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Early-onset colorectal cancer (EOCRC), defined as colorectal cancer in individuals under 50 years of age, has shown an alarming increase in incidence worldwide. We report a case of a twenty-four-year-old female with a strong family history of colorectal cancer (CRC) but without an identified underlying genetic predisposition syndrome. Two years after primary surgery and adjuvant chemotherapy, the patient developed new liver lesions. Extensive diagnostic imaging was conducted to investigate suspected liver metastases, ultimately leading to a diagnosis of focal nodular hyperplasia. The young age of the patient has prompted comprehensive genomic and transcriptomic profiling in order to identify potential oncogenic drivers and inform further clinical management of the patient. Besides a number of oncogenic mutations identified in the patient's tumour sample, including KRAS G12D, TP53 R248W and TTN L28470V, we have also identified a homozygous deletion of 24.5 MB on chromosome 8. A multivariate Cox regression analysis of this patient's mutation profile conferred a favourable prognosis when compared with the TCGA COADREAD database. Notably, the identified deletion on chromosome 8 includes the WRN gene, which could contribute to the patient's overall positive response to chemotherapy. The complex clinical presentation, including the need for emergency surgery, early age at diagnosis, strong family history, and unexpected findings on surveillance imaging, necessitated a multidisciplinary approach involving medical, radiation, and surgical oncologists, along with psychological support and reproductive medicine specialists. Molecular profiling of the tumour strongly indicates that patients with complex mutational profile and rare genomic rearrangements require a prolonged surveillance and personalised informed interventions.

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Background: Early-onset colorectal cancer (EOCRC) is increasing in incidence and poses a growing threat. Urgent research is needed, especially in survival analysis, to enhance comprehension and treatment strategies. This study aimed to explore the risk factors associated with cancer-specific mortality (CSM) and other-cause mortality (OCM) in patients with EOCRC. Additionally, the study aimed to develop a nomogram predicting CSM using a competitive risk model and validate its accuracy through the use of training, using internal and external cohorts. Methods: Data from EOCRC patients were collected from the Surveillance, Epidemiology, and End Results (SEER) database (2008-2017). EOCRC patients who were treated at a tertiary hospital in northeast China between 2014 and 2020 were also included in the study. The SEER data were divided into the training and validation sets at a 7:3 ratio. A univariate Cox regression model was employed to identify prognostic factors. Subsequently, multivariate Cox regression models were applied to ascertain the presence of independent risk factors. A nomogram was generated to visualize the results, which were evaluated using the concordance index (C-index), area under the curve (AUC), and calibration curves. The clinical utility was assessed via decision curve analysis (DCA). Results: Multivariable Cox regression analysis demonstrated that factors such as race, tumor differentiation, levels of carcinoembryonic antigen (CEA), marital status, histological type, American Joint Committee on Cancer (AJCC) stage, and surgical status were independent risk factors for CSM in EOCRC patients. In addition, age, gender, chemotherapy details, CEA levels, marital status, and AJCC stage were established as independent risk factors for OCM in individuals diagnosed with EOCRC. A nomogram was developed using the identified independent risk factors, demonstrating excellent performance with a C-index of 0.806, 0.801, and 0.810 for the training, internal validation, and external validation cohorts, respectively. The calibration curves and AUC further confirmed the accuracy and discriminative ability of the nomogram. Furthermore, the DCA results indicated that the model had good clinical value. Conclusions: In this study, a competing risk model for CSM was developed in EOCRC patients. The model demonstrates a high level of predictive accuracy, providing valuable insights into the treatment decision-making process.

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Metabolic dysfunction associated with obesity leads to a chronic pro-inflammatory state with systemic effects, including the alteration of macrophage metabolism. Tumor-associated macrophages have been linked to the formation of cancer through the production of metabolites such as itaconate. Itaconate downregulates peroxisome proliferator-activated receptor gamma as a tumor-suppressing factor and upregulates anti-inflammatory cytokines in M2-like macrophages. Similarly, leptin and adiponectin also influence macrophage cytokine expression and contribute to the progression of colorectal cancer via changes in gene expression within the PI3K/AKT pathway. This pathway influences cell proliferation, differentiation, and tumorigenesis. This work provides a review of obesity-related hormones and inflammatory mechanisms leading to the development and progression of early-onset colorectal cancer (EOCRC). A literature search was performed using the PubMed and Cochrane databases to identify studies related to obesity and EOCRC, with keywords including 'EOCRC', 'obesity', 'obesity-related hormones', 'itaconate', 'adiponectin', 'leptin', 'M2a macrophage', and 'microbiome'. With this concept of pro-inflammatory markers contributing to EOCRC, increased use of chemo-preventative agents such as aspirin may have a protective effect. Elucidating this association between obesity-related, hormone/cytokine-driven inflammatory effects with EOCRC may help lead to new therapeutic targets in preventing and treating EOCRC.

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PURPOSE: The credible data about the burden of early-onset colorectal cancer (EOCRC) in China when compared to other countries in the group of twenty (G20) remained unavailable. We aimed to assess the burden and trends of EOCRC and attributable risk factors in China. Meanwhile, the comparison in the burden and attributable risk factors between China and other G20 countries was also evaluated. METHODS: Data on the incidence, prevalence, mortality, disability-adjusted life years (DALYs), and attributable risk factors of EOCRC in China were obtained from Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 and compared with other G20countries. Temporal trends of age-standardized rates for incidence, prevalence, mortality, and DALYs were evaluated by estimated annual percentage change (EAPC). The autoregressive integrated moving average (ARIMA) model was used to forecast the incidence, mortality, and DALY rates of EOCRC in China from 2020 to 2029. RESULTS: From 1990 to 2019, the age-standardized incidence rate (ASIR) and age-standardized prevalence rate (ASPR) of EOCRC in China increased with the EAPCs of 4.61 [95% confidence interval (CI): 4.45-4.77] and 5.82 (95% CI: 5.60-6.05). When compared to G20 countries, China was ranked 13th in the ASIR in 1990 and then increased to 2nd in 2019, second only to Japan. The ASPRs increased in all G20 countries, being highest in Saudi Arabia, followed by China and Mexico. Moreover, China had the highest age-standardized mortality rate and highest age-standardized DALY rate in 2019. In China, the five leading risk factors, for both sexes, were diet low in milk [18.54% (95% UI: 12.71-24.07)], diet low in calcium [15.06% (95% UI: 10.70-20.03)], alcohol use [12.16% (95% UI: 8.87-15.64)], smoking [9.08% (95% UI: 3.39-14.11)], and diet high in red meat [9.08% (95% UI: 3.39-14.11)] in 2019. Over the next 10 years, ASIR, ASMR, and age-standardized DALY rate of EOCRC will increase continuously in males and females. CONCLUSION: The burden of EOCRC in China and other G20 countries is worrisome, indicating that coordinated efforts are needed to conduct high-quality researches, allocate medical resources, adjust screening guidelines, and develop effective treatment and prevention strategies in the G20 countries.

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BACKGROUND: Early-onset colorectal cancer (EOCRC) has been increasing in incidence worldwide but its genomic pathogenesis is mostly undetermined. This study aimed to identify robust EOCRC-specific gene expression patterns in non-familial adenomatous polyposis (FAP) and non-hereditary nonpolyposis colorectal cancer syndrome (HNPCC) EOCRC. METHOD: We first performed gene expression profiling analysis using RNA sequencing of discovery cohort comprised of 49 EOCRC (age <50) and 50 late-onset colorectal cancer (LOCRC) (age >70) specimens. To obtain robust gene expression data from this analysis, we validated differentially expressed genes (DEGs) through TCGA cohort (EOCRC:59 samples, LOCRC:229 samples) and our validation cohort (EOCRC:72 samples, LOCRC:43 samples) using real-time RT-PCR. After the validation of DEGs, we validated the selected gene at protein levels using Western blotting. To identify whether genomic methylation regulates the expression of a particular gene, we selected methylation sites using The Cancer Genome Atlas (TCGA) datasets and validated them by pyrosequencing in our validation cohort. RESULTS: The EOCRC patients included in this study had significantly more prominent family history of cancer than the LOCRC patients (23 [46.9%] vs. 13 [26%], p = 0.050). Alanyl aminopeptidase (ANPEP) was significantly downregulated in the EOCRC tissues (FC = 1.78, p = 0.0007) and was also commonly downregulated in the TCGA cohort (FC = -1.08, p = 0.0021). Moreover, the ANPEP mRNA and protein expression levels were significantly downregulated in the EOCRC tissues of our validation cohort (p = 0.037 and 0.027). In comparisons of the normal and tumor tissues in public datasets, the ANPEP level was significantly lower in the tumor tissue in the TCGA dataset (p < 2.2 × 10-16 ) and GSE196006 dataset (p = 0.0005). Furthermore, the ANPEP expression level did not show a decreasing tendency at a young age in the normal colon tissue of the GTEx dataset. Lastly, the hypermethylation of cg26222247 in ANPEP was identified to be weakly associated with reduced ANPEP expression in our EOCRC cohort. CONCLUSION: The reduced expression of ANPEP was identified as a novel biomarker of non-FAP and non-HNPCC EOCRC.

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Probiotics and postbiotics mechanisms of action and applications in early-onset colorectal cancer (EOCRC) prevention and treatment have significant importance but are a matter of debate and controversy. Therefore, in this review, we aimed to define the probiotics concept, advantages and limitations in comparison to postbiotics, and proposed mechanisms of anti-tumor action in EOCRC prevention and treatment of postbiotics. Biotics (probiotics, prebiotics, and postbiotics) could confer the health benefit by affecting the host gut microbiota directly and indirectly. The main mechanisms of action of probiotics in exerting anticancer features include immune system regulation, inhibition of cancer cell propagation, gut dysbiosis restoration, anticancer agents' production, gut barrier function renovation, and cancer-promoting agents' reduction. Postbiotics are suggested to have different mechanisms of action to restore eubiosis against EOCRC, including modulation of gut microbiota composition, gut microbial metabolites regulation, and intestinal barrier function improvement via different features such as immunomodulatory, anti-inflammatory, antioxidant, and anti-proliferative properties. A better understanding of postbiotics challenges and mechanism of action in therapeutic applications will allow us to sketch accurate trials in order to use postbiotics as bio-therapeutics in EOCRC.

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PURPOSE: The incidence of early-onset colorectal cancer (EO-CRC), which occurs in people under age 50, has been increasing annually. The aim of this study was to provide an up-to-date estimate of the global EO-CRC burden. METHODS: We used Global Burden of Disease Study data and methodologies to describe changes in the EO-CRC burden from 1990 to 2019, including incidence, prevalence, mortality, and disability-adjusted life years (DALYs). The driving factors for cancer burden variation were further analyzed using decomposition analysis. Frontier analysis was used to visually demonstrate the potential for burden reduction in each country or region based on their development levels. RESULTS: The global EO-CRC incidence more than doubled, increasing from 95,737 (95% uncertainty interval (UI): 90,838-101.042) /100,000 in 1990 to 226,782 (95% UI: 207,495-248,604) /100,000 in 2019. Additionally, related deaths increased from 50,997 (95% UI: 47,692-54,410) /100,000 to 87,014 (95% UI: 80,259-94,339) /100,000, and DALYs increased from 256,1842 (95% UI: 239,4962-2,735,823) /100,000 to 4,297,573 (95% UI: 3,965,485-4,650,790) /100,000. Regarding age-standardized rates, incidence and prevalence increased significantly, while mortality and DALYs rate were basically unchanged. Decomposition analysis showed a significant increase in DALYs in the middle sociodemographic index (SDI) quintile region, in which aging and population growth played a major driving role. Frontier analysis showed that countries or regions with a higher SDI quintile tend to have greater improvement potential. CONCLUSION: The current EO-CRC burden was found to be the greatest in the high-middle SDI quintile region and East Asia, which may need to adjust screening guidelines accordingly and introduce more effective interventions.

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BACKGROUND: Amid increasing awareness of early-onset colorectal cancer (CRC), guidelines in the United States (US) recently lowered the recommended routine CRC screening age from 50 to 45 in average-risk individuals. There are little data on the number of patients in this age group diagnosed with CRC prior to these changes. Our objective was to audit the historic CRC case trends and impact of CRC in the 45-to-50-year-old category prior to new screening recommendations. METHODS: Colorectal adenocarcinoma cases in 45-to-50-year-old patients were queried from the NCDB (2004-2017). Cases were stratified by sex, race, and site. The disability-adjusted lost years (DALY) and lost earnings were estimated. The average annual percentage changes (AAPC) of CRC incidence were estimated using jointpoint analysis. The main outcome measures were DALY and lost earnings. Secondary outcome measures were the 2004-2017 AAPC and the cumulative incidence of potential CRC cases in the 45-to-50 cohort through 2030 without guideline changes. RESULTS: 67,442 CRC patients in the 45-to-50 demographic were identified. The CRC burden resulted 899,905 DALY and $17 billion in lost earnings. The 2004-2017 AAPC was 1.6%, with an estimated 13-year increase of 25%. There were sex-, race-, and anatomic site-specific discrepancies with estimated 13-year increases of 30% for males, 110% for American Indian/ Alaska Natives/ Asian American/ Pacific Islander races, and 31% for rectal cancer by 2030. CONCLUSION: CRC has been steadily increasing in the 45-to-50 age group, with tremendous disability and cost ensuing. There is great potential benefit from lowering the recommended routine CRC screening age to 45. Targeted intervention could ensure the most vulnerable segments benefit from the new guidelines, in both reducing the incidence and improving survivorship in CRC patients.

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There is about three times higher incidence of young patients <50 years old with colorectal cancer, termed EOCRC, in Indonesia as compared to Europe, the UK and USA. The aim of this study was to investigate the frequency of Lynch Syndrome (LS) in Indonesian CRC patients. The previously described Nottingham Lynch Syndrome Test (N_LyST) was used in this project. N_LyST is a robust high-resolution melting (HRM)-based test that has shown 100% concordance with standard reference methods, including capillary electrophoresis and Sanger sequencing. The test consisted of five mononucleotide microsatellite markers (BAT25, BAT26, BCAT25, MYB, EWSR1), BRAF V600E mutation and MLH1 region C promoter for methylation (using bisulphite-modified DNA). A total of 231 archival (2016-2019) formalin-fixed, paraffin-embedded (FFPE) tumour tissues from CRC patients collected from Dr. Sardjito General Hospital Yogyakarta, Indonesia, were successfully tested and analysed. Among those, 44/231 (19.05%) were MSI, 25/231 (10.82%) were harbouring BRAF V600E mutation and 6/231 (2.60%) had MLH1 promoter methylation. Almost all-186/197 (99.45%)-MSS cases were MLH1 promoter unmethylated, while there were only 5/44 (11.36%) MSI cases with MLH1 promoter methylation. Similarly, only 9/44 (20.45%) of MSI cases were BRAF mutant. There were 50/231 (21.65%) EOCRC cases, with 15/50 (30%) regarded as MSI, as opposed to 29/181 (16.02%) within the older group. In total, 32/231 patients (13.85%) were classified as "Probable Lynch" (MSI, BRAF wildtype and MLH1 promoter unmethylated), which were enriched in EOCRC as compared to older patients (24% vs. 11.05%, p = 0.035). Nonetheless, 30/50 (76.00%) cases among the EOCRC cases were non-LS (sporadic) and were significantly associated with a left-sided tumour. The overall survival of both "Probable Lynch" and non-LS (sporadic) groups (n = 227) was comparable (p = 0.59), with follow up period of 0-1845 days/61.5 months. Stage, node status, histological grading and ECOG score were significantly associated with patient overall survival (p < 0.005), yet only ECOG was an independent factor for OS (HR: 4.38; 95% CI: 1.72-11.2; p = 0.002). In summary, this study is the first to reveal a potentially higher frequency of LS among CRC patients in Indonesia, which may partially contribute to the reported much higher number of EOCRC as compared to the incidence in the West.

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Introduction: While colorectal cancer (CRC) incidence and mortality have decreased for older adults, the rates are increasing in adults younger than 50 years of age in the United States as well as globally. In response to strong epidemiologic evidence as well as sophisticated models, the American Cancer Society (ACS) has recommended screening adults for CRC starting at age 45. Understanding the factors associated with the rise of incidence in adults younger than age 50 may help to identify those adults who may be at greatest risk.Areas covered: In this review, we provide an overview of the recent literature and discuss possible explanations for the increase in CRC in young adults including obesity and other recognized CRC risk factors, delay in diagnosis of symptomatic patients (<50 years of age), and review perspectives on the current and future status of the field.Expert opinion: Currently there are little data regarding risk factors for CRC in average risk young adults who are asymptomatic. With potential endorsement of screening at 45 years of age by US Preventive Services Task Force, more data regarding clinical and molecular risk factors associated with CRC in young adults will be available.

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