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BACKGROUND: Given the global issue of the rising incidence of early-onset colorectal cancer (CRC), we tested the hypothesis that tumor vasculature phenotypes might vary with age at CRC diagnosis.METHOD: We used in situ multispectral immunofluorescence combined with digital image analysis and machine learning to measure expression of endothelial cell markers [ACKR1 (DARC), CD34, CD36, KDR (VEGFR2), LAMB1 (laminin β1), MADCAM1] and KRT (keratin) in 843 tumors derived from 4476 CRC cases in U.S.-wide prospective cohorts under the prospective cohort incident-tumor biobank method.RESULTS: Overall CD34 vessel and CD34LAMB1 vessel densities inversely correlated with younger age at CRC diagnosis (both P < 0.0001). In the inverse probability-weighted multivariable-adjusted logistic regression analyses, compared to age ≥70, odds ratios (with 95% confidence interval) for high (vs. low) overall vessel density were 0.85 (0.74-0.99) for age 55-69 and 0.63 (0.48-0.81) for age <55, and those for high (vs. low/negative) CD34LAMB1 vessel density were 0.56 (0.47-0.65) for age 55-69 and 0.28 (0.20-0.40) for age <55.CONCLUSIONS: Hypovascularities of overall and CD34LAMB1 vessels may be microenvironmental characteristics of early-onset CRC if validated by independent studies. Our findings highlight age-related tumor pathobiological differences. Identifying specific biomarkers of early-onset CRC can provide pathogenetic and etiological clues.