Late-onset Colorectal Cancer Research Articles

Clinicopathological Features of Colorectal Cancer in the Iraqi Population Focusing on Age and Early-Onset of Malignancy: A Descriptive Cross-Sectional Study

Background: Colorectal cancer (CRC) is one of the top ten most common cancers worldwide. There are multiple risk factors for CRC, one of which is aging. However, in recent years, CRC has been reported in children. Objective: To describe the main characteristics and symptoms of CRC as well as highlight pathologic data for early-onset CRC. Methods: 79 CRC patients were recruited from the Oncology Teaching Hospital in the period February–December 2022. A questionnaire was used to collect demographic and clinical data. Results: 25 (31.6%) of patients were below 50 years of age. 52 (65.8%) patients had tumors in the colon. The most common symptom is bleeding per rectum in both age groups. There was no significant difference in pathologic characteristics between early- and late-onset CRC. Conclusion: Although older people are more likely to develop CRC, both age groups can be affected. Younger and older individuals both had roughly similar symptoms and clinicopathologic features.

A novel nomogram based on cell cycle-related genes for predicting overall survival in early-onset colorectal cancer

BackgroundAlthough the incidence of late-onset colorectal cancer (LOCRC) has decreased, the incidence of early-onset colorectal cancer (EOCRC) is still rising dramatically. Heterogeneity in the genomic, biological, and clinicopathological characteristics between EOCRC and LOCRC has been revealed. Therefore, the previous prognostic models based on the total CRC patient population might not be suitable for EOCRC patients. Here, we constructed a prognostic classifier to enhance the precision of individualized treatment and management of EOCRC patients.MethodsEOCRC expression data were downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. The regulatory pathways were explored by gene set enrichment analysis (GSEA). The prognostic model was developed by univariate Cox-LASSO-multivariate Cox regression analyses of GEO samples. TCGA samples were used to verify the model. The expression and mutation profiles and immune landscape of the high-risk and low-risk cohorts were analyzed and compared. Finally, the expression and prognostic value of the model genes were verified by immunohistochemistry and qRT‒PCR analysis.ResultsThe cell cycle was identified as the most significantly enriched oncological signature of EOCRC. Then, a 4-gene prognostic signature comprising MCM2, INHBA, CGREF1, and KLF9 was constructed. The risk score was an independent predictor of overall survival. The area under the curve values of the classifier for 1-, 3-, and 5-year survival were 0.856, 0.893, and 0.826, respectively, in the training set and 0.749, 0.858, and 0.865, respectively, in the validation set. Impaired DNA damage repair capability (p < 0.05) and frequent PIK3CA mutations (p < 0.05) were found in the high-risk cohort. CD8 T cells (p < 0.05), activated memory CD4 T cells (p < 0.01), and activated dendritic cells (p < 0.05) were clustered in the low-risk group. Finally, we verified the expression of MCM2, INHBA, CGREF1, and KLF9. Their prognostic value was closely related to age.ConclusionIn this study, a robust prognostic classifier for EOCRC was established and validated. The findings may provide a reference for individualized treatment and medical decision-making for patients with EOCRC.

Could Microplastics Be a Driver for Early Onset Colorectal Cancer?

Introduction: The incidence of colorectal cancer in those under 50 years of age (early onset colorectal cancer (EOCRC)) is increasing throughout the world. This has predominantly been an increase in distal colonic and rectal cancers, which are biologically similar to late onset colorectal cancer (LOCRC) but with higher rates of mucinous or signet ring histology, or poorly differentiated cancers. The epidemiology of this change suggests that it is a cohort effect since 1960, and is most likely driven by an environmental cause. We explore the possible role of microplastics as a driver for this change. Review: The development of sporadic colorectal cancer is likely facilitated by the interaction of gut bacteria and the intestinal wall. Normally, a complex layer of luminal mucus provides colonocytes with a level of protection from the effects of these bacteria and their toxins. Plastics were first developed in the early 1900s. After 1945 they became more widely used, with a resultant dramatic increase in plastic pollution and their breakdown to microplastics. Microplastics (MPs) are consumed by humans from an early age and in increasingly large quantities. As MPs pass through the gastrointestinal tract they interact with the normal physiological mechanism of the body, particularly in the colon and rectum, where they may interact with the protective colonic mucus layer. We describe several possible mechanisms of how microplastics may disrupt this mucus layer, thus reducing its protective effect and increasing the likelihood of colorectal cancer. Conclusions: The epidemiology of increase in EOCRC suggests an environmental driver. This increase in EOCRC matches the time sequence in which we could expect to see an effect of rapid increase of MPs in the environment and, as such, we have explored possible mechanisms for this effect. We suggest that it is possible that the MPs damage the barrier integrity of the colonic mucus layer, thus reducing its protective effect. MPs in CRC pathogenesis warrants further investigation. Future directions: Further clarification needs to be sought regarding the interaction between MPs, gut microbiota and the mucus layer. This will need to be modelled in long-term animal studies to better understand how chronic consumption of environmentally-acquired MPs may contribute to an increased risk of colorectal carcinogenesis.

Early-Onset Colorectal Cancer: Current Insights

Over the past decade, the incidence of colorectal cancer has increased in individuals under the age of 50 years. Meanwhile, the incidence has gradually decreased in the older population. As described herein, we reviewed the available literature to summarize the current landscape of early-onset colorectal cancer, including risk factors, clinicopathological presentation, genetic makeup of patients, and management. Currently, early-onset colorectal cancer is treated similarly as late-onset colorectal cancer, yet the available literature shows that early-onset colorectal cancer is more aggressive and different, and this remains a significant unmet need. A detailed understanding of early-onset colorectal cancer is needed to identify risk factors for the increased incidence and tailor treatments accordingly.

Colorectal cancer in patients of advanced age is associated with increased incidence of BRAF p.V600E mutation and mismatch repair deficiency.

The highest incidence of colorectal cancer (CRC) is in patients diagnosed at 80 years or older highlighting a need for understanding the clinical and molecular features of these tumors. Methods. In this retrospective cohort study, 544 CRCs underwent next generation sequencing and mismatch repair (MMR) evaluation. Molecular and clinical features were compared between 251 patients with traditional-onset CRC (50-69 years at diagnosis) and 60 with late-onset CRC (>80 years at diagnosis). Late-onset CRC showed a significantly higher rate of right-sided tumors (82% vs 35%), MMR deficiency (35% vs. 8%) and BRAF p.V600E mutations (35% vs. 8%) and a significantly lower rate of stage IV disease (15% vs 28%) and APC mutations (52% vs. 78%). Association of these features with advanced age was supported by stratifying patients into 6 age groups (<40, 40-49, 50-59, 60-69, 70-79 and >80 years). However, the age-related rise in MMR deficient (dMMR) CRC was only seen in the female patients with an incidence of 48% (vs. 10% in the male patient) in the >80y group. In addition, BRAF p.V600E was significantly enriched in MMR deficient CRC of advanced age (67% in late-onset CRC). Categorizing CRC by mutational profiling, late-onset CRC revealed a significantly higher rate of dMMR/BRAF + APC - (18% vs. 2.0%), dMMR/BRAF - APC - (8.3% vs. 1.2%) and MMR proficient (pMMR)/BRAF + APC - (12% vs. 4.0%) as compared to traditional-onset CRC. In summary, there was a higher rate of dMMR and BRAF p.V600E in late-onset CRC, independently or in combination. The higher incidence of dMMR in late-onset CRC in females is most likely predominantly driven by BRAF p.V600E induced hypermethylation. Prospective studies with treatment plans designed specifically for these older patients are warranted to improve their outcomes.

Comprehensive study of the intratumoral microbiome in early- vs. late-onset colorectal cancer: Final analysis of COSMO CRC.

3530 Background: Although colorectal cancer (CRC) incidence has declined overall, CRC in individuals under age 45 (early-onset CRC, EOCRC) has risen dramatically. Obesity and diabetes may partially explain this epidemiologic shift; however, many patients (pts) with EOCRC are neither obese nor diabetic. Certain bacteria disrupt colonic luminal integrity and promote inflammation, leading to oncogenic mutations in colonic epithelial cells. Fusobacterium nucleatum ( F. nuc) promotes CRC by suppressing immune response within the tumor microenvironment, activating the β-catenin pathway, and causing chemoresistance due to autophagy. The intratumoral microbiome (MB) in pts with EOCRC may differ from pts with late-onset CRC (LOCRC). Methods: We compared the intratumoral MB in pts with CRC diagnosed before age 45 (EOCRC) and after age 65 (LOCRC) in a prospective/retrospective study between 2017 and 2022. Primary and metastatic tumors were included. DNA was extracted from tumors and analyzed using 16S ribosomal gene sequencing. We compared the frequency of F. nuc and other bacterial and fungal DNA in tumors EOCRC vs. LOCRC pts. Next-generation tumor sequencing and diet questionnaire data were available for some pts. Results: Tumors from 36 EOCRC pts (median age 38 years) and 27 LOCRC pts (median age 72 years) were analyzed. In total, 917 unique bacterial and fungal species were detected. F. nuc was found in 30.6% of EOCRC and 29.6% of LOCRC (p = 0.94). Cladosporium sp. was seen more commonly in EOCRC (30.6% vs. 11%, p = 0.04), whereas Pseudomonas luteola (2.8% vs. 22.2%), Ralstonia sp. (22.2% vs. 48.1%), and Moraxella osloensis (19.4% vs. 44.4%) were seen more commonly in LOCRC (p &lt; 0.05). Clostridium perfringens (11.1%), Escherichia coli (11.1%), Leptotrichia hofstadii (11.1%) , Mycosphaerella sp. (11.1%), Neodevriesia modesta (11.1%), Penicillium sp. (11.1%), and Leptosphaeria sp. (11.1%) were seen exclusively in LOCRC (p &lt; 0.05). There was no significant difference in median MB diversity in EOCRC vs. LOCRC (43 vs. 45 organisms per pt). Median follow up from time of diagnosis was 39.6 months (mo). Twenty-three EOCRC pts (64%) and 19 LOCRC pts (70%) are alive. Median overall survival (mOS) was 75.5 mo (95 CI: 40 - NA) in EOCRC and 60 mo (95% CI: 50.5 - NA) in LOCRC. There was no significant difference in OS in LOCRC vs. EOCRC (Log-rank test p = 0.85). Pts with F. nuc positive tumors (N = 17) had a mOS of 75.5 mo (95 CI: 23 – NA), whereas pts with F. nuc negative tumors (N = 46) had a mOS of 60 mo (95% CI: 50.5 – NA). There was no significant difference in OS in F. nuc positive vs. F. nuc negative groups (Log-rank test p = 0.87). Conclusions: There are significant differences in the intratumoral microbiome in EOCRC and LOCRC. These findings warrant larger, prospective studies to elucidate the role the intratumoral microbiome plays in the carcinogenesis, the tumor immune microenvironment, and responsiveness to specific therapies.

The analysis between clinicopathological aspect of early-onset vs. late-onset colorectal cancer and mortality rate: a cross-sectional study.

The authors performed a case-control study on 170 subjects with CRC from November 2021 to November 2022 in a Tertiary Hospital in Bandung. Data were extracted from electronic medical records CRC Registry. Bivariate and correlation analyses were used to analyse the difference between variables using IBM SPSS 24.0. P less than 0.05 was considered statistically significant. Anaemia and tumour location variables were significantly different in the early-onset group compared with the late-onset group (P<0.001). It was also found that anaemia (P<0.001), pathological features (P<0.001), and tumour location (P=0.013) had significantly low correlation with onset of CRC (r=0.325; r=0.397; r=0.342, respectively). There is no statistically significant correlation between the clinicopathological features of CRC in both onset and mortality rates in this study.

Colorectal cancer mortality in young adults in the United States.

e15530 Background: Colorectal cancer (CRC) is typically considered a disease that affects older adults. However, recently a concerning increase in the incidence rates of CRC among young adults (age &lt; 50) has been noted. Given the limited analysis of colorectal cancer mortality assessing for age-based differences, we aimed to characterize trends in mortality rates of CRC between 1999 and 2020 in the United States, with the hypothesis that younger patients would also experience an increasing morality rate from CRC in concert with the increasing incidence. Methods: We queried the Centers for Disease Control database for mortality statistics with an underlying cause of death of colon and rectal cancer between the years 1999 - 2020. Crude mortality rates (CMR) were calculated per 100,000 deaths. Patients were stratified based on early-onset (30-49 years), average-onset (50-69 years), and late-onset (70+ years) CRC. For each cohort, we examined race and U.S. Census Region variables to assess drivers in mortality. Temporal trends were assessed using Joinpoint regression software. Average annual percent change (AAPC) were considered statistically significant if p &lt; 0.05. Results: Between 1999 and 2020, 1,166,158 deaths due to CRC occurred and the CMR decreased from 20.3 to 15.7. For patients aged &gt; 70, colorectal cancer mortality rate decreased from 148.6 to 75.9 at an average of 3.2% annually during this time frame. For the group aged 50-69, there was a decrease in CMR from 32.7 to 24.2, reflecting an average annual decrease of1.4%. In patients aged 30-49, CMR increased from 3.6 to 4.2, reflecting an average annual percent increase in mortality of 0.7%. This increase in CRC mortality in the youngest cohort occurred independent of geographical location. Mortality in young adults increased the fastest in the West at a rate of 1.1% annually and slowest in the South at 0.4% annually. Similar increases in mortality rates were identified when cohorts were stratified by race, with Non-Hispanic American Indian/Native American populations experiencing the most rapid increases in mortality at 3.4% annually. Conclusions: These results demonstrate age-related disparities in recent CRC mortality trends. While the overall mortality of CRC has decreased over the last two decades, this decrease was largely due to declining mortality in older adults. In contrast, younger adults experienced a sharp rise in CRC mortality rates, increasing at an average annual percentage increase of almost 1% each year independent of racial or geographic factors. These results highlight a concerning emerging trend with significant public health implications and provide rationale for increased surveillance in young adults.

Evaluation of genomic alterations in early-onset versus late-onset colorectal cancer.

3511 Background: The etiology of the rising incidence of early-onset colorectal cancer (EOCRC), defined as CRC in patients aged &lt; 50, remains unknown. In this study, we evaluated tumor genomic differences in patients with EOCRC versus average-onset CRC (AOCRC, age &gt; 60). Methods: The cohort included 13,262 patients diagnosed with stages I-III colon or rectal cancer who had whole exome sequencing as part of their ctDNA testing (Signatera, bespoke mPCR NGS assay). Tumor mutational burden (TMB) and microsatellite instability (MSI) status were derived from tumor whole exome sequencing analysis. The prevalence of somatic variants and mutations in known oncogenic pathways was compared between EOCRC and AOCRC groups, stratified by TMB and MSI status. Fisher’s exact test was used to test significance between the groups and p-values were adjusted using the FDR method for multiple test correction. Results: A total of 3,093 patients with EOCRC (70.8% colon, 27.4% rectal, 1.9% unknown) and 10,169 patients with AOCRC (79.9% colon, 18.3% rectal, 1.7% unknown) were included, where 9.0%/37.3%/53.7% were AJCC stages I, II, and III, respectively. Early-onset patients compared to average-onset patients had fewer cases of stage II CRC (30.7% vs. 39.3%, p &lt; 0.01) and more cases of stage III CRC (60.9% vs 51.6%, p &lt; 0.01). Patients with EOCRC were less commonly MSI-H compared to patients with AOCRC (10% vs. 17%, p &lt; 0.01), or have high tumor mutational burden (15% vs. 19%, p &lt; 0.01). The BRAF V600E mutation and truncated RNF43 mutations were less prevalent in EOCRC (3% vs. 15% and 2% vs. 9%, p &lt; 0.01), regardless of TMB and MSI status. Molecular alterations of the RTK-RAS pathway were less prevalent in the EOCRC cohort (p &lt; 0.01), while TP53 pathway alterations were more frequent in the EOCRC cohort (p &lt; 0.01). In the TMB-low/MSS group, TP53 mutations were more common in EOCRC (8% vs. 5%, p &lt; 0.01), but APC gene mutations were less common in EOCRC (56% vs. 66%, p &lt; 0.01). In the TMB-H/MSI-H group, BRAF V600E (4% vs. 60%), RNF43G659V (16% vs. 45%), and WNT1 G619A (6% vs. 20%) mutations were less prevalent in EOCRC (p &lt; 0.01 for all mutations); however, patients with EOCRC had more PIK3CA H1047R (22% vs. 9%) , APC R1468* (11% vs. 3%), and KRAS A146T (7% vs. 2%) variants (p &lt; 0.01 for all mutations). In the TMB-H/MSS group, EOCRC patients were more likely to have driver mutations in the PI3K pathway (74% vs. 56%, p &lt; 0.01). The POLE P286R mutation was more common in TMB-H/MSS patients with EOCRC (38% vs. 13%, p &lt; 0.01), whereas ACVR2A K437R was less common (11% vs. 30%, p &lt; 0.01). Prevalence of somatic variants and mutated oncogenic pathways did not vary significantly by tumor stage. Conclusions: Patients with AOCRC harbored more somatic variants and mutations in established pathways of CRC carcinogenesis. Tumors in EOCRC cases carried unique genomic alterations that varied across the TMB and microsatellite subpopulations. BRAF V600E and RNF43 truncating mutations were more frequent in AOCRC.

Field Synopsis of Environmental and Genetic Risk Factors of Sporadic Early-Onset Colorectal Cancer and Advanced Adenoma.

To systematically appraise and synthesize available epidemiologic evidence on the associations of environmental and genetic factors with the risk of sporadic early-onset colorectal cancer (EOCRC) and early-onset advanced colorectal adenoma (EOCRA). Multiple databases were comprehensively searched to identify eligible observational studies. Genotype data from UK Biobank were incorporated to examine their associations with EOCRC in a nested case-control design. Meta-analyses of environmental risk factors were performed, and the strength of evidence was graded based on predefined criteria. Meta-analyses of genetic associations were conducted using the allelic, recessive, and dominant models, respectively. A total of 61 studies were included, reporting 120 environmental factors and 62 genetic variants. We found 12 risk factors (current overweight, overweight in adolescence, high waist circumference, smoking, alcohol, sugary beverages intake, sedentary behavior, red meat intake, family history of colorectal cancer, hypertension, hyperlipidemia, and metabolic syndrome) and three protective factors (vitamin D, folate, and calcium intake) for EOCRC or EOCRA. No significant associations between the examined genetic variants and EOCRC risk were observed. Recent data indicate that the changing patterns of traditional colorectal cancer risk factors may explain the rising incidence of EOCRC. However, research on novel risk factors for EOCRC is limited; therefore, we cannot rule out the possibility of EOCRC having different risk factors than late-onset colorectal cancer (LOCRC). The potential for the identified risk factors to enhance the identification of at-risk groups for personalized EOCRC screening and prevention and for the prediction of EOCRC risk should be comprehensively addressed by future studies.

Quality of life in early-onset colorectal cancer patients: systematic review

There is an increasing incidence of early-onset colorectal cancer; however, the psychosocial impacts of this disease on younger adults have been seldom explored. A systematic review was conducted according to the PRISMA guidelines. The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, PubMed, and Scopus were searched, and papers were included if published in English within the last 10 years and if they reported results separately by age (including early-onset colorectal cancer, defined as colorectal cancer diagnosed before the age of 50 years). Critical appraisal of all studies was done using the Joanna Briggs Institute tools. The primary outcome of interest was the global quality of life in patients with early-onset colorectal cancer. Secondary outcomes included the effect on sexual function, body image, finances, career, emotional distress, and social and family functioning. The search yielded 168 manuscripts and 15 papers were included in the review after screening. All studies were observational, and included a total of 18 146 patients, of which 5015 were patients with early-onset colorectal cancer. The studies included scored highly using Joanna Briggs Institute critical appraisal tools, indicating good quality and a low risk of bias, but data synthesis was not performed due to the wide range of scoring systems that were used across the studies. Six papers reported significant negative impacts on quality of life in patients with early-onset colorectal cancer. Three of the four studies that compared the quality of life in patients with early-onset colorectal cancer with older patients found that the younger group had worse mean quality-of-life scores (P ≤ 0.05). Secondary outcomes measured in five studies in relation to sexual dysfunction, body image, financial and career impacts, and social and family impacts and in eight studies in relation to emotional distress were found to be more severely impacted in those with early-onset colorectal cancer compared with those with late-onset colorectal cancer. Whilst data are limited, the impact of colorectal cancer is different in patients with early-onset colorectal cancer compared with older patients in relation to several aspects of the quality of life. This is particularly prominent in areas of global quality of life, sexual functioning, family concerns, and financial impacts.

Abstract 6696: Genomic alterations associated with early-onset and late-onset colorectal cancer

Abstract Background: The causes of the rising incidence of early-onset colorectal cancer (EOCRC), defined as CRC in patients aged &amp;lt;50, remain unknown. In this study, we evaluated tumor genomic differences in patients with EOCRC versus late-onset CRC (LOCRC, age &amp;gt;60). Methods: The international cohort included 13,262 patients diagnosed with stages I-III colon or rectal cancer who had ctDNA testing using a personalized and tumor-informed multiplex PCR assay (Signatera™ 16-plex bespoke mPCR NGS assay), from which whole-exome sequencing (WES) on the surgically resected tumor was performed. Tumor mutational burden (TMB) and microsatellite instability (MSI) status were derived from WES analysis. The prevalence of gene-wide mutations, pathogenic gene variants, and mutations in known oncogenic pathways was compared between EOCRC and LOCRC groups, stratified by TMB and MSI status. Fisher’s exact test was used to test significance between the groups and p-values were adjusted using the FDR method for multiple test correction. Results: A total of 3,093 patients with EOCRC (70.8% colon, 27.4% rectal, 1.9% unknown) and 10,169 patients with LOCRC (79.9% colon, 18.3% rectal, 1.7% unknown) were included, where 9.0%/37.3%/53.7% were AJCC stages I, II, and III, respectively. Early-onset patients compared to late-onset patients had fewer cases of stage II CRC (30.7% vs. 39.3%, p&amp;lt;0.01) and more cases of stage III CRC (60.9% vs 51.6%, p&amp;lt;0.01). Adjusted by stage, patients with EOCRC were less likely to be MSI-H compared to patients with LOCRC (10% vs. 17%, p&amp;lt;0.01), or have high tumor mutational burden (TMB-H) (15% vs. 19%, p&amp;lt;0.01). Genes of the Hippo, NOTCH, WNT, and RTK-RAS oncogenic pathways were less commonly mutated in the EOCRC cohort (p&amp;lt;0.01). The BRAF V600E mutation was less prevalent in the EOCRC group (3% vs. 15%, p&amp;lt;0.01), regardless of TMB and MSI status. In the TMB-low/MSS group, TP53 mutations were more common in EOCRC (8% vs. 5%, p&amp;lt;0.01), but APC gene mutations were less common in EOCRC (56% vs. 66%, p&amp;lt;0.01). When comparing EOCRC and LOCRC in the TMB-H/MSI-H group, BRAF V600E (4% vs. 60%), RNF43 G659V (16% vs. 45%), and WNT1 G619A (6% vs. 20%) mutations were less prevalent in EOCRC (p&amp;lt;0.01 for all mutations); however, patients with EOCRC had more mutations in PIK3CA H1047R (22% vs. 9%), APC R1468* (11% vs. 3%), and KRAS A146T (7% vs. 2%) gene variants (p&amp;lt;0.01 for all mutations). In the TMB-H/MSS group, EOCRC patients were more likely to have driver mutations in the PI3K pathway (74% vs. 56%, p&amp;lt;0.01). Further, POLE P286R mutations were more common in TMB-H/MSS patients with EOCRC compared to LOCRC (38% vs. 13%, p&amp;lt;0.01), whereas ACVR2A K437R was less common (11% vs. 30%, p&amp;lt;0.01). Conclusion: Patients with LOCRC were more likely to have pathogenic gene variants and mutations in established pathways of CRC carcinogenesis. Tumors in EOCRC cases harbored unique genomic alterations that varied between the TMB-low/MSS, TMB-H/MSI-H, and TMB-H/MSS subpopulations. Citation Format: Eric M. Lander, Samuel Rivero-Hinojosa, Vasily N. Aushev, Jesús Izaguirre-Carbonell, Adham Jurdi, Minetta C. Liu, Cathy Eng. Genomic alterations associated with early-onset and late-onset colorectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6696.

Abstract 6165: Identification of biomarkers of early onset colorectal cancer from transciptome and whole genome data

Abstract Colorectal cancer (CRC) is not only the third most commonly occurred cancer worldwide, but it is the leading cause of cancer deaths in 2018. However, the overall incidence of CRC and death from CRC has declined since 1998, the case of early-onset CRC (EOCRC) defined as CRC diagnosed under age 50 has been increasing. Including the etiology of EOCRC, the reasons underlying this upward trend are not well understood. Moreover, some suggested that EOCRC patients have difficulty in early diagnosis compared to late-onset colorectal cancer (LOCRC). For this reason, EOCRC patients tend to be diagnosed at advanced stages. In addition to the clinical feature, EOCRC tumors have different features in pathology and molecularity compared with LOCRC tumors. With these distinct characteristics of EOCRC, there is necessary to characterize EOCRC compared to LOCRC patients. In this study, patients under 50 years (from hereon referred to as ‘‘early-onset’’) and over 70 (‘‘late-onset’’) were considered for comparison. Whole transcriptome sequencing (WTS) for profiling gene expression and whole genome sequencing for mutations were carried out with tumor tissues of early-onset (n=49) and late-onset (n=50) CRC patients. Subsequently, we performed bioinformatic analysis to identify genomic and transcriptomic features. For the precise selection of differentially expressed genes, we selected constantly differentially expressed genes (DEG) in TCGA COAD and READ data. Genes up-regulated in both data set were CPS1, CCL19, CHGB, GLDC, WASF3, RPL39L and MAP9. The down-regulated were PRSS33, ANPEP, DKK4 and NTS. To identify whether CMS classification had different feature in each type if age onset was different, we classified CMS subtypes using transcriptome data. The ratio of each CMS subtypes both early and late-onset group had no significant difference. In terms of somatic mutations reported for driving colorectal cancer, three genes (ATM, BCL9L, NF1) had significantly mutated in early-onset group. Moreover, Non-synonymous mutation frequency had no significant difference while total mutation frequency had significantly difference between early and late-onset group. Lastly, Mutational signature had difference in both groups, assuming that the early-onset group had been through different event attributing to mutational changes. Although these findings should be further validated by detailed functional experiments, our genomic and transcriptomic analysis provide additional insights into understanding of young CRC patients. Citation Format: Yejin Ha, Yun-Jae Shin, Ka Hee Tak, Jong-Lyul Park, Jeong-Hwan Kim, Jong Lyul Lee, Seon-Young Kim, Chan Wook Kim. Identification of biomarkers of early onset colorectal cancer from transciptome and whole genome data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6165.

Early onset colorectal cancer in Canterbury, New Zealand.

The overall incidence of colorectal cancer is decreasing in much of the world, yet the incidence in those under 50 years of age is increasing (early onset colorectal cancer (EOCRC)). The reasons for this are unclear. This study was undertaken to describe the clinical, pathological and familial characteristics of patients with EOCRC and their oncological outcomes and compare this with previously published data on late onset colorectal cancer (LOCRC). A retrospective review of all patients diagnosed with EOCRC in Canterbury between 2010 and 2017 was conducted. Data was collected on demographics, family history, treatment, and oncologic outcomes. Kaplan-Meier survival curves were calculated to assess overall survival based on disease stage. During the study period (2010-2017) there were 3340 colorectal cancers diagnosed in Canterbury, of which 201 (6%) were in patients under 50 years (range: 17-49). Of these, 87 (43.3%) were female and 125 (62.2%) were aged between 40 and 49 years. 28 (13.9%) were associated with hereditary conditions. Of the 201 patients, 139 (69.2%) had rectal or left-sided cancers. 142 (70.6%) patients presented with either stage 3 or 4 disease and the 5-year overall survival by stage was 79.1% and 14.4%, respectively. EOCRC is increasing and usually presents as distal left sided cancers, and often at an advanced stage. They do not appear to have the common risk factors of family history or inherited pre-disposition for colorectal cancer. Planning by healthcare providers for this epidemiological change is imperative in investigating symptomatic patients under 50 and optimizing early detection and prevention.

A systematic analysis of the global and regional burden of colon and rectum cancer and the difference between early- and late-onset CRC from 1990 to 2019.

The burden of colorectal cancer (CRC) varies substantially across different geographical locations. However, there was no further quantitative analysis of regional social development and the disease burden of CRC. In addition, the incidence of early- and late-onset CRC has increased rapidly in developed and developing regions. The main purpose of this study was to investigate the trends in CRC burden across different regions, in addition to the epidemiological differences between early and late-onset CRC and their risk factors. In this study, estimated annual percentage change (EAPC) was employed to quantify trends in age-standardized incidence rate (ASIR), mortality rate, and disability-adjusted life-years. Restricted cubic spline models were fitted to quantitatively analyze the relationship between trends in ASIR and Human Development Index (HDI). In addition, the epidemiological characteristics of early- and late-onset CRC were investigated using analyses stratified by age groups and regions. Specifically, meat consumption and antibiotic use were included to explore the differences in the risk factors for early- and late-onset CRC. The quantitative analysis showed that the ASIR of CRC was exponentially and positively correlated with the 2019 HDI in different regions. In addition, the growing trend of ASIR in recent years varied substantially across HDI regions. Specifically, the ASIR of CRC showed a significant increase in developing countries, while it remained stable or decreased in developed countries. Moreover, a linear correlation was found between the ASIR of CRC and meat consumption in different regions, especially in developing countries. Furthermore, a similar correlation was found between the ASIR and antibiotic use in all age groups, with different correlation coefficients for early-onset and late-onset CRC. It is worth mentioning that the early onset of CRC could be attributable to the unrestrained use of antibiotics among young people in developed countries. In summary, for better prevention and control of CRC, governments should pay attention to advocate self-testing and hospital visits among all age groups, especially among young people at high risk of CRC, and strictly control meat consumption and the usage of antibiotics.

Reduced expression of alanyl aminopeptidase is a robust biomarker of non-familial adenomatous polyposis and non-hereditary nonpolyposis colorectal cancer syndrome early-onset colorectal cancer.

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. 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. 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. The reduced expression of ANPEP was identified as a novel biomarker of non-FAP and non-HNPCC EOCRC.

Geographic Variation and Risk Factor Association of Early Versus Late Onset Colorectal Cancer

The proportion of patients diagnosed with colorectal cancer (CRC) at age < 50 (early-onset CRC, or EOCRC) has steadily increased over the past three decades relative to the proportion of patients diagnosed at age ≥ 50 (late-onset CRC, or LOCRC), despite the reduction in CRC incidence overall. An important gap in the literature is whether EOCRC shares the same community-level risk factors as LOCRC. Thus, we sought to (1) identify disparities in the incidence rates of EOCRC and LOCRC using geospatial analysis and (2) compare the importance of community-level risk factors (racial/ethnic, health status, behavioral, clinical care, physical environmental, and socioeconomic status risk factors) in the prediction of EOCRC and LOCRC incidence rates using a random forest machine learning approach. The incidence data came from the Surveillance, Epidemiology, and End Results program (years 2000-2019). The geospatial analysis revealed large geographic variations in EOCRC and LOCRC incidence rates. For example, some regions had relatively low LOCRC and high EOCRC rates (e.g., Georgia and eastern Texas) while others had relatively high LOCRC and low EOCRC rates (e.g., Iowa and New Jersey). The random forest analysis revealed that the importance of community-level risk factors most predictive of EOCRC versus LOCRC incidence rates differed meaningfully. For example, diabetes prevalence was the most important risk factor in predicting EOCRC incidence rate, but it was a less important risk factor of LOCRC incidence rate; physical inactivity was the most important risk factor in predicting LOCRC incidence rate, but it was the fourth most important predictor for EOCRC incidence rate. Thus, our community-level analysis demonstrates the geographic variation in EOCRC burden and the distinctive set of risk factors most predictive of EOCRC.

Comparative analyses of intratumoral microbiome with diet in patients with early- vs late-onset colorectal cancer.

208 Background: Early-onset colorectal cancer (CRC) is a growing public health problem with an incidence rate increase of 7.9% in individuals aged 20-29, 4.9% in those aged 30-39, and 1.6% in those aged 40-49 during 2004-2016. The etiology of this rise is not well established, but there is emerging evidence that the intra-tumoral microbiome may be implicated. We sought to categorize the interaction between diet and intra-tumoral microbiome in early- vs. late-onset CRC. Methods: Intra-tumoral microbiome data were collected from patients enrolled in a retrospective/prospective study of early ( &lt; 45 years) vs. late-onset (≥ 65 years) CRC. Formalin-fixed paraffin-embedded tumor samples were microdissected for tumor vs. non-tumor, then DNA was extracted and analyzed using 16S ribosomal gene sequencing. The DHQ3 diet questionnaire was used to ascertain diet history for a period of 12 months prior to diagnosis. Twelve bacteria of interest were selected for analysis based on increased prevalence and known potential association with CRC. Diet groups of interest for analysis included high-risk groups: fried foods, red meat, and alcohol. Results: A subset of 3 bacteria were further analyzed, Bacillus sp., Fusobacterium nucleatum, and Moraxella osloensis, based on relation to the group of patients diagnosed with CRC before the age of 45 (N = 8) and after age 65 (N = 12). Bacteria of interest had a similar prevalence in early- (38%, 3/8) and late-onset patients (33%, 4/12). Fifteen of the 20 patients had one or more of the bacteria of interest present. 71% (5/7) of both early- and late-onset patients who had Bacillus present had no alcohol in their diets. 100% (4/4) of the late onset patients with Bacillus present all had the same diet pattern: no tree nuts, high amounts of potato chips, no alcohol, and no red meat. 83% (5/6) of the early onset patients with 1 or more bacteria present had a high amount of potato chips in their diets. 80% (4/5) patients who had none of the bacteria of interest present also had no red meat in their diet. All early- and late-onset patients with Moraxella had a diet that consisted of more high-risk food groups, in particular potato chips. Conclusions: There were no significant differences in intra-tumoral microbiome in patients with early- vs. late-onset CRC. However, there may be an association between certain bacteria and high-risk diets. Results were limited by a small sample size, and further research should be done to better understand the relationship between intra-tumoral microbiome and diet.

Early Onset Colorectal Cancer in Arabs, Are We Dealing with a Distinct Disease?

Early-onset colorectal cancer (EOCRC) incidence is increasing worldwide. Efforts are directed to understand the biological and clinical signatures of EOCRC compared to late-onset colorectal cancer (LOCRC). EOCRC is thought to present differently across different ethnic groups and geographical regions. This study was an attempt to contribute with data from the Arab world toward the understanding of the clinicopathological parameters of EOCRC compared to LOCRC. Data from 254 CRC patients diagnosed at Sultan Qaboos University Hospital from the period 2015-2020 were studied. About 32.6% of all diagnosed CRC patients are below 50 years old, with no differences in gender distribution between EOCRC and LOCRC (p-value 0.417). Rectal involvement and tumor laterality were comparable among the two groups. Adenocarcinoma accounts for 83.3% and 94.2% of EOCRC and LOCRC, respectively. More mucinous and signet ring adenocarcinoma (8.3% each) were reported in EOCRC than LOCRC (2.9% and 2.2%, respectively). MLH1 and PMS2 loss are more common among LOCRC, but MSH6 loss is more frequent in EOCRC. The overall survival of EOCRC and LOCRC was comparable (median survival 64.88 and 67.24 months, respectively). This study showed comparable clinicopathological parameters between EOCRC and LOCRC from Arabs, which adds to the bigger picture of understand the disease.

The prognostic significance of clinicopathological characteristics in early-onset versus late-onset colorectal cancer liver metastases.

This study aimed to explore the prognostic significance of clinicopathological characteristics in early-onset versus late-onset colorectal liver metastases (CRLM). The data of CRLM patients who underwent hepatectomy from September 2010 to September 2020 were retrospectively analyzed. According to the age of primary cancer diagnosis, patients were divided into early-onset CRLM (EOCRLM) and late-onset CRLM (LOCRLM) groups. Clinicopathological parameters were compared between the two groups. Cox regression model and Kaplan-Meier method were used to analyze the effect of clinicopathological parameters on overall survival (OS) and recurrence-free survival (RFS). In total, 431 CRLM patients were identified, 130 with EOCRLM and 301 with LOCRLM. Compared with LOCRLM patients, EOCRLM patients had lower American Society of Anesthesia (ASA) grade and longer operation time (204 vs. 179min). More aggressive features were presented in EOCRLM patients including synchronous liver metastases (76.9% vs. 61.1%) and bilobar involvement (43.8% vs. 33.2%). No significant difference in OS or RFS was found between the two groups. Multivariate analysis of EOCRLM group showed that preoperative CA19-9 level and RAS/BRAF status were predictive of OS, while bilobar involvement and preoperative CEA level were associated with RFS. In LOCRLM group, the number of CRLM, preoperative CA19-9 level, and BRAF status were associated with OS, while the number of CRLM was associated with RFS. The preoperative CA19-9 level, RAS/BRAF status, bilobar involvement, and preoperative CEA level were predictive of EOCRLM patient prognosis, while the number of CRLM, preoperative CA19-9 level, and BRAF status were predictive of LOCRLM patient prognosis.