Explore the vast range of titles available.

Treatment of young adults with colorectal cancer (CRC) represents an unmet clinical need, especially as diagnosis in this population might lead to the greatest loss of years of life. Since 1994, CRC incidence in individuals younger than 50 years has been increasing by 2% per year. The surge in CRC incidence in young adults is particularly alarming as the overall CRC frequency has been decreasing. Early‐onset CRC are characterized by a more advanced stage at diagnosis, poorer cell differentiation, higher prevalence of signet ring cell histology, and left colon‐sided location of the primary tumor. Among EO‐CRC, approximately 30% of patients are affected by tumors harboring mutations causing hereditary cancer predisposing syndromes, and 20% have familial CRC. Most notably, the remaining 50% of EO‐CRC patients have neither hereditary syndromes nor familial CRC, thus representing a formidable challenge for research. In this review article we summarize epidemiology, clinical and molecular features, heredity and outcome of treatments of EO‐CRC, and provide considerations for future perspectives. The prevalence of hereditary syndromes, familial syndromes and neither hereditary or familial (‘terra incognita’) syndromes among early‐onset colorectal cancer in young individuals. Figures are derived from studies in the text.

Abstract Background The incidence of individuals diagnosed with colorectal cancer under the age of 50, often referred to as early-onset colorectal cancer (EOCRC), has risen worldwide. The EOCRC patients have unique needs; however, there are no clear guidelines on how to address them. The objective of the present study was to propose a blueprint for EOCRC program development and implementation. Materials and Methods A consensual qualitative design was used to frame the present study. Seven leaders of North American EOCRC centers were invited to devise a stepwise blueprint for developing and implementing EOCRC programs. Discussions were transcribed and conceptually organized into a framework. An analysis of documents detailing and describing the services offered within each center was also conducted. Results The analysis was organized around 2 domains: (1) the rationale underlying the creation of EOCRC programs, and (2) the lessons learned from developing and implementing EOCRC programs. Participants agreed that as the EOCRC programs represent innovative initiatives, a program manager who closely monitors the program is core to successful implementation. Conclusions This study outlines a 10-step actionable guideline for developing and implementing EOCRC programs aiming at addressing the unmet needs of this growing population.

Background/Objectives This study aims to characterize PI3K and TP53 pathway alterations in Hispanic/Latino patients with early‐onset colorectal cancer (CRC), focusing on potential differences compared to non‐Hispanic White patients. Understanding these differences may shed light on the molecular basis of CRC health disparities. Methods Using cBioPortal, we conducted a bioinformatics analysis to evaluate CRC mutations within the PI3K and TP53 pathways. CRC patients were stratified by age and ethnicity: (1) early‐onset (< 50 years) versus late‐onset (≥ 50 years) and (2) early‐onset in Hispanic/Latino patients compared to early‐onset in non‐Hispanic White patients. Mutation frequencies were assessed using descriptive statistics, with chi‐squared tests comparing proportions between early‐onset Hispanic/Latino and non‐Hispanic White groups. Kaplan–Meier survival curves were generated to assess overall survival for early‐onset Hispanic/Latino patients, stratified by the presence or absence of PI3K and TP53 pathway alterations. Results Significant differences were noted when comparing early‐onset CRC in Hispanic/Latino patients to early‐onset CRC in non‐Hispanic White patients. PI3K (47.1% vs. 35.2%, p = 9.39e‐3) and TP53 (89.1% vs. 81.7%, p = 0.04) pathway alterations were more prevalent in early‐onset CRC among Hispanic/Latino patients, with AKT1 (5.1% vs. 1.8%, p = 0.03), INPP4B (4.3% vs. 1.4%, p = 0.04), and TSC1 (7.2% vs. 3.1% p = 0.03) gene alterations also significantly higher in this group. Significant differences were observed in TP53 mutations between colon adenocarcinomas (90% vs. 79.1%, p = 0.03), with higher prevalence in Hispanic/Latino patients when stratified by tumor site. No significant differences were observed between early‐onset and late‐onset CRC patients within the Hispanic/Latino cohort. Conclusions These findings highlight the distinct role of PI3K and TP53 pathway disruptions in early‐onset CRC among Hispanic/Latino patients, suggesting that pathway‐specific mechanisms may drive cancer health disparities. Insights from this study could inform the potential development of precision medicine approaches and targeted therapies aimed at addressing these disparities. This study identifies distinct PI3K and TP53 pathway disruptions in early‐onset colorectal cancer among Hispanic/Latino patients, with findings suggesting a higher prevalence of PI3K alterations and potential differences in outcomes associated with TP53 disruptions compared to non‐Hispanic Whites. While these results provide valuable insights into potential molecular drivers of disparities, further research is needed to fully understand their clinical implications. These findings may suggest new directions for precision medicine approaches aimed at addressing cancer health disparities and improving equity in colorectal cancer care.

Background The incidence of colorectal cancer (CRC) in patients under age 50 is rising for unclear reasons. We examined the effects of socioeconomic factors on outcomes for patients with early‐onset CRC compared to late‐onset CRC. Methods Patients with CRC from 2004 to 2015 in the National Cancer Database were included and categorized by age (under or over 50 years). Differences in demographic and socioeconomic factors, disease characteristics, and survival outcomes between early‐onset versus late‐onset CRC patients were assessed by Chi‐squared test and Cox models. Results The study population included 1,061,204 patients, 108,058 (10.2%) of whom were under age 50. The proportion of patients diagnosed under age 50 increased over time: 9.4% in 2004–2006, 10.1% in 2007–2009, 10.5% in 2010–2012, and 10.7% in 2013–2015 (p < 0.0001). Early‐onset CRC patients were more likely to be Black (15.1% vs. 11.3%) or Hispanic (8.6% vs. 4.6%) and to present with stage 4 disease (24.9% vs. 17.0%), p < 0.0001 for all. Black patients had the worst median OS (58.3 months) compared to White (67.0 months), Hispanic (91.6 months), or Asian (104.9 months) patients, p < 0.0001. Within the subgroup of early‐onset CRC patients with private insurance, Black patients had worse OS compared to White patients, even in communities with higher income and education status. Conclusions Early‐onset CRC continues to increase. Patients with early‐onset CRC are more likely to be Black or Hispanic and to present with stage 4 cancer. Early‐onset Black patients showed worse OS compared to White patients in all income subgroups, even with private insurance. Patients with early‐onset colorectal cancer are more likely to be Black or Hispanic and to present with stage 4 cancer. Within the subgroup of early‐onset CRC patients with private insurance, Black patients had worse OS compared to White patients, even in communities with higher income and education status.

Background Identifying the risk factors for distant metastasis in early‐onset colorectal cancer (EOCRC) is crucial for elucidating its etiology and facilitating preventive treatment. This study aims to characterize the variability in EOCRC incidence and discern both heterogeneous and homogeneous risk factors associated with synchronous liver, lung, and hepato‐lung metastases. Methods This study included patients with EOCRC enrolled in the SEER database between 2010 and 2015 and divided patients into three groups by synchronous liver, lung, and hepato‐lung metastases. Each group of patients with different metastasis types was randomly assigned to the development and validation cohort in a ratio of 7:3. Logistic regression was used to analyze the heterogeneous and homogenous risk factors for synchronous liver, lung, and hepato‐lung metastases in the development cohort of patients. Nomograms were built to calculate the risk of metastasis, and the receiver operating characteristic (ROC) curve and calibration curve were used to quantitatively evaluate their performance. Results A total of 16,336 eligible patients with EOCRC were included in this study, of which 17.90% (2924/16,336) had distant metastases. The overall incidences of synchronous liver, lung, and hepato‐lung metastases were 11.90% (1921/16,146), 2.42% (390/16,126), and 1.50% (241/16,108), respectively. Positive CEA values before treatment, increased lymphatic metastases, and deeper invasion of intestinal wall were positively correlated with three distant types of metastases. On the contrary, the correlation of age, ethnicity, location of primary tumor, and histologic grade among the three types was inconsistent. The ROC curve and calibration curve proved to have fine performance in predicting distant metastases of EOCRC. Conclusions There are significant differences in the incidence of distant metastases in EOCRC, and related risk factors are heterogeneous and homogenous. Although limited risk factors were incorporated in this study, the established nomograms indicated good predictive performance.

Genome‐wide 5hmC profiling in cell‐free DNA acquired from CRC patients, adenoma patients, and healthy individuals revealed that the differential 5hmC‐modified regions were gathered into four clusters with no overlap, although there are a few overlapped genes shared between the different clusters. CRC patients with adenoma history showed exclusive 5hmC‐gain characteristics, which was consistent with the ‘parallel’ evolution hypothesis in adenoma. Approximately 85% colorectal cancers (CRCs) are thought to evolve through the adenoma‐to‐carcinoma sequence associated with specific molecular alterations, including the 5‐hydroxymethylcytosine (5hmC) signature in circulating cell‐free DNA (cfDNA). To explore colorectal disease progression and evaluate the use of cfDNA as a potential diagnostic factor for CRC screening, here, we performed genome‐wide 5hmC profiling in plasma cfDNA and tissue genomic DNA (gDNA) acquired from 101 samples (63 plasma and 38 tissues), collected from 21 early‐stage CRC patients, 21 AD patients, and 21 healthy controls (HC). The gDNA and cfDNA 5hmC signatures identified in gene bodies and promoter regions in CRC and AD groups were compared with those in HC group. All the differential 5hmC‐modified regions (DhMRs) were gathered into four clusters: Disease‐enriched, AD‐enriched, Disease‐lost, and AD‐lost, with no overlap. AD‐related clusters, AD‐enriched and AD‐lost, displayed the unique 5hmC signals in AD patients. Disease‐enriched and Disease‐lost clusters indicated the general 5hmC changes when colorectal lesions occurred. Cancer patients with a confirmable adenoma history segmentally gathered in AD‐enriched clusters. KEGG functional enrichment and GO analyses determined distinct differential 5hmC‐modified profiles in cfDNA of HC individuals, AD, and CRC patients. All patients had comprehensive 5hmC signatures where Disease‐enriched and Disease‐lost DhMR clusters demonstrated similar epigenetic modifications, while AD‐enriched and AD‐lost DhMR clusters indicated complicated subpopulations in adenoma. Analysis of CRC patients with adenoma history showed exclusive 5hmC‐gain characteristics, consistent with the ‘parallel’ evolution hypothesis in adenoma, either developed through the adenoma‐to‐carcinoma sequence or not. These findings deepen our understanding of colorectal disease and suggest that the 5hmC modifications of different pathological subtypes (cancer patients with or without adenoma history) could be used to screen early‐stage CRC and assess adenoma malignancy with large‐scale follow‐up studies in the future.

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. Visualization of differentially expressed genes (DEGs) identified between early‐onset colorectal cancer (EOCRC) and late‐onset colorectal cancer (LOCRC). (A) DEG heatmap. Genes were sorted in accordance with their fold‐change values. The top and bottom rows represent upregulated and downregulated genes in the EOCRC patients, respectively. (B) Pathway terms associated with the DEGs. (C) Gene ontology terms associated with the DEGs.

The incidence of early-onset colorectal cancer (EO-CRC) has been consistently rising leading to a significant cancer burden among younger adults in Asian and Middle Eastern high-income countries. The study aims to investigate the survival outcomes of EO-CRC among high-income Asian and Middle Eastern populations from 1990 to 2019 using the mortality-to-incidence ratio, with a focus on examining the differences in gender. This is a systematic analysis of the Global Burden of Disease (GBD) 2019 study. We include individuals aged 15 to 49 years old in high-income Asian and the Middle Eastern countries. The colorectal cancer mortality-to-incidence ratio (MIR) was calculated for both genders by dividing the age-specific mortality rate per 100,000 for colorectal cancer by the age-specific incidence rate per 100,000 for each nation in the sample for a given year. An overall decline in male and female MIR was observed from 1990 to 2019 in Asian and Middle Eastern countries. Ten out of thirteen Asian and Middle Eastern countries had a higher female MIR compared to their male counterparts. The global male MIR was found to be significantly higher than that of female (p-value 0.008, coefficient estimate: 1.51). In Middle Eastern countries, Saudi Arabia had a significantly higher female MIR compared to their male counterparts (p < 0.0001, coefficient estimate: 12.65). This research addresses the knowledge gap concerning gender-based differences in EO-CRC survival outcomes in high-income Asian and Middle Eastern countries, providing insights into the factors influencing these disparities in these regions. Policymakers should focus on developing targeted prevention and treatment programs for women, and addressing cultural and social barriers that may prevent women from seeking timely medical care.

Background High tumor budding and elevated systemic inflammation are adverse prognostic indicators in colorectal cancer. Its underlying mechanisms remain poorly understood. It is unclear whether systemic inflammation, angiogenesis, and cell‐to‐cell adhesion influence tumor budding. Methods We investigated n = 132 stage I–III colorectal cancer patients recruited at Huntsman Cancer Institute enrolled in the ColoCare Study. Tumor budding was evaluated using an evidence‐based scoring system, and patient sera were analyzed for nine circulating biomarkers using the Meso Scale Discovery platform. We examined associations between biomarkers and tumor budding using multivariable linear regression models adjusted for age, sex, neoadjuvant treatment, stage, and non‐steroidal anti‐inflammatory drug use. Results The study population was predominantly non‐Hispanic White (95%), with a mean age of 61 years; 56% were male. Most tumors were stage III (47%), located in the colon (64%), and exhibited low‐grade tumor budding (58%). Soluble intercellular adhesion molecule 1 was inversely associated with tumor budding overall (M1: β = −0.57, p = 0.03), among females (M1: β = −0.81, p‐value = 0.03) and later‐onset (≥ 50 years) colorectal cancer (M1: β = −0.71, p‐value = 0.008). C‐reactive protein was positively associated with tumor budding in males (M1: β = 0.23, p = 0.001), while interleukin‐8 (M1: β = 0.96, p‐value = 0.01) and soluble vascular adhesion molecule 1 (M2: β = 1.48, p‐value = 0.04) were positively associated with tumor budding in early‐onset patients. However, these associations did not remain statistically significant after correction for multiple testing. Conclusion Overall, our findings do not provide evidence of a significant association between biomarkers of systemic inflammation, angiogenesis, and cell‐to‐cell adhesion with tumor budding count. We observed patterns for some biomarkers, yet none remained statistically significant after correction for multiple testing. These findings provide preliminary insights for future studies. Trial Registration: ClinicalTrials.gov: NCT02328677. This study identified patterns between biomarkers of systemic inflammation, angiogenesis, and cell‐to‐cell adhesion with tumor budding in colorectal cancer, suggesting differences by age of disease onset and sex. These findings contribute to our understanding of the underlying mechanism of tumor budding and may provide guidance for future studies investigating the biological mechanisms of tumor budding that may be relevant for prognostic assessments and therapeutic interventions in colorectal cancer.

Background Although the overall colorectal cancer (CRC) incidence has been steadily declining in the United States, a dramatic increase in the number of CRC cases among individuals younger than 50 years of age (early‐onset CRC) has been observed. CRC is the second and first leading cause of cancer death in the United States and among Hispanic men and women living in Puerto Rico (PRH), respectively. We report CRC incidence rates from 2000 to 2021 among PRH and compare them to data in the Surveillance, Epidemiology, and End Results Program (SEER). Methods Data on colorectal adenocarcinomas diagnosed between January 1, 2000, and December 31, 2021, were obtained from the Puerto Rico Central Cancer Registry and SEER17, including race and ethnicity. Age‐standardized incidence rates were calculated using the direct method. The Joinpoint Regression Program calculated temporal trends on CRC incidence rates based on age‐adjusted Average Annual Percent Change (AAPC) estimates. Results A total of 729,479 incident cases of CRC were analyzed. US Hispanics had the highest percentage of early‐onset CRC (EOCRC) cases (17.0%) among the racial and ethnic groups studied. PRH had the highest age‐standardized EOCRC incidence rate (12.18 per 100,000 persons) and the highest increase in EOCRC incidence temporal trends (AAPC = 2.68; 95% CI: 1.83 to 3.51). Conclusions A significantly higher increase in EOCRC incidence was observed among Hispanic populations. Future studies should disaggregate Hispanic subpopulations by considering the country of ancestral origin, which will help identify specific risk factors and exposures and aid in developing tailored prevention and risk stratification strategies to reduce EOCRC incidence.