Abstract 2275: Exploring the genetic underpinnings of cancer-related fatigue in colorectal cancer patients

Abstract Background: Cancer-related fatigue (CRF) is a prevalent and debilitating symptom among colorectal cancer (CRC) patients. This study aimed to identify genetic variants associated with CRF trajectories and assess their relationships with clinical and demographic factors. Methods: Participants (N=1,219) were recruited from the ColoCare Study across six U.S. sites and the University of Heidelberg in Germany. Eligible participants were adults (≥18 years) with a new diagnosis of primary colon or rectal cancer. CRF was assessed at five timepoints (baseline, 3, 6, 12, and 24 months) using the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30) fatigue subscale. Longitudinal analysis of CRF patterns was performed using piecewise growth mixture models (GMMs), which identified three distinct trajectories: high, moderate, and low fatigue. Fatigue outcomes were assessed in three ways: as a binary variable (high vs. moderate/low trajectories), as a continuous measure (mean fatigue scores), and through an extreme phenotype approach (highest fatigue observed across all timepoints). Genome-wide association analyses (GWAS) were conducted using PLINK. Analyses were adjusted for potential confounders, including age, sex, cancer stage, smoking status, and population stratification (top two principal components). We performed fine-mapping analyses to identify independent secondary signals in known loci, focusing on SNPs previously associated with CRF and regions with p-values <5 × 10-6 in at least two of our GWAS models. Results: Among 1,219 CRC patients, 378 (31.0%) reported high fatigue, while 651 (53.4%) were categorized as having low/moderate fatigue. Significant differences in cancer-related fatigue were observed by race/ethnicity, smoking status, cancer stage, recurrence status, and receipt of neoadjuvant treatment. When examining fatigue as a binary outcome, a locus on chromosome 4 near LINC02505 was associated with higher risk of fatigue (rs6531463, OR = 3.25, 95% CI: 2.83-3.67, p=3.88 × 10-8). Several variants near NEK10 and SLC4A7 on chromosome 3 also showed suggestive associations (p-value range: 5×10−8<p<5×10−6). Similar results were observed when examining average fatigue as the outcome. The most significant locus was on chromosome 3p24.1 near NEK10 and SLC4A7 (rs7617094, OR = 0.57, 95% CI: 0.47-0.69, p=2.21 × 10-8). For extreme fatigue, loci on chromosomes 3p24.1 and 5q13.1 also were associated with elevated risk (p-value range: 5×10−8<p<5×10−6). Fine-mapping analyses identified 3 credible sets across 3 loci including 5q13.1, 3p24.1 and 5q13.1. Conclusion: This study investigates the genetic basis of CRF in CRC patients, identifying novel loci and refining known susceptibility regions. Key loci associated with CRF include LINC02505, NEK10, and SLC4A7. These findings if validated offer potential targets for interventions focused on CRF prevention and management.</p<5×10</p<5×10 Citation Format: Elham Kazemian, Qianxing Mo, Xiaoyin Li, Aasha I. Hoogland, Sylvia L. Crowder, Brian D. Gonzalez, Laura B. Oswald, Alix G. Sleight, Nathalie Nguyen, Nicole C. Lorona, Victoria Damerell, Khaled R. Komrokji, Kathi Mooney, Mary C. Playdon, Cornelia M. Ulrich, Christopher I. Li, David Shibata, Adetunji T. Toriola, Jennifer Ose, Anita R. Peoples, Erin M. Siegel, Julienne E. Bower, Biljana Gigic, Heather S. L. Jim, Jane C. Figueiredo. Exploring the genetic underpinnings of cancer-related fatigue in colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2275.