Introduction

Colorectal cancer (CRC) is a global health problem with high incidence and mortality rates. Although the incidence has decreased with the use of screening tests, the mortality rate is approximately 1,6 – 2,0 % per year. Recent studies have shown a steady increase in the incidence of early onset (<50 years) CRC compared to that of patients >50 years of age. Early-onset CRC cancer is reported to have a more progressive course and may have a genetic and epigenetic background. In this study, we aimed to investigate the disease characteristics and risk factors for colorectal cancer in patients <50 years old and compare with patients over 50 years of age.

Aims & Methods

Patients younger than 50 years, diagnosed with colorectal adenocarcinoma and followed in our hospitals' gastroenterology, oncology, or general surgery departments between January/2009 and June/2022 were included in this retrospective study. A total of 6102 patients’ files were examined. Among these, 1166 were under the age of 50, whilst 4936 were 50 years and older. Patients younger than 18 years, who had a previous history of CRC, a known familial CRC syndrome, who had synchronous tumors at the time of diagnosis or had in situ CRC were not included in the study. After applying the exclusion criteria, 989 patients were included in the under-50 age group. The comparison group consisted of 1009 patients randomly selected from a group of 4000 patients aged 50 years or older. Patients were divided into Group A (<50 years) and Group B (≥ 50 years) according to the age at diagnosis. Patients’ demographic characteristics, body mass index, history of cigarette smoking and alcohol use, presenting symptoms, history of H. pylori infection, co-morbidities and medications were recorded from the files. Tumour characteristics, localization, size, TNM stage, and treatment methods were also analyzed and the relationship with each other was examined comparatively.

Results

The results of 1998 patients included in the study are shown in Table 1. TNM stages and the duration of symptoms before the diagnosis were similar between the groups but the rate of stage 1 disease was higher in group B. The rates of metastatic disease and rectal cancer were higher in Group A, but statistically non-significant. Abdominal pain was significantly more frequent in Group A, while anemia was significantly more common in Group B. Patients in Group A had higher rates of IBD, family history of CRC, mucinous adenocarcinoma, poorly differentiated tumor, higher histological grade and higher microsatellite instability (MSI-H). Although perineural and lymphatic invasion rates were similar, vascular invasion was higher in group B.

Table1. Comparison of Patients in Group A and Group B

Conclusion

Our study revealed that Early-onset CRC is more frequently diagnosed at the metastatic stage, is characterized by a more common presence of mucinous cells, poorly differentiated histology, and microsatellite instability.

Introduction

Colorectal cancer (CRC)-driven liver metastasis formation is one of the main drivers of cancer-related deaths. As CRC development has formerly been identified as a disease of elderly people, recent epidemiological data shows an increasing incidence of CRC in people younger than 50 years of age (early-onset colorectal cancer, EOCRC) while less people are being diagnosed with CRC after the age of 50 years (late-onset CRC, LOCRC). Recent studies have identified disparities between these two forms, with early-onset cases often diagnosed at more advanced stages, including elevated risks for recurrence and metastasis formation, including liver metastasis.

Aims & Methods

Here, we have studied how CRC and CRC-dependent liver metastasis develops in an age-dependent manner by using 8-weeks old and 78-weeks old C57BL/6 mice from the same vendor under the same housing conditions. To this end, we used an orthotopic mouse model of CRC-related liver tumor formation, in which colorectal tumor organoids were engrafted in the liver via injection into the portal circulation, solely leading to liver metastasis formation without any primary colon tumor growth. To study age-dependency of primary CRC growth, we injected CRC organoids into the mucosa of the rectum. We further analyzed the molecular mechanisms of disease development, using antibody depletion, genetic mouse and ex vivo tumor models, as well as spatial transcriptomics approaches.

Results

Interestingly, we could demonstrate that young mice exhibit more and larger liver metastases compared to older counterparts, while the formation of primary CRC was unaffected by the age of the host. Liver metastases in old mice display increased necrosis formation which is accompanied by an elevated abundance of different immune cells such as CD8⁺ T cells. Spatial transcriptomics analysis further revealed a distinct anaplerotic metabolic phenotype in liver metastases of young hosts, showing that tumor-surrounding metabolic factors differ between young and old mice, which highlights important metastatic niche dependencies to control tumor growth. Current investigations therefore are directed towards elucidating the factors driving enhanced metastatic development in young hosts and their interactions within the tumor microenvironment, focusing on spatial metabolomics approaches and human cohorts for early-onset CRC.

Conclusion

Our findings demonstrate more aggressive liver metastasis formation in young hosts, as similarly observed in humans, and offer valuable insights into the pathogenesis of early-onset colorectal cancer.

Introduction

The number of colorectal cancer (CRC) cases and deaths in Japan is on the increase and is higher than in Western countries. In Europe and US, the increase in CRC among young people is a problem, in contrast to the decreasing trend among middle-aged and older people. In Japan, there is concern about the increase in CRC, and to prevent colorectal tumors (CRTs) in young people aged 40 years or younger, it is necessary to urgently understand the current situation and to carry out efficient screening by clarifying risk factors, together with CRC screening using fecal immunochemical test (FIT).

Aims & Methods

In this study, we conducted a retrospective study of the clinicopathological characteristics and risk factors of 303 CRTs diagnosed by colonoscopy (CS) at our institution in patients aged 40 years or younger.
(1) In the CRT group, the pathological diagnosis and location were investigated. (2) The examination period was divided into early (2012-2017) and late (2018-2024), and the frequency of tumor detection was examined. (3) The association of various background factors (family history of CRC, body mass index (BMI), hypertension (HT), dyslipidemia, diabetes, alcohol drinking, smoking and exercise habits) as risk factors for tumors was statistically investigated. SPSS29 (IBM) was used for statistical analysis.

Results

(1) CRTs included 237 adenomas, 38 serrated adenomas and 28 colorectal carcinomas (24 intra-mucosal carcinomas, 3 invasive carcinomas and 1 neuroendocrine tumor). Solitary tumors were 63.7% and 71.3% (89.3% for CRC) were located in the left colon. (2) The frequency of tumor detection was markedly increased: 2.04% in early male (M)/ 20.2% in late M and 0.29% in early female (F)/ 16.4% in late F. (3) Risk factors: overall risk factors for CRTs [odds ratio (OR) 95% confidence interval (CI)] were 2.998 (1.244-7.176) for family history of CRC, 1.786 (1.007-3.168) for BMI>30, 3.875 (1.082-13.878) for BMI>35, 2.456 (1.337-4.511) for HT, 1.596 (1.153-2.210) for alcohol drinking, 2.111 (1.306-3.412) for >20g/day alcohol drinking, 1.635 (1.170-2.285) for smoking. In M, risk factors for CRTs were family history of CRC 2.933 (1.036-8.300), HT 2.240 (1.124-4.463), alcohol drinking 1.760 (1.182-2.619, >20 g/day alcohol drinking 2.409 (1.402-4.138)) and in F, smoking 2.724 (1.223-6.070). In Logistic Regression, which added age and sex to the factors that were significant in univariate analysis, the risk factors for CRTs were: family history of CRC 3.542 (1.376-9.119), HT 2.032 (1.096-4.147), alcohol drinking 1.524 (1.076-2.159), smoking 1.665 (1.148-2.415).

Conclusion

The frequency of CRTs in young people aged 40 years or younger is increasing in Japan. Family history of CRC, HT, alcohol drinking and smoking are risk factors, and along with FIT, efficient screening based on these background factors is needed.

Introduction

Lynch syndrome (LS) is the most frequent hereditary cancer syndrome, responsible for 3-5% of all colorectal cancer (CRC) cases. Patients with LS are at increased risk for metachronous CRC, influenced by the specific gene involved and the extent of prior surgical intervention¹. However, the impact of colonoscopy surveillance on metachronous CRC incidence in LS carriers has not been clearly defined.

Aims & Methods

To characterize LS carriers at risk of developing metachronous CRC based on the affected gene and the extent of prior surgery. To describe follow-up characteristics, particularly the rate of colonoscopy surveillance. To report the incidence of metachronous CRC according to surgical extent and gene mutation. To analyze potential risk factors associated with metachronous CRC development.
This retrospective multicenter study included 583 LS carriers diagnosed with CRC; 43 were excluded due to missing surgical or follow-up data, resulting in 540 patients analyzed. Patients were categorized by high-risk genes (MLH1, MSH2) or low-risk genes (MSH6, PMS2) and by surgical extent (extensive or partial colectomy). Colonoscopy surveillance was defined as at least one colonoscopy following the initial CRC diagnosis or between successive CRC events in cases of metachronous CRC. Survival analysis assessed the incidence of metachronous CRC.

Results

Among the 540 included carriers, 247 (45.7%) had MLH1 mutations, 181 (33.5%) MSH2, 80 (14.8%) MSH6, and 32 (5.9%) PMS2. Participants were grouped into four categories: high-risk/extensive colectomy (N=58), high-risk/partial colectomy (N=370), low-risk/extensive colectomy (N=9), and low-risk/partial colectomy (N=103). Age at first CRC diagnosis was significantly higher in high-risk groups compared to low-risk groups. No differences were found between groups regarding sex, tumor location, or tumor stage. Median follow-up duration was 8.6 years (IQR 4.5-14.6), with no significant differences among groups. During follow-up, 107 cases of metachronous CRC occurred. Survival analysis revealed significant differences in metachronous CRC incidence (Log-rank test: p=0.006), with 10-year incidence rates of 6.4% for high-risk/extensive colectomy, 17.9% for high-risk/partial colectomy, 0% for low-risk/extensive colectomy, and 4.8% for low-risk/partial colectomy groups. Risk factors significantly associated with metachronous CRC included high-risk gene mutations (HR 2.49, 95% CI 1.2-4.77) and initial CRC diagnosis before the year 2000 (HR 1.61, 95% CI 1.02-2.55). Colonoscopy surveillance was associated with a reduced risk of metacronous CRC (HR 0.06, 95% CI 0.04-0.09).

Table 3. Metachronous CRC risk factors

Conclusion

Individuals carrying pathogenic variants in MLH1 or MSH2 who undergo partial colectomy face a markedly increased risk of developing metachronous CRC. Nonetheless, the introduction of structured colonoscopic surveillance and optimized management strategies after the year 2000 has significantly mitigated this risk. These findings are essential for informing surgical decision-making in patients with LS and CRC, particularly when evaluating the most appropriate extent of colectomy.

References

Eikenboom EL, Moen S, Van Leerdam ME, Papageorgiou G, Doukas M, Tanis PJ, et al. Metachronous colorectal cancer risk according to Lynch syndrome pathogenic variant after extensive versus partial colectomy in the Netherlands: a retrospective cohort study. The Lancet Gastroenterology & Hepatology. 2023 Dec;8(12):1106–17.