Supplemental Table 6 from Elevated <i>EVL</i> Methylation Level in the Normal Colon Mucosa Is a Potential Risk Biomarker for Developing Recurrent Adenomas

2025-11-26

<p>Supplemental Table 6: Summary statistics for methylated EVL measurements in Comparison Set 2</p>

Abstract PR007: Tumor-adjacent visceral adipose tissue displays an altered transcriptomic landscape in early-onset colorectal cancer patients: Results from the ColoCare Study

Clinical Cancer Research · 2025-12-10

Abstract Introduction: Obesity is commonly characterized by high levels of internal (visceral) adiposity. Visceral adipose tissue (VAT) is highly metabolically active and secretes proteins and metabolites in paracrine and endocrine signaling pathways. The phenotype of tumor-adjacent VAT may be an unexplored factor for risk and progression of early-onset colorectal cancer (EOCRC). Thus, we aimed to identify transcriptomic differences in tumor-adjacent visceral adipose tissue (VAT) in patients with EOCRC (<50 years at diagnosis) vs. those diagnosed with later-onset colorectal cancer (LOCRC; >50 years at diagnosis). Methods: VAT samples were collected from 332 patients with stage 0-III colorectal cancer enrolled in the ColoCare Study and recruited at Huntsman Cancer Institute (Utah), Heidelberg University Hospital (Germany), University of Tennessee Health Science Center (Tennessee), and Moffitt Cancer Center (Florida). Patients in our study were treatment naïve. VAT tissue was collected 1-3 cm from the colorectal tumor during surgery. VAT transcriptomes were measured with bulk RNA sequencing. Participants were classified as EOCRC vs. LOCRC. Normalized differentially expressed genes were identified (DESeq2), with analyses adjusted for sex, body mass index (BMI), study site, and tumor stage. Gene set enrichment analysis (GSEA) identified enriched pathways within the 2025 Hallmark gene sets. Significance was assessed using false discovery rate (FDR) p-adj<0.05. We replicated our analyses, adjusting for tumor site (colon vs. rectal), to account for potential differences by anatomical subgroup. Results: Patients with EOCRC (n=45, average age: 41±9 years) had higher disease stages compared to LOCRC patients (n=287, average age: 66±10 years) (EOCRC: 64% Stage III vs LOCRC: 39% Stage III) and similar BMI (EOCRC: 28.8±7.0 kg/m2 vs. LOCRC: 28.5±5.9 kg/m2). GSEA revealed 5 significantly enriched gene sets (FDR p-adj<0.05) in VAT when comparing EOCRC to LOCRC patients. VAT of EOCRC patients exhibited upregulation of immune pathways (Interferon Alpha Response, Interferon Gamma Response, TNFA Signaling via NF- κB), and fibrosis Hallmark pathways (Epithelial Mesenchymal Transition) (Normalized Enrichment Score (NES) >1.5, p-adj<0.05). Additionally, the VAT of patients with EOCRC showed upregulation of the glycolysis gene set relative to LOCRC (NES>1.5, p-adj<0.05). These pathways remained significantly enriched regardless of tumor site adjustment. Conclusions: VAT of patients with EOCRC displays a differential gene expression landscape relative to LOCRC patients, suggesting enhanced immune, fibrotic, and metabolic activity. These findings suggest that tumor-adjacent VAT physiology may be a relevant factor of the tumor-microenvironment in EOCRC progression. Citation Format: Victoria M. Bandera, Patricia Erickson, Caroline Himbert, Elaine M. Glenny, Tengda Lin, Sheetal Hardikar, Aik Choon Tan, Jennifer Ose, Victoria Damerell, Christy Warby, Olena Aksonova, Chris Stubben, David Nix, Kenneth Boucher, Peter Schirmacher, Ildiko Strehli, Megan Mclaws, Alejandro Sanchez, Jolanta Jedrzkiewicz, Lyen C. Huang, Vaia Florou, Jessica N. Cohan, Alexander Brobeil, Hans-Ulrich Kauczor, Christoph Kahlert, Meghana Karchi, Elizabeth H. Wood, Doratha A. Byrd, Erin M. Siegel, Adetunji T. Toriola, David Shibata, Christopher I. Li, Jane C. Figueiredo, Biljana Gigic, Jatin Roper, Stephen Hursting, Cornelia M. Ulrich. Tumor-adjacent visceral adipose tissue displays an altered transcriptomic landscape in early-onset colorectal cancer patients: Results from the ColoCare Study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr PR007.

Data from Presurgery Adhesion Molecules and Angiogenesis Biomarkers Are Differently Associated with Outcomes in Colon and Rectal Cancer: Results from the ColoCare Study

2025-11-26

<div>AbstractBackground:<p>Cell-to-cell adhesion and angiogenesis are hallmarks of cancer. No studies have examined associations of adhesion molecules and angiogenesis biomarkers with clinical outcomes in colorectal cancer.</p>Methods:<p>In presurgery serum from <i>n</i> = 426 patients with colorectal cancer (stage I–III), we investigated associations of CRP, SAA, adhesion molecules (sICAM-1, sVCAM-1), and angiogenesis markers (VEGF-A and VEGF-D) with overall survival (OS), disease-free survival (DFS), and risk of recurrence. We computed HRs and 95% confidence intervals; adjusted for age, sex, BMI, stage, site, and study site, stratified by tumor site in exploratory analyses.</p>Results:<p><i>N</i> = 65 (15%) were deceased, and 39 patients (14%) had a recurrence after a median follow-up of 31 months. We observed significant associations of biomarkers with OS, DFS, and risk of recurrence on a continuous scale and comparing top to bottom tertile, with HRs ranging between 1.19 and 13.92. CRP was associated with risk of death and recurrence in patients in the top tertile compared with patients in the bottom tertile, for example, risk of recurrence HR<sub>Q3-Q1</sub>: 13.92 (1.72–112.56). Significant heterogeneity between biomarkers and clinical outcomes was observed in stratified analysis by tumor site for CRP, SAA, sICAM-1, sVCAM-1, and VEGF-D. VEGF-D was associated with a 3-fold increase in risk of death for rectal cancer (HR<sub>log2</sub>: 3.26; 95% CI, 1.58–6.70) compared with no association for colon cancer (HR<sub>log2</sub>: 0.78; 95% CI, 0.35–1.73; <i>P</i><sub>heterogenity</sub> = 0.01).</p>Conclusions:<p>Adhesion molecules and angiogenesis biomarkers are independent prognostic markers for colorectal cancer, with differences by tumor site.</p>Impact:<p>There is need for tailored treatment for colon and rectal cancer.</p></div>

Data from Evaluating and Improving Cancer Screening Process Quality in a Multilevel Context: The PROSPR II Consortium Design and Research Agenda

2025-11-26

<div>AbstractBackground:<p>Cancer screening is a complex process involving multiple steps and levels of influence (e.g., patient, provider, facility, health care system, community, or neighborhood). We describe the design, methods, and research agenda of the Population-based Research to Optimize the Screening Process (PROSPR II) consortium. PROSPR II Research Centers (PRC), and the Coordinating Center aim to identify opportunities to improve screening processes and reduce disparities through investigation of factors affecting cervical, colorectal, and lung cancer screening in U.S. community health care settings.</p>Methods:<p>We collected multilevel, longitudinal cervical, colorectal, and lung cancer screening process data from clinical and administrative sources on >9 million racially and ethnically diverse individuals across 10 heterogeneous health care systems with cohorts beginning January 1, 2010. To facilitate comparisons across organ types and highlight data breadth, we calculated frequencies of multilevel characteristics and volumes of screening and diagnostic tests/procedures and abnormalities.</p>Results:<p>Variations in patient, provider, and facility characteristics reflected the PROSPR II health care systems and differing target populations. PRCs identified incident diagnoses of invasive cancers, <i>in situ</i> cancers, and precancers (invasive: 372 cervical, 24,131 colorectal, 11,205 lung; <i>in situ</i>: 911 colorectal, 32 lung; precancers: 13,838 cervical, 554,499 colorectal).</p>Conclusions:<p>PROSPR II's research agenda aims to advance: (i) conceptualization and measurement of the cancer screening process, its multilevel factors, and quality; (ii) knowledge of cancer disparities; and (iii) evaluation of the COVID-19 pandemic's initial impacts on cancer screening. We invite researchers to collaborate with PROSPR II investigators.</p>Impact:<p>PROSPR II is a valuable data resource for cancer screening researchers.</p></div>

Abstract B038: Differences in metabolomic profiles predictive of fatigue in early-onset vs. later-onset colorectal cancer

Clinical Cancer Research · 2025-12-10

Abstract Background: Cancer-related fatigue (CRF) affects up to 90% of patients with cancer during chemotherapy and persists in approximately 30% of patients after treatment completion, with some patients describing CRF as “devastating,” “never-ending,” and “totally consuming.” For patients with early-onset cancer (diagnosed<50 years) in particular, CRF is associated with worse quality of life and lower likelihood of returning to normal daily activities, including work. Alterations in certain metabolic pathways have been hypothesized to influence the development of CRF. The purpose of the present study is to identify differences in metabolic longitudinal predictors of CRF in a prospective cohort of patients with colorectal cancer (CRC) using serum metabolomics data. Methods: The ColoCare Study includes six U.S. sites and one Germany site and consists of men and women ages 18 to 89 at diagnosis with newly diagnosed primary CRC of stage I-IV. Patients are consented during a pre-surgery visit to complete questionnaires, provide biologic specimens at multiple time points, and for medical record reviews. Patients were categorized as early (age<50) or later-onset (age≥50). CRF was measured using the three-item fatigue subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) before CRC surgery (baseline), and 6, 12, and 24 months post-surgery. CRF scores were categorized as no, low, moderate, and high CRF using previously validated cutpoints. Using blood specimens at each time point, we performed semi-targeted metabolomics to identify aqueous metabolites following comprehensive protocols for measurement and quality control. Using multivariable ordinal logistic regression, we assessed the association between 1) individual metabolites and CRF cross-sectionally at each timepoint, and 2) metabolites measured at baseline and 6 months post-surgery and CRF at 12 months post-surgery. We adjusted for multiple testing using the number of effective independent tests. Further analyses using machine learning methods and metabolic pathway analysis are ongoing. Results: ColoCare Study participants with at least one measurement of CRF and metabolomic profiling (N=1,098) were included in the present study. Early-onset and later-onset patients had similar CRF prevalence. N=173 distinct polar metabolites were detected. Five metabolites (e.g. tryptophan metabolites, xenobiotic metabolites) were inversely associated and a nicotine metabolite (C16H20N2O8) was positively associated with CRF at baseline only among later-onset patients. A phenylalkylamine xenobiotic metabolite (C18H31NO) measured at 6 months post-surgery was inversely associated with CRF at 12 months post-surgery only among early-onset patients. Conclusions: CRF is prevalent in both early-onset and late-onset CRC patients. Metabolites associated with CRF in patients with CRC differed by age at onset. Further research profiling metabolic pathways associated with CRF by age can aid in identifying targetable mechanisms of CRF in early-onset CRC patients. Citation Format: Nicole C. Loroña, Mary Playdon, James Cox, Xiaoyin Li, Aasha I. Hoogland, Patricia A. Erickson, Maria F. Gomez, Sheetal Hardikar, Mmadili N. Ilozumba, Jennifer Ose, Anita Peoples, Brent Small, Victoria Damerell, Vaia Florou, Mark Lewis, Shannon M. Christy, William Grady, Biljana Gigic, David Shibata, Doratha A. Byrd, Adetunji Toriola, Christopher I. Li, Cornelia Ulrich, Heather S L. Jim, Jane C. Figueiredo. Differences in metabolomic profiles predictive of fatigue in early-onset vs. later-onset colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr B038.

Supplemental Figure 2 from Elevated <i>EVL</i> Methylation Level in the Normal Colon Mucosa Is a Potential Risk Biomarker for Developing Recurrent Adenomas

2025-11-26

<p>Supplemental Figure 2: Methylation levels of normal colon mucosa in patients with no history of adenoma or cancer ever (group on left) and levels for patients with a history of adenoma(s) or colorectal cancer at initial or a follow-up colonoscopy (group on right) in Comparison Set 1. %mEVL=percentage of DNA that is methylated at the EVL locus assayed.</p>

Supplemental Table 1 from Elevated <i>EVL</i> Methylation Level in the Normal Colon Mucosa Is a Potential Risk Biomarker for Developing Recurrent Adenomas

2025-11-26

<p>Supplemental Table 1: Primer/probe sequences used in the duplex mEVL assay</p>

Supplementary Table S4 from Pre-Surgery Inflammatory and Angiogenesis Biomarkers as Predictors of 12-Month Cancer-Related Distress: Results from the ColoCare Study

2025-11-26

<p>Supplementary Table S4 shows the associations of doubling of pre-surgery biomarkers with Cancer and Treatment Distress overall score and subscores by study center.</p>

Data from Pre-Surgery Inflammatory and Angiogenesis Biomarkers as Predictors of 12-Month Cancer-Related Distress: Results from the ColoCare Study

2025-11-26

<div>AbstractBackground:<p>Patients with colorectal cancer commonly suffer from complex psychological distress. Elevated distress may be linked to systemic biomarkers. We investigated associations of biomarkers of inflammation and angiogenesis with cancer-related distress (CTXD) score.</p>Methods:<p><i>N</i> = 315 patients (stage I–IV) from 2 centers of the ColoCare Study were included: Huntsman Cancer Institute and University of Heidelberg. Biomarkers (e.g., IL6, VEGF-A, VEGF-D) were measured in serum collected pre-surgery and 12 months thereafter. The CTXD overall score and 4 subscales were collected 12 months after surgery and dichotomized to investigate biomarkers as predictors of distress 12 months after surgery; adjusted for age, sex, body mass index, tumor stage, center, and baseline levels of biomarkers.</p>Results:<p>Doubling of IL6 predicted future increased risk of overall distress [odds ratio (OR), 1.20; 95% confidence interval (CI), 1.02–1.41; <i>P</i> = 0.03]. VEGF-A–predicted future increased risk of high family strain (VEGF-A: OR, 1.21; 95% CI, 1.01–1.44; <i>P</i> = 0.04) and VEGF-D was associated with medical and financial demands (OR, 1.34; 95% CI, 1.01–1.74; <i>P</i> = 0.03).</p>Conclusions:<p>This is the first study to show that systemic biomarkers are significantly associated with future CTXD score. Distress was not measured at baseline; we cannot rule out ongoing associations of inflammation and distress throughout treatment versus a direct effect of inflammation on distress. Nonetheless, these data add to evidence that biobehavioral processes interact and that systemic biomarkers are associated with cancer-related distress one year after surgery.</p>Impact:<p>Exercise and diet interventions that lower systemic cytokine levels may impact longer-term CTXD score and improve quality of life of patients with colorectal cancer.</p></div>

Abstract PR015: Multidimensional assessment of toxicities and survivorship among people with early-onset colorectal cancer – Results from the ColoCare Study

Clinical Cancer Research · 2025-12-10

Abstract Background: In 2024, colorectal cancer (CRC) emerged as the leading cause of cancer death in men under 50 and the second leading cause in women (referred to as early-onset CRC (EOCRC). The incidence of EOCRC is growing by 1.4% annually. Understanding the “multidimensional spectrum of toxicities”, including the effects of the disease, treatments, and emotional and physical experiences of CRC at a young age, along with the indirect impacts on family and work life, remains poorly understood. The ColoCare Study is dedicated to investigating the interconnected factors that drive these complex toxicities. The goal is to identify high-risk EOCRC patients who could benefit from targeted strategies to improve their physical health, socioeconomic status, and overall quality of life during and after treatment. Methods: The ColoCare Study is an international, prospective cohort study including six U.S. sites and one site in Germany. Individuals ages 18 to 89 at diagnosis with newly diagnosed primary invasive CRC stage I-IV were enrolled (n=4,442 patients (1,238: age <50 y; 1,718: age 50-64 y; and 1,486: age 65+ y)). We collected longitudinal, repeated assessments of patient-reported symptoms, health-related quality of life, and financial health, in addition to blood-, stool-, and tumor-derived biomarkers, and linked these to medical records for clinicopathological characteristics, toxicities, comorbidities, recurrence, and vital status. Results: In our cohort, more than half of EOCRC patients face treatment-related adverse events (AEs) both during and after their treatment. Compared to older patients, those with EOCRC experience more severe symptoms such as nausea/vomiting, fatigue, pain, and sleep disturbances. Among female EOCRC patients, 72% discussed reproductive and fertility-related challenges with their clinicians, yet only 19% proceeded with fertility preservation. Alarmingly, only 13% of all patients had insurance coverage for fertility preservation. Furthermore, employment and financial stability pose significant challenges for working-age EOCRC patients. They report greater financial difficulties than those over 65 (p<0.001). Individuals aged 18–49 also reported more frequent challenges in mental and physical function compared to their older counterparts. Additionally, EOCRC patients experience higher rates of material and psychological hardships. Further analyses are ongoing. Conclusions: These findings highlight the need for more targeted clinical management for many early-onset colorectal cancer (EOCRC) patients, especially during the first year following diagnosis and into survivorship. Addressing specific concerns related to ongoing toxicities—such as physical, socioeconomic, and emotional issues—could greatly benefit these patients. With approximately 1,000 EOCRC patients involved, the ColoCare Study is uniquely positioned to conduct research focused on EOCRC survivorship. Citation Format: Jane C. Figueiredo, Nicole C. Loroña, Anne Kirchoff, Karely V T. Van Thiel Berghuijs, Heydon Kaddas, Mary Playdon, Patricia A. Erickson, Maria F. Gomez, Sheetal Hardikar, Mmadili N. Ilozumba, Jennifer Ose, Victoria Damerell, Vaia Florou, Mark A. Lewis, Shannon Christy, William M. Grady, Biljana Gigic, Doratha A. Byrd, Adetunji Toriola, Christopher I. Li, David Shibata, Cornelia M. Ulrich. Multidimensional assessment of toxicities and survivorship among people with early-onset colorectal cancer – Results from the ColoCare Study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr PR015.