Tumor long interspersed nucleotide element-1 (LINE-1) hypomethylation in relation to age of colorectal cancer diagnosis and prognosis

Naohiko Akimoto, Melissa Zhao, Tomotaka Ugai, Rong Zhong, Mai Chan Lau, Kenji Fujiyoshi, Junko Kishikawa, Koichiro Haruki, Kota Arima, Tyler S. Twombly, Xuehong Zhang, Edward L. Giovannucci, Kana Wu, Mingyang Song, Andrew T. Chan, Yin Cao, Jeffrey A. Meyerhardt, Kimmie Ng, Marios Giannakis, Juha P. VäyrynenJonathan A. Nowak, Shuji Ogino

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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-PCRpyrosequencing (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.

Original languageEnglish
Article number2016
JournalCancers
Volume13
Issue number9
DOIs
StatePublished - 1 May 2021
Externally publishedYes

Keywords

  • Carcinogenesis
  • Colorectal neoplasms
  • Epigenomics
  • Genomic instability
  • Long interspersed nuclear element
  • Molecular pathology
  • Retrotransposon
  • Screening
  • Transposable element
  • Youngonset cancer

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