Early-onset Colorectal Cancer Research Articles

Colorectal cancer screening: A review of current knowledge and progress in research

Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide, being the third most commonly diagnosed malignancy and the second leading cause of cancer-related deaths globally. Despite the progress in screening, early diagnosis, and treatment, approximately 20%-25% of CRC patients still present with metastatic disease at the time of their initial diagnosis. Furthermore, the burden of disease is still expected to increase, especially in individuals younger than 50 years old, among whom early-onset CRC incidence has been increasing. Screening and early detection are pivotal to improve CRC-related outcomes. It is well established that CRC screening not only reduces incidence, but also decreases deaths from CRC. Diverse screening strategies have proven effective in decreasing both CRC incidence and mortality, though variations in efficacy have been reported across the literature. However, uncertainties persist regarding the optimal screening method, age intervals and periodicity. Moreover, adherence to CRC screening remains globally low. In recent years, emerging technologies, notably artificial intelligence, and non-invasive biomarkers, have been developed to overcome these barriers. However, controversy exists over the actual impact of some of the new discoveries on CRC-related outcomes and how to effectively integrate them into daily practice. In this review, we aim to cover the current evidence surrounding CRC screening. We will further critically assess novel approaches under investigation, in an effort to differentiate promising innovations from mere novelties.

Do treatment patterns differ in those with early-onset colorectal cancer?

ABSTRACT Background The incidence of early-onset colorectal cancer (EOCRC) is increasing. International guidelines state that treatment should not differ from that of older patients. Several studies have shown that patients under 50 years are receiving more aggressive treatment, without any survival benefit. We aim to determine if treatment for stages 2 and 3 EOCRC differs from those of late-onset colorectal cancer (LOCRC) patients. Methods This was a retrospective, population-based, cohort study of the treatment patterns of patients diagnosed with colorectal cancer in Canterbury, New Zealand, from 2010 to 2021 age <50 years, compared to those aged 60–74 years. Results A total of 3263 patients were diagnosed with CRC between 2010 and 2021. Following exclusions, we identified 130 EOCRC and 668 LOCRC patients. Stage 2 EOCRC patients are more likely to be offered adjuvant chemotherapy (p = <0.001). Furthermore, EOCRC patients with either stage 2 or 3 disease are more likely to receive multi-agent therapy (p =  <0.01), without any associated increase in survival. Conclusion EOCRC patients are given more adjuvant chemotherapy, without a corresponding improvement in outcomes, highlighting a potential for increased treatment-related harms, particularly in stage 2 disease. Clinicians should be mindful of these biases when treating young cancer patients and need to carefully consider treatment-related harms.

The incidence of early onset colorectal cancer in Aotearoa New Zealand: 2000–2020

BackgroundThe incidence of early-onset colorectal cancer (EOCRC), diagnosed before age 50, has been rising in many countries in the past few decades. This study aims to evaluate this trend in Aotearoa New Zealand and assess its impact on Māori.MethodsCrude incidence and age-standardized incidence of colorectal cancer (CRC) was analyzed from all new cases from the Aotearoa New Zealand national cancer registry for the period 2000–2020. Trends were estimated by sex, ethnicity, age group and location of cancer and projections made to 2040.ResultsBetween 2000 and 2020, there were a total of 56,761 cases of CRC diagnosed in Aotearoa New Zealand, 3,702 of these being EOCRC, with age-standardized incidence decreasing significantly (P = 8.2 × 10− 80) from 61.0 to 47.3 cases per 100,000. EOCRC incidence increased on average by 26% per decade (incidence rate ratio (IRR) 1.26, p = < 0.0001) at all sites (proximal colon, distal colon and rectum), while the incidence in those aged 50–79 years decreased on average by 18% per decade (IRR 0.82, p = < 0.0005), again across all sites. There was no significant average change in CRC incidence in those over 80 years. In Māori, there was no significant change in age-standardized incidence. There was however a significant increase in crude incidence rates (IRR 1.28, p = < 0.0005) driven by significant increases in EOCRC (IRR1.36, p = < 0.0005). By 2040, we predict the incidence of EOCRC will have risen from 8.00 to 14.9 per 100,000 (6.33 to 10.00 per 100,000 in Māori). However, due to the aging population an estimated 43.0% of all CRC cases will be diagnosed in those over 80 years of age (45.9% over 70 years of age in Māori).ConclusionThe age-standardized incidence of CRC from 2000 to 2020 decreased in Aotearoa New Zealand, but not for Māori. The incidence of EOCRC over the same period continues to rise, and at a faster rate in Māori. However, with the ageing of the population in Aotearoa New Zealand, and for Māori, CRC in the elderly will continue to dominate case numbers.

Identification of differentially expressed genes and splicing events in early-onset colorectal cancer

BackgroundThe incidence of colorectal cancer (CRC) has been steadily increasing in younger individuals over the past several decades for reasons that are incompletely defined. Identifying differences in gene expression profiles, or transcriptomes, in early-onset colorectal cancer (EOCRC, &amp;lt; 50 years old) patients versus later-onset colorectal cancer (LOCRC, &amp;gt; 50 years old) patients is one approach to understanding molecular and genetic features that distinguish EOCRC.MethodsWe performed RNA-sequencing (RNA-seq) to characterize the transcriptomes of patient-matched tumors and adjacent, uninvolved (normal) colonic segments from EOCRC (n=21) and LOCRC (n=22) patients. The EOCRC and LOCRC cohorts were matched for demographic and clinical characteristics. We used The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) database for validation. We used a series of computational and bioinformatic tools to identify EOCRC-specific differentially expressed genes, molecular pathways, predicted cell populations, differential gene splicing events, and predicted neoantigens.ResultsWe identified an eight-gene signature in EOCRC comprised of ALDOB, FBXL16, IL1RN, MSLN, RAC3, SLC38A11, WBSCR27 and WNT11, from which we developed a score predictive of overall CRC patient survival. On the entire set of genes identified in normal tissues and tumors, cell type deconvolution analysis predicted a differential abundance of immune and non-immune populations in EOCRC versus LOCRC. Gene set enrichment analysis identified increased expression of splicing machinery in EOCRC. We further found differences in alternative splicing (AS) events, including one within the long non-coding RNA, HOTAIRM1. Additional analysis of AS found seven events specific to EOCRC that encode potential neoantigens.ConclusionOur transcriptome analyses identified genetic and molecular features specific to EOCRC which may inform future screening, development of prognostic indicators, and novel drug targets.

Construction and validation of a nomogram for predicting overall survival of patients with stage III/IV early−onset colorectal cancer

PurposeThis study aimed to identify prognostic factors and develop a nomogram for predicting overall survival (OS) in stage III/IV early-onset colorectal cancer (EO-CRC).MethodsStage III/IV EO-CRC patients were identified from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. The datasets were randomly divided (2:1) into training and validation sets. A nomogram predicting OS was developed based on the prognostic factors identified by Cox regression analysis in the training cohort. Moreover, the predictive performance of the nomogram was assessed using the receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA). Subsequently, the internal validation was performed using the validation cohort. Finally, a risk stratification system was established based on the constructed nomogram.ResultsOf the 10,387 patients diagnosed with stage III/IV EO-CRC between 2010 and 2015 in the SEER database, 8,130 patients were included. In the training cohort (n=3,071), sex, marital status, race/ethnicity, primary site, histologic subtypes, grade, T stage, and N stage were identified as independent prognostic variables for OS. The 1-, 3-, and 5-year area under the curve (AUC) values of the nomogram were robust in both the training (0.751, 0.739, and 0.723) and validation cohorts (0.748, 0.733, and 0.720). ROC, calibration plots, and DCA indicated good predictive performance of the nomogram in both the training and validation sets. Furthermore, patients were categorized into low-, middle-, and high-risk groups based on the nomogram risk score. Kaplan-Meier curve showed significant survival differences between the three groups.ConclusionWe developed a prognostic nomogram and risk stratification system for stage III/IV EO-CRC, which may facilitate clinical decision-making and individual prognosis prediction.

Symptom Burden and Time from Symptom Onset to Cancer Diagnosis in Patients with Early-Onset Colorectal Cancer: A Multicenter Retrospective Analysis

Background: The incidence of colorectal cancer (CRC) is decreasing in individuals &gt;50 years due to organised screening but has increased for younger individuals. We characterized symptoms and their timing before diagnosis in young individuals. Methods: We identified all patients diagnosed with CRC between 1990–2017 in British Columbia, Canada. Individuals &lt;50 years (n = 2544, EoCRC) and a matched cohort &gt;50 (n = 2570, LoCRC) underwent chart review to identify CRC related symptoms at diagnosis and determine time from symptom onset to diagnosis. Results: Across all stages of CRC, EoCRC presented with significantly more symptoms than LoCRC (Stage 1 mean ± SD: 1.3 ± 0.9 vs. 0.7 ± 0.9, p = 0.0008; Stage 4: 3.3 ± 1.5 vs. 2.3 ± 1.7, p &lt; 0.0001). Greater symptom burden at diagnosis was associated with worse survival in both EoCRC (p &lt; 0.0001) and LoCRC (p &lt; 0.0001). When controlling for cancer stage, both age (HR 0.87, 95% CI 0.8–1.0, p = 0.008) and increasing symptom number were independently associated with worse survival in multivariate models. Conclusions: Patients with EoCRC present with a greater number of symptoms of longer duration than LoCRC; however, time from patient reported symptom onset was not associated with worse outcomes.

Abstract LB134: Mutational signatures in colorectal cancer from 11 countries reveal new insights in early-onset colorectal cancer

Abstract Background: Colorectal cancers (CRC) have an important impact on both incidence and mortality worldwide, with varying rates in different parts of the world. Despite an overall decrease in incidence in the past years, an alarming increase in early onset colorectal cancer (CRC in patients under 50 years of age) rates has been observed. As part of the Cancer Research UK Grand Challenge Mutographs project, we aim to better understand the underlying mutagenic causes contributing to the differences in CRC incidence rates through mutational signatures. Methods: We collected epidemiological data and performed whole genome sequencing and mutational signature analysis on 981 CRC tumor samples from 11 countries with varying incidence rates, including intermediate incidence regions (Iran, Colombia, Thailand, and Brazil) and higher incidence regions (Argentina, Russia, Canada, Poland, Czechia, Serbia, and Japan). Results: The average mutational profiles were similar across the countries. Mutational signatures associated with DNA repair deficiencies, including POLE and POLD1 associated signatures (SBS10a/b/c/d and SBS28), MUTYH (SBS36), NTHL1 (SBS30), homologous recombination deficiency (SBS3), and a plethora of microsatellite instability (MSI) signatures, were found in 177 cancers (18% of all samples) and at comparable levels across all countries. Multiple signatures with known etiologies were found in 802 DNA repair proficient colorectal cancers including clock-like (SBS1 and SBS5), reactive oxygen species (SBS18), APOBEC (SBS2 and SBS13), and the microbiome-product colibactin (SBS88) signatures. The colibactin signature SBS88 was observed in 14% of samples overall, being more prevalent in distal and rectum tumors. SBS88 was significantly enriched in younger patients (33% &amp;lt;40y, 23% 40-49y, 20% 50-59y,10% 60-69y, 10% ≥70y; p-value = 0.0001). Tumors from early onset patients also showed higher prevalence of another mutational signature with unknown etiology (19% &amp;lt;40y, 16% 40-49y, 13% 50-59y, 6% 60-69y, 7% ≥70y, p-value = 0.005). Conclusions: These results indicate a potential association between SBS88 with early onset CRC, suggesting that the recent increase in incidence may be at least partially explained by the genotoxic compound colibactin, and associated bacteria. Citation Format: Wellington dos Santos, Marcos Diaz-Gay, Sarah Moody, Sergey Senkin, Behnoush Abedi-Ardekani, Mariya Kazachkova, Stephen Fitzgerald, Saamin Cheema, Valerie Gaborieau, Jingwei Wang, Christine Carreira, Thomas Cattiaux, Priscilia Chopard, Calli Latimer, David Zaridze, Riley Cox, Reza Malekzadeh, Miodrag Ognjanovic, Suleeporn Sangrajrang, Maria P. Curado, Rui M. Reis, Ivana Holcatova, Carlos Vaccaro, Beata Swiatkowska, Jolanta Lissowska, Carolina Wiesner, Tatsuhiro Shibata, Surasak Sangkhathat, Patricia Ashton-Prolla, Laura Humphreys, Sandra Perdomo, Ana C. de Caravalho, Mike Stratton, Paul Brennan, Ludmil Alexandrov. Mutational signatures in colorectal cancer from 11 countries reveal new insights in early-onset colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB134.

Obesity and Inflammatory Factors in the Progression of Early-Onset Colorectal Cancer.

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.

A new clinical model for predicting lymph node metastasis in T1 colorectal cancer

PurposeLymph node metastasis (LNM) is a crucial factor that determines the prognosis of T1 colorectal cancer (CRC) patients. We aimed to develop a practical prediction model for LNM in T1 CRC.MethodsWe conducted a retrospective analysis of data from 825 patients with T1 CRC who underwent radical resection at a single center in China. All enrolled patients were randomly divided into a training set and a validation set at a ratio of 7:3 using R software. Risk factors for LNM were identified through multivariate logistic regression analyses. Subsequently, a prediction model was developed using the selected variables.ResultsThe lymph node metastasis (LNM) rate was 10.1% in the training cohort and 9.3% in the validation cohort. In the training set, risk factors for LNM in T1 CRC were identified, including depressed endoscopic gross appearance, sex, submucosal invasion combined with tumor grade (DSI-TG), lymphovascular invasion (LVI), and tumor budding. LVI emerged as the most potent predictor for LNM. The prediction model based on these factors exhibited good discrimination ability in the validation sets (AUC: 79.3%). Compared to current guidelines, the model could potentially reduce over-surgery by 48.9%. Interestingly, we observed that sex had a differential impact on LNM between early-onset and late-onset CRC patients.ConclusionsWe developed a clinical prediction model for LNM in T1 CRC using five factors that are easily accessible in clinical practice. The model has better predictive performance and practicality than the current guidelines and can assist clinicians in making treatment decisions for T1 CRC patients.

Number of older biological siblings and early-onset colorectal cancer risk

Number of older biological siblings and early-onset colorectal cancer risk

Risk Factors of Early Age Colorectal Cancer among Patients Attending at National Institute of Cancer Research &amp; Hospital

Background: Colorectal cancer (CRC) poses a significant public health burden worldwide, with a notable trend of increasing incidence among individuals aged 20 to 50 years. Understanding the risk factors associated with early-onset CRC is crucial for developing targeted prevention and intervention strategies, particularly in limited-resource settings. Objective: This study aimed to identify and analyze the risk factors contributing to the development of early-onset CRC in a population from a limited-resource country. Method: A comparative study was conducted among 178 CRC patients admitted to the National Institute of Cancer Research &amp; Hospital (NICRH), Dhaka. Patients were divided into two groups: Group-A (age 20-50 years) and Group-B (age &gt;50 years). Demographic and clinical data were collected, and statistical analyses were performed to determine associations between various risk factors and early-onset CRC. Results: The mean age of Group-A subjects was 43.6±7.1 years, significantly younger than Group-B subjects (59.2±9.3 years). Male patients constituted 69.1% of the cohort, with a statistically significant male-to-female ratio of 2.2:1. Higher BMI (≥25) was strongly associated with early-onset CRC (p&lt;0.01). Occupations such as business and middle socioeconomic status were significantly linked to early-onset CRC. Regular exercise (&gt;30 minutes daily) demonstrated a protective effect against CRC development. Consumption of red meat and fast food was associated with a higher risk of CRC, while regular consumption of vegetables was protective. Familial adenomatous polyposis (FAP) presence was significantly associated with early-onset CRC. Conclusions: Male sex, high BMI, specific occupations, dietary factors, and presence of FAP emerged as key risk factors for early-onset CRC. Encouraging regular exercise and promoting healthy dietary habits, particularly reducing red meat and fast-food intake, are crucial in mitigating the risk of early-onset CRC in similar populations.

Sexual Functioning and Impact on Quality of Life in Patients with Early-Onset Colorectal Cancer: A Systematic Review

This systematic review investigates the intersection of early-onset colorectal cancer (EOCRC), sexual functioning, and associated quality of life (QoL), aiming to understand the comprehensive impact of EOCRC on these critical dimensions. Through an extensive search across PubMed, Scopus, and Embase up until November 2023, this study synthesized evidence from the literature while adhering to PRISMA guidelines. The studies included EOCRC patients under 50 years, which examined sexual functioning and QoL using validated instruments, and were published in English. After a rigorous screening process, five relevant studies were identified from an initial pool of 2184 articles. This review includes data from five studies involving 2031 EOCRC patients. The key findings revealed a high prevalence of sexual dysfunction, with up to 50% of men experiencing impotence and 58% reporting sexual dysfunction, alongside 36% of women in some studies. Pain was described by 12% to 31% of patients. Anxiety and depression were notably prevalent, affecting up to 69% of participants. EOCRC profoundly impacts sexual functioning and QoL, with a significant prevalence of sexual dysfunction and psychological distress among affected individuals. These findings suggest the need for oncological management strategies that include not only medical treatment but also psychological support and sexual health interventions. This systematic review emphasizes the importance of holistic patient care approaches, advocating for further research and clinical attention to address the complex needs of younger EOCRC patients.

Abstract 1011: A comprehensive comparative analysis of African Americans’ early onset and late onset colorectal cancer: A 60 year study in underserved population serving hospital

Abstract Background: The incident of early onset of colorectal cancer (EOCRC) is increasing in adults including in African Americans (AA). Aim: To investigate differences between EOCRC compared to late onset colorectal cancer (LOCRC) in AA patients. Methods: We reviewed demography, pathology and colonoscopy records of patients seen at Howard University Hospital from 1959 to 2023. This retrospective cohort consists of 175 EOCRC cases (&amp;lt;45 years) and 2025 LOCRC cases (&amp;gt;45 years). The age-adjusted rates for EOCRC and LOCRC were calculated for the age categories &amp;lt;45 and above 45. Results: The cohort comprised predominantly AA individuals (&amp;gt;85%). Gender distribution showed slightly more females (1074, 53%) than males, with no significant difference observed between EOCRC and LOCRC groups (p=0.94). Initial symptoms at presentation were prevalent in both EOCRC (93.8%) and LOCRC (92.6%). Notably, EOCRC exhibited a higher incidence of abdominal pain (23.3% vs. 17.2%, p=0.05) and changes in bowel habits (24.4% vs. 14%, p=0.05) compared to LOCRC. However, other symptoms such as melena, hematochezia, weight loss, and anemia were less prevalent in EOCRC than in LOCRC. Additionally, comorbidities like hypertension (HTN), diabetes mellitus (DM), and inflammatory bowel disease (IBD) were less frequent in EOCRC compared to LOCRC. Family history of colon cancer in first-degree relatives was notably higher in EOCRC (15.5%) compared to LOCRC (3.2%, p=0.01). Pathology reports indicated a higher occurrence of neuroendocrine tumors in EOCRC (2.8%) than in LOCRC (1.4%). Complications such as gastrointestinal bleeding and abdominal CT abnormalities were more frequent in EOCRC. Location-wise, EOCRC was primarily observed in the left sigmoid and rectosigmoid regions (p=0.01). Metastasis to other organs was more prevalent in EOCRC than in LOCRC (p=0.04) suggesting more aggressive and advanced lesions. Surgical interventions were slightly more common in EOCRC (80.4%) than in LOCRC (79.1%). Type of polyps and stage distribution showed some variations between the two groups. Interestingly, the incidence of colorectal cancer showed fluctuations over the years, peaking between 1980 and 1989 before declining in recent years, probably as a result of colonoscopy popularization. Conclusion: CRC incidence is increasing among young AA who display highly advanced and more metastatic tumors in comparison with LOCRC. While current screening programs seems to have decreased CRC prevalence in individuals older than 45, special attention needs to be addressed to young AA adults as well, to counter the observed trend, as they have the highest incidence of CRC among young population groups by race/ethnicity. Detailed analysis of the molecular landscape of EOCRC AA tumors is needed to understand the differential pathways and mechanisms defining these early onset cancers. Citation Format: Suryanarayana Reddy Challa, Mrinalini Deverapalli, Nasrin Farjana, Lakshmi Gayathri Chirumamilla, Reza Oskrouchi, Swetha Mynedi, Mudasir Rashid, Karthikeyan Senthilvelan, Babak Shokrani, Rabia Zafar, Angesom Kibreab, Farshad Aduli, Adeyinka Laiyemo, Zaki Sharif, Hassan Brim, Hassan Ashktorab. A comprehensive comparative analysis of African Americans’ early onset and late onset colorectal cancer: A 60 year study in underserved population serving hospital [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1011.

Abstract 7005: Distinct DNA methylation patterns between early-onset and average-onset colorectal cancer patients

Abstract Objective: Early onset colorectal cancer (EO CRC) is rising at an alarming rate. While average onset colorectal cancer (AO CRC) affects patients mostly above 65 years of age, EO CRC affects patients under 50 years of age, disproportionately affecting males from low-income communities and racial/ethnic minorities. Chronic inflammation has been identified as a strong contributor to pathogenesis. We hypothesize that methylation of DNA may serve as a potential mechanism associated with chronic inflammation that contributes to the etiology differentially between EO and AO CRC. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue specimens from four AO and EO CRC patients each were retrieved from the Tissue Repository. Paraffin curls containing tumor and adjacent normal tissues were generated from appropriate EO and AO CRC patient tissues. The Qiagen GeneRead DNA FFPE genomic DNA kit was then used to extract the DNA from the paraffin curls. Illumina Methylation EPIC v2.0 kit was used to evaluate DNA methylation (DNAm) patterns after the restoration process from deamination in the fixed/embedded sample using the Uracil-N-Glycosylase enzyme. Unreliable and non-specific probes were removed before statistical analysis for differentially methylated CpG sites. Age acceleration for each tissue was calculated by comparing the estimated DNAm age with chronological age using the Horvath approach. Results: A clear clustering of DNAm patterns by age of onset were observed for both normal and tumor tissues. However, there was no difference when comparing tumor and normal tissues after multiple corrections. Four-way ANCOVA adjusting for race, gender, BMI, and tissue type suggested that age onset was the most significant factor. We also found that age acceleration in EO CRC tissue is greater than in AO CRC. After applying Bonferroni correction, significant differentially methylated regions (DMRs) were found in the promoter and the gene body of SNTB1, NFATC3, SLC25A24, RABGAP1L, WDSUB1, WWOX, SELB, SLC28A3, and PPP6R2 in EO CRC patients when compared to AO CRC. SNTB1 regulates colorectal cancer progression and stemness, while NFATC3 has been associated with inflammation and cancer. Conclusions: The preliminary results from this study showed a significant difference in the DNAm profile of FFPE samples between AO and EO CRC. The finding suggests that epigenetics may play a role in the etiology of CRC, potentially involved in the chronic inflammation pathway. The analysis of a larger patient number is underway to strengthen these findings. Citation Format: L. Joseph Su, Ping-Ching Hsu, Aniruddha Rathod, Yulun Liu, Jacopo Ferruzzi, Syed Kazmi, Emina Huang. Distinct DNA methylation patterns between early-onset and average-onset colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7005.

Abstract 7449: Incidence of secondary malignancies in early onset colorectal cancer (EOCRC) patients

Abstract Introduction: The incidence of colorectal cancer in the younger population (20-49) continues to rise at a rapid pace. EOCRC patients are potentially at risk for developing additional secondary malignancies. There is a lack of reported data in the EOCRC space. In this analysis, we seek to examine the incidence, trends, and outcomes of secondary malignancies in EOCRC patients. Methods: The surveillance, epidemiology, and end-result (SEER) database was utilized to assess and compare the incidence and factors associated with development of secondary malignancies among EOCRC patients. Patient characteristics were summarized by secondary cancer status and compared using the Pearson chi-square test. Further OS was assessed using Kaplan- -Meier methods and compared across groups using the log-rank test. Multivariable Logistic regression models using backward selection approach were used to evaluate the association between patient characteristics and risk of secondary cancers. All statistics were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). Results: Of the 53,891 patients analyzed, 2578 (4.8%) patients with EOCRC developed a secondary malignancy in the SEER database from 2000-2019. The mean age for developing a secondary malignancy was 47.6 yo (median 48 yo; range 20-69). There was a higher likelihood of second cancers among men(56%), white patients (61.4%), those with stage II (25.5%). and III (32.8%) CRC. The patients who most commonly developed a secondary malignancy were in the age group 40-49(p &amp;lt;.001). Of the patients who developed a secondary malignancy, 1843 (71.5%) initially had a primary colon cancer compared to 920 (22.6%) having rectal cancer, with the remainder having a rectosigmoid cancer. Of the patients who developed secondary malignancies, a majority had received prior chemotherapy (58.5%), and a minority of patients received radiation therapy (20.6%) Patients who had a partner had a higher incidence of secondary malignancy (59.5%) and they were more likely to have resided in a metropolitan area compared to a nonmetropolitan area (86.6 versus 13.2% respectively). The most common sites of secondary malignancy were: an additional colorectal cancer (47.7%), followed by breast cancer (8.2%) urinary tract cancer (7.1%), thyroid cancer (7%) and prostate cancer (5%). Patients who developed a secondary cancer were found to have an improved disease specific survival (DSS) compared to those who did not develop a secondary malignancy (3 year mDSS 89% vs 74%; p &amp;lt;.001)The overall survival of patients who developed a secondary malignancy was worse than those who did not develop one (mOS 208 months vs 229 mos respectively). Conclusion: EOCRC patients are likely to develop secondary malignancies. Long-term screening should be recommended for these patients and integrated into their survivorship plans. Citation Format: Deepak Vadehra, Kristopher Attwood, Anthony George, Shailesh Advani, Sahithi Sonti, Sarbajit Mukherjee. Incidence of secondary malignancies in early onset colorectal cancer (EOCRC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7449.

Abstract 4409: FBXW7 and BCL9L altered pathways as hallmarks of early-onset colorectal cancer

Abstract Background: The incidence of early-onset colorectal cancer (EO-CRC) has been alarmingly increasing, particularly among non-Hispanic Whites (NHWs), resulting in similar rates to ones in African Americans (AAs). Overall, the median age of diagnosis has decreased from 72 to 66 years. The molecular features that could potentially distinguish this phenotype are still not well-established. This study aimed to identify genetic, epigenetic, and transcriptomic factors associated with EO-CRC. Methods: 510 patients with microsatellite-stable tumors analyzed for somatic mutations, targeting 20 cancer driver genes. We included a cohort of 175 AAs from the Yale New Haven Health System, a previously studied cohort of 51 AAs from the Chicago Colorectal Cancer Consortium, and the publicly available molecular data from TCGA COAD-READ PanCancer cohort (50 AAs and 229 NHWs). We analyzed the transcriptomic and methylation profiles from the Yale cohort using Tempo-SeqTM and Illumina EPIC array, respectively. Results: Of the 510 patients, 18% were diagnosed with EO-CRC. Using a multiple variant analysis, adjusting for sex, race, tumor location, and stage, EO-CRC patients were less likely to be male (OR = 0.59, 95% CI: 0.37-0.94, p-value = 0.03), their tumors lacked mutations in APC (OR = 0.37, 95% CI: 0.22-0.63, p-value = 0.0002), and they were more likely to have mutations in FBXW7 (OR = 3.1, 95% CI: 1.60-6.00, p-value = 0.0007) and BCL9L (OR = 3.1, 95% CI: 1.00-8.72, p-value = 0.04). We compared tumors with and without mutations in FBXW7 or BCL9L in two independently analyses. Combining transcriptomics and methylation data, we identified 10 candidate genes that showed significant gene downregulation with hypermethylation or upregulation with hypomethylation. Among FBXW7 mutant tumors, we found the Cartilage oligomeric matrix protein (COMP) gene was significantly downregulated and hypermethylated. In CRC, COMP has been associated with a crosstalk between the TGF-β pathway and immune cell infiltration. Moreover, inactivation of FBXW7 resulted in the accumulation of phosphorylated TGIF1 molecules and repression of TGFβ-dependent transcription in cancer cell lines. Deficiency of FBXW7 is a key element in the phosphorylation-dependent ubiquitination and subsequent proteasome degradation of oncoproteins, such as c-MYC, NOTCH, and Cyclin E. Among BCL9L mutant tumors, keratin 20 (KRT20), the intermediate filament protein and marker of intestinal differentiation in CRC, was downregulated and hypermethylated. BCL9L plays an important role in tumorigenesis induced by aberrant Wnt signaling or aneuploidy tolerance. Conclusion: Our findings further demonstrate the importance of specific etiologic mechanisms in EO-CRC at the level of somatic alterations, providing new ways to understand the biology of EO-CRC and prospects for the development of targeted therapies. Citation Format: Reger Mikaeel, Dante Bellomo, Seeta Rajpara, David Buckley, Mary Yagle, Baris Kerimoglu, Curtis Thorne, Megha Padi, Bodour Salhia, Nathan A. Ellis, Xavier Llor, Rosa Xicola. FBXW7 and BCL9L altered pathways as hallmarks of early-onset colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4409.

Abstract 2175: Multiple exposures to antibiotics and increased risk of colorectal cancer

Abstract Colorectal cancer (CRC) is the second leading cause of cancer related deaths in the United States and worldwide. In 2023, approximately 153,020 individuals will be diagnosed with CRC and 52,550 will die, including 19,550 cases and 3750 deaths in patients under 50 years of age. CRC in younger patients (less than 55 years) is known as early onset colorectal cancer (EOCRC). It is a growing global phenomenon whose incidence and mortality has incidence from 11% to 20% between 1995 to 2019 and is expected to increase by 140% by 2030. While it has been linked to known and established risks for CRC, the underlying causes and mechanisms are poorly understood. Based on our current knowledge of the disease, we propose that EOCRC results from exposure of children and young adults to exposome factors that have been increasing globally in the last four decades that may impact the microbiome causing dysbiosis and inflammation in the distal colon and rectum, the anatomical site of EOCRC. Among the likely factors is the use of antibiotics, particularly in infants and children. In this study we hypothesized that early life exposure to antibiotics causes dysbiosis and inflammation in the distal colon and rectum leading to increased mutations and epigenetic events that promote EOCRC development. Specifically, we examined the effect of the most commonly prescribed pediatric antibiotics on the gut microbiota and inflammatory environment in the colon, and their impact on tumor development upon exposure to a carcinogen. We treated A/J mice with multiples rounds of antibiotics and then exposed them to azoxymethane, a carcinogen to determine the effect on tumor development in the colon. The results showed that antibiotic exposure caused dysbiosis and inflammation in the colon of antibiotic treated mice as well as systemic inflammation in mice treated with antibiotics. Treatment with azoxymethane, a carcinogen in the presence of antibiotic-induced dysbiosis led to increased tumor burden in the distal colon. These results suggest a possible involvement of antibiotics on increased risk of EOCRC. Citation Format: Niti Jani, Maredith Richardson, Kristen Hogan, Maria M. Pena. Multiple exposures to antibiotics and increased risk of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2175.

Abstract 4979: Genomic profiling of early-onset metastatic colorectal cancer based on tumor sample location

Abstract Background: Here, we describe analyses towards identifying and comparing genetic variations between the primary and metastatic sites in early-onset metastatic colorectal cancer patients. Methods: We selected patients with early-onset metastatic colorectal cancer (under 50 years old) using data from the American Association for Cancer Research Project GENIE (version 14.1). We used the Fisher exact test to compare genetic mutations between the primary tumor and metastatic sites, complemented by the Benjamini-Hochberg adjustment method. Results: In a total of 1,791 patients with early-onset metastatic colorectal cancer, 27.1% had tumor samples from metastatic sites, while the majority, 72.9%, were from the primary tumor location. The most common mutations found were in the TP53 gene (77.6%), followed by APC (76.0%), KRAS (42.4%), and PIK3CA (19.0%). Notably, the metastatic samples had a significantly higher occurrence of SMAD4 mutations compared to their primary site counterparts (20.8% vs. 14.0%, p&amp;lt;0.001, q&amp;lt;0.001). Conversely, the primary tumor samples exhibited higher frequencies of TCF7L2 and ARID1A mutations (16.9% vs. 10.6%, p&amp;lt;0.001, q&amp;lt;0.001, and 13.0% vs. 6.4%, p&amp;lt;0.001, q&amp;lt;0.001, respectively). Conclusion: Determining the specific genes responsible for the formation of metastatic tumors is crucial for a deeper understanding of the disease's underlying biology in early-onset metastatic colorectal cancer. Such genomic details are crucial to pave the way to the discovery of potential biomarkers for diagnosis and the development of new cancer therapeutics. Citation Format: Muhammet Ozer, Suleyman Y. Goksu, Busra Bacik Goksu, Nina N. Sanford, Amy Jones, Nilesh Verma, Syed Kazmi. Genomic profiling of early-onset metastatic colorectal cancer based on tumor sample location [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4979.

Abstract 6201: Early-onset CRC, vitamin A deficiency, and stem cell origin of cancer

Abstract The recent surge in early-onset CRC (EOCRC) has been attributed to a Westernized lifestyle, but the underlying molecular mechanism is largely unknown. In our cancer genetics clinic, we provide care for 10-20 young (&amp;lt;50 age) CRC patients per year. But, only a fraction (~15%) of these young CRC patients are found to have CRC-predisposing germline mutations which doesn’t provide a hereditary factor that can explain EOCRC. Other genetic studies have found that the spectrum of somatic alterations was largely comparable between EOCRC and adult-onset CRC, particularly common are mutations occurring in APC and other members of the WNT pathway. Since a genetic etiology has not turned-up, we are exploring possible lifestyle factors. We hypothesize that vitamin A (retinol) deficiency is a likely etiologic factor because vitamin A is an essential nutrient that is not made by the human body. Thus, young individuals might be prone to any cancer-initiating effects of a vitamin A deficient diet. Indeed, many population-based studies (including ones on well-nourished populations) have reported a high prevalence of vitamin A deficiency in pre-school-aged children. Since APC mutation commonly occurs in early-onset CRCs, we conjecture that vitamin A (retinol) metabolism and APC mutation-induced activation of WNT signaling may be co-factors in promoting EOCRC. Accordingly, we have been investigating whether there is a functional connection between WNT and vitamin A/retinoic acid (RA) signaling, and if APC mutation generates an imbalance in a WNT:RA-linked mechanism that contributes to CRC development by impeding retinoid-induced colonic stem cell (SC) differentiation. We previously reported that RA signaling mainly occurs in aldehyde dehydrogenase-positive (ALDH+) SCs and that APC mutation leads to overpopulation of ALDH+ SCs and incomplete differentiation during CRC development. Thus, our findings suggest that APC mutation attenuates RA signaling in ALDH+ SCs, which might explain how vitamin A deficiency contributes to EOCRC development. Citation Format: Bruce M. Boman, Victoria O. Hunsu, Caroline O. Facey. Early-onset CRC, vitamin A deficiency, and stem cell origin of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6201.

Abstract 250: Sex differences in cancer stemness among individuals with early onset colorectal cancer

Abstract Since 1990, the overall incidence and mortality rates of late onset colorectal cancer (LOCRC ≥50 years) have been decreasing due to improvements in access to screening and available treatment options. However, the rates for early onset CRC (EOCRC ≤ 49 years) have steadily increased in men and women. Less than 30% of LOCRC patients present with late-stage tumors (clinical stages III or IV) at the time of diagnosis compared to 70% of EOCRC patients. Despite this, the cellular and molecular mechanisms underlying the incidence and stage are unclear, as are appropriate strategies for prevention of recurrence in men and women with EOCRC. Effective prognostic markers are therefore urgently needed. To address this issue, we performed a detailed bioinformatics analysis based on Gene Expression Omnibus database (GSE39582; n=585 patients), wherein we identified 7 prognostic biomarkers for EOCRC: KRAS, LGR5, CTNNB1, MYC, BMI1, CD44 and ASNS. Importantly, Kaplan Meier analysis revealed tumor onset at a younger age was significantly (p = 0.0082) associated with poorer 5-year survival in men with EOCRC only, after adjusting for KRAS status. CTNBB1 and CD44 transcript levels were higher in men with EOCRC versus men with LOCRC. Conversely, female EOCRC had a higher frequency of KRAS mutations (52.6%) compared to their LOCRC counterpart (38.8%), and an increased expression of markers of tumor stem cell and metabolic reprogramming including LGR5, MYC, BMI, and ASNS. A single CRISPR-Cas9 deletion of ASNS in HCT116 cell lines, a pre-clinical model of EOCRC, caused an inhibition of 3D spheroid formation compared to HCT116 ASNS wild type cells. In vivo study using a cell line derived R2G2 mouse xenograft model showed that ASNS disruption caused a reduction in tumor burden that was accompanied by low Lgr5 and Myc transcripts compared to the ASNS wild type group, indicating that ASNS may regulate cancer stemness. Together, this data suggests a unique molecular fingerprint for EOCRC and highlights sex-specific influences on cellular metabolism during EOCRC progression. Citation Format: Oladimeji Aladelokun, Kaelyn Sumigray, Sajid A. Khan, Caroline Johnson. Sex differences in cancer stemness among individuals with early onset colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 250.