associated with a substantial proportion of early-onset colorectal cancer, they are not necessarily responsible for the increased incidence
.

Patients with early-onset colorectal cancer have a broad spectrum of pathogenic germline variants, including polyposis-associated variants such as APC and SMAD4, and BRCA1, TP53, and CHEK2 variants, but these patients often do not display the expected phenotype or expected family history
.

Different studies have shown that 19%-26% of patients diagnosed with an inherited syndrome do not have a family history consistent with the diagnosed syndrome
.
Similarly, in the other two cohorts, 19% of patients with the pathogenic variant and 26% of patients, respectively, had no family history of cancer
.

2.
Polygenic Risk

Polygenic risk was associated with early-onset colorectal cancer, and the association was stronger with early-onset disease than with late-onset disease
.

The 25% with the highest polygenic risk score had a higher risk of colorectal cancer in those younger than 50 years compared with those 50 years and older (risk odds ratio [OR] 3.
73 vs 2.
92)
.
The strongest association was in patients with early-onset colorectal cancer without a family history of colorectal cancer (OR 4.
26, 95% CI 3.
61-5.
01)
.

3.
Family Risk

In the absence of clear germline susceptibility, the majority of patients with early-onset colorectal cancer still have a family history of colorectal tumors
.
Up to 33.
5% of early-onset patients had a family history of colorectal cancer
.
Patients with early-onset disease were more likely than those with late-onset disease to have a family history of CRC (24.
9% vs 16.
8%)
.

When patients with germline genetic syndromes were explicitly excluded, 14.
058%–16.
3% of patients with early-onset colorectal cancer had first-degree relatives with CRC
.
This proportion may also be underestimated because the proportion of their first-degree relatives with advanced adenomas is unknown
.

4.
Molecular Pathology

Early-onset colorectal cancer has heterogeneous somatic and molecular features
.
The study showed that of 450 patients under the age of 50 who were diagnosed with CRC, 43 (9.
5%) had microsatellite instability-high (MSI-H) tumors (21.
5% had germline pathogenicity) variant, 9.
3% of patients had no germline variant)
.

After excluding patients with genetic syndromes, 37 (29.
4%) of 126 CRC patients aged 13-39 years had tumors with a microsatellite unstable phenotype
.

Microsatellite-stable and chromosomally stable tumors are near-diploid tumors and are observed more frequently in early-onset colorectal cancer than in late-onset colorectal cancer
.
Microsatellite-stabilized tumors were reported to be more common in the early-onset colorectal cancer group than in the late-onset disease group in patients over 65 years of age with microsatellite-stable colorectal cancer (46% vs 26%, p<0.
01) , and more advanced tumors (42% vs 18%, p=0.
02) and more were located in the rectum (50% vs 23%, p=0.
04)
.

Studies by next-generation genome sequencing found that genomic alterations were similar between young and older cohorts, except that TP53 and CTNNB1 alterations were more common in the youngest cohort, while APC, KRAS, BRAF and FAM123B variants were more common in older cohorts for common
.

Consensus molecular subtypes (CMS) of colorectal cancer vary according to age at diagnosis
.
In addition, early-onset colorectal cancer has unique epigenetic signatures
.
Studies have reported a lower prevalence of CpG island methylation phenotype (CIMP) in early-onset colorectal cancer
.

5.
Gut flora

There is evidence that the characteristics of the gut microbiome are associated with colorectal cancer risk; however, data for early-onset colorectal cancer are scarce
.
The study found that patients with high levels of F.
nucleatum had a 1.
58-fold (95% CI 1.
04–2.
39) risk of mortality compared with cancers without the F.
nucleatum species
.

Colibacins are also thought to be involved in genetic changes
.
The researchers exposed human intestinal organoids to E.
coli containing polyketide synthase islands and found that the mutation signature was similar to that of colorectal cancer
.

The study also found that polymicrobial bacterial biofilms were found in 89% of right-sided tumor lesions and 12% of left-sided tumor lesions in colorectal cancer.
It is worth noting that normal mucosa distant from tumor tissue also exhibited similar characteristics to tumor tissue.
biofilm communities
.
This further suggests that microbiome signatures may be helpful in diagnosis and prognosis
.

Early detection and prevention of early-onset colorectal cancer

1.
Assess symptoms promptly

There is still a large delay from the onset of symptoms to the diagnosis of early-onset colorectal cancer.
It is necessary to timely evaluate the symptoms to avoid the delay of the disease
.
Bleeding is a common symptom of early-onset colorectal cancer, and symptoms such as hemorrhoids, especially bleeding hemorrhoids, cannot be ignored
.

One study found that patients with iron deficiency anemia and blood in the stool had a nearly 10-fold increased risk of early-onset colorectal cancer (HR 10.
81 and 10.
66, respectively)
.
The U.
S.
Colorectal Cancer Services Task Force recommends that all patients under the age of 50 with symptoms of unexplained bleeding or iron-deficiency anemia undergo colonoscopy
.

A research team has proposed a symptom assessment framework that recommends completing the following steps within 60 days of a patient’s first report to a healthcare provider: (1) systematically identify symptoms; (2) guideline-based triage for lower gastrointestinal endoscopy; ( 3) Timely and systematic follow-up for differential diagnosis and treatment of symptoms; (4) Colonoscopy should be performed in time for unexplained or unresolved symptoms
.

2.
Strengthen precise screening of high-risk groups and general population screening

About 16% of patients with early-onset colorectal cancer have an associated genetic syndrome, and another 25% have a family history of CRC, who can be screened early according to current screening guidelines in the United States and the United Kingdom
.

Improving the identification and management of people at high risk for CRC based on family history and genetics is an important step toward reducing the burden of early-onset colorectal cancer
.
In addition, ensuring closed-loop communication between different specialties, including gastroenterology, pathology, oncology, genetics, and surgery, can help ensure that genetic testing is completed for timely action, or new diagnoses of hereditary cancers patients
.

Another approach to reducing the burden of early-onset colorectal cancer is to advance the age at which screening begins in all average-risk individuals
.
Expanding screening to people under the age of 50 could detect cancer at an early stage and even prevent CRC with colonoscopic polypectomy
.

Several professional societies in the United States recommend lowering the starting age for screening in the general population from 50 to 45
.
As these recommendations are implemented, it is critical to ensure equitable access to screening for all eligible populations and to improve low adherence rates among young people
.

The "Guidelines for Colorectal Cancer Screening, Early Diagnosis and Early Treatment in China" recommends that the general population should receive colorectal cancer risk assessment from the age of 40, and those assessed as low- and medium-risk and high-risk groups should receive colorectal cancer from the age of 50 and 40, respectively.
Cancer Screening
.
Screening programs prioritize colonoscopy
.

Epilogue

In conclusion, the incidence of early-onset colorectal cancer is increasing globally, but the reasons are not fully understood
.
Future studies will further elucidate the pathogenesis and assess whether to modify screening methods for average-risk individuals
.

The main current clinical intervention is aimed at early genomic testing of all individuals with early-onset colorectal cancer, or by identifying those with genetic syndromes and screening for those with a family history of CRC, and for those with risk signals assessment in response to rising morbidity
.

References

[1] Latest global cancer data: Cancerburden rises to 19.
3 million new cases and 10.
0 million cancer deaths in 2020.
Retrieved Dec 16, 2020, from https:// data-cancer-burden-rises-to-19-3-million-new-cases-and-10-0-million-cancer-deaths-in-2020/

[2] Swati G Patel, Jordan J Karlitz, etal.
, (2022).
The rising tide of early-onset colorectal cancer: a comprehensive review of epidemiology, clinical features, biology, risk factors, prevention, and early detection.
The Lancet Gastroenterology & Hepatology.
DOI: https://doi.
org/10.
1016/S2468-1253(21)00426-X

[3] National Cancer Center China Colorectal Cancer Screening, Early Diagnosis and Early Treatment Guidelines Development Expert Group.
China Colorectal Cancer Screening, Early Diagnosis and Early Treatment Guidelines (2020, Beijing) [J].
China Oncology, 2021,30(01)