Abstract C006: Association of high birth weight with risk of early-onset colorectal cancer

Introduction: The incidence of early-onset colorectal cancer (eoCRC) diagnosed under age 50 years has been increasing. The causes of this trend could be multifactorial and remain to be understood. The average birth weight has been increasing in the US since 1950. Intrauterine conditions can affect health outcomes later in life. Prior studies showed a link between high birth weight and risk of certain cancers in adolescent and young adults. Here we evaluated the hypothesis that high birth weight increases risk of eoCRC in a nested case-control study. Methods: We included patients diagnosed with colorectal adenocarcinoma at age 15-49 years at Kaiser Permanente Southern California (KPSC) (2009-2021). Cancer-free controls were matched at 10:1 ratio on age, sex, and length of prior KPSC membership using incidence density sampling. Study data were collected from KPSC’s electronic health records and birth data from California Department of Public Health. Record linkage with birth certificates from 1960 to 2005 was performed using date of birth, sex, and first, last, middle, and maiden names. Conditional logistic regression was used to estimate the association between eoCRC and high birth weight, measured using (1) neonatal macrosomia (birth weight > 4,000 grams), (2) large for gestational age (LGA; defined as birth weight > 90th percentile for gestational age and sex, using population references at KPSC), and (3) LGA stratified by sex and race/ethnicity. Analyses were repeated for colon and rectal cancer. Potential confounders or intermediates were assessed in crude models using threshold p-value <0.10. Two-stage model adjustments were performed: adjusting for race/ethnicity only, then additionally adjusting for obesity and hypertension (both had crude p-value <0.10). Results: Of 1,400 eligible eoCRC cases and 13,608 matched controls, 486 cases and 4,706 controls had linked birth certificate data (35% linked in both groups). After excluding cases without controls and vice versa, 471 cases (mean diagnosis age: 41.1 years) and 1,931 controls were included in the analysis. Of the 471 cases, 64% were male; 40% were non-Hispanic white; 64% had colon cancer, 36% had rectal cancer; and 12% had neonatal macrosomia. Both stages of models yielded similar results. In the fully adjusted model, high birth weight was associated with an elevated risk of overall eoCRC with marginal significance [odds ratio (OR)= 1.31 (95% CI: 0.94-1.82), 1.39 (0.96-2.02), and 1.38 (0.98-1.95) for neonatal macrosomia, LGA, and LGA stratified by sex and race/ethnicity, respectively]. Neonatal macrosomia and LGA were significantly associated with rectal cancer [OR= 1.80 (1.03-3.14) and 1.90 (1.04-3.48), respectively], but not with colon cancer [OR= 1.13 (0.75-1.71) and 1.17 (0.73-1.86), respectively]. Conclusions: We observed an association between high birth weight and risk of early-onset rectal cancer independent of adult metabolic abnormality, which should be confirmed in larger studies. Our finding suggests potentially distinct pathogenesis for rectal vs. colon cancer. Citation Format: Chun R. Chao, Lanfang Xu, Amrita Mukherjee, Darios Getahun, Jessica Chubak, Jane C. Figueiredo, Kimberly L. Cannavale, Alec Gilfillan, Bechien Wu. Association of high birth weight with risk of early-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 C006.