biostudies-literatureAkimoto NMassachusetts General HospitalAmerican Cancer SocietyAmerican Society of Clinical OncologyNCI NIH HHSUehara Memorial FoundationNational Institutes of HealthHuazhong University of Science and TechnologyNIH HHSAmerican Association for Cancer ResearchNational Colorectal Cancer Research AllianceJapan Society for the Promotion of Science2016https://www.ebi.ac.uk/biostudies/studies/S-EPMC8122644biostudies-literatureUnknown13(9)Evidence indicates the pathogenic role of epigenetic alterations in early-onset colorectal cancers diagnosed before age 50. However, features of colorectal cancers diagnosed at age 50-54 (hereafter referred to as "intermediate-onset") remain less known. We hypothesized that tumor long interspersed nucleotide element-1 (LINE-1) hypomethylation might be increasingly more common with decreasing age of colorectal cancer diagnosis. In 1356 colorectal cancers, including 28 early-onset and 66 intermediate-onset cases, the tumor LINE-1 methylation level measured by bisulfite-PCR-pyrosequencing (scaled 0 to 100) showed a mean of 63.6 (standard deviation (SD) 10.1). The mean tumor LINE-1 methylation level decreased with decreasing age (mean 64.7 (SD 10.4) in age ≥70, 62.8 (SD 9.4) in age 55-69, 61.0 (SD 10.2) in age 50-54, and 58.9 (SD 12.0) in age <50; p < 0.0001). In linear regression analysis, the multivariable-adjusted β coefficient (95% confidence interval (CI)) (vs. age ≥70) was -1.38 (-2.47 to -0.30) for age 55-69, -2.82 (-5.29 to -0.34) for age 50-54, and -4.54 (-8.24 to -0.85) for age <50 (Ptrend = 0.0003). Multivariable-adjusted hazard ratios (95% CI) for LINE-1 methylation levels of ≤45, 45-55, and 55-65 (vs. >65) were 2.33 (1.49-3.64), 1.39 (1.05-1.85), and 1.29 (1.02-1.63), respectively (Ptrend = 0.0005). In conclusion, tumor LINE-1 hypomethylation is increasingly more common with decreasing age of colorectal cancer diagnosis, suggesting a role of global DNA hypomethylation in colorectal cancer arising in younger adults.CancersTumor Long Interspersed Nucleotide Element-1 (LINE-1) Hypomethylation in Relation to Age of Colorectal Cancer Diagnosis and Prognosis.PMC8122644N/AR35 CA197735U01 CA167552P01 CA87969201960541201860083P01 CA55075Stuart and Suzanne Steele MGH Research ScholarCareer Development AwardUM1 CA167552SU2C-AACR-DT22-17R37 CA246175R01 CA205406R01 CA151993R35 CA253185RSG NEC-130476fellowship granUM1 CA186107Wu KNg KGiovannucci ELChan ATGiannakis MTwombly TSLau MCUgai TKishikawa JVayrynen JPArima KOgino SZhao MSong MZhong RAkimoto NFujiyoshi KZhang XCao YHaruki KMeyerhardt JANowak JAfalseTumor Long Interspersed Nucleotide Element-1 (LINE-1) Hypomethylation in Relation to Age of Colorectal Cancer Diagnosis and Prognosis.Evidence indicates the pathogenic role of epigenetic alterations in early-onset colorectal cancers diagnosed before age 50. However, features of colorectal cancers diagnosed at age 50-54 (hereafter referred to as "intermediate-onset") remain less known. We hypothesized that tumor long interspersed nucleotide element-1 (LINE-1) hypomethylation might be increasingly more common with decreasing age of colorectal cancer diagnosis. In 1356 colorectal cancers, including 28 early-onset and 66 intermediate-onset cases, the tumor LINE-1 methylation level measured by bisulfite-PCR-pyrosequencing (scaled 0 to 100) showed a mean of 63.6 (standard deviation (SD) 10.1). The mean tumor LINE-1 methylation level decreased with decreasing age (mean 64.7 (SD 10.4) in age ≥70, 62.8 (SD 9.4) in age 55-69, 61.0 (SD 10.2) in age 50-54, and 58.9 (SD 12.0) in age <50; p < 0.0001). In linear regression analysis, the multivariable-adjusted β coefficient (95% confidence interval (CI)) (vs. age ≥70) was -1.38 (-2.47 to -0.30) for age 55-69, -2.82 (-5.29 to -0.34) for age 50-54, and -4.54 (-8.24 to -0.85) for age <50 (Ptrend = 0.0003). Multivariable-adjusted hazard ratios (95% CI) for LINE-1 methylation levels of ≤45, 45-55, and 55-65 (vs. >65) were 2.33 (1.49-3.64), 1.39 (1.05-1.85), and 1.29 (1.02-1.63), respectively (Ptrend = 0.0005). In conclusion, tumor LINE-1 hypomethylation is increasingly more common with decreasing age of colorectal cancer diagnosis, suggesting a role of global DNA hypomethylation in colorectal cancer arising in younger adults.2021-01-01T00:00:00Z2021 Apr2024-11-09T05:21:46.04Z2022-02-10T10:48:07.091ZS-EPMC81226443392202410.3390/cancers13092016