University of Oulu

Akimoto, N.; Zhao, M.; Ugai, T.; Zhong, R.; Lau, M.C.; Fujiyoshi, K.; Kishikawa, J.; Haruki, K.; Arima, K.; Twombly, T.S.; Zhang, X.; Giovannucci, E.L.; Wu, K.; Song, M.; Chan, A.T.; Cao, Y.; Meyerhardt, J.A.; Ng, K.; Giannakis, M.; Väyrynen, J.P.; Nowak, J.A.; Ogino, S. Tumor Long Interspersed Nucleotide Element-1 (LINE-1) Hypomethylation in Relation to Age of Colorectal Cancer Diagnosis and Prognosis. Cancers 2021, 13, 2016. https://doi.org/10.3390/cancers13092016

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

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Author: Akimoto, Naohiko1,2; Zhao, Melissa1; Ugai, Tomotaka1,3;
Organizations: 1Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
2Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, Tokyo 1138602, Japan
3Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston 02115, MA, USA
4Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
5Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
6Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
7Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
8Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA
9Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
10Division of Public Health Sciences, Department of Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA
11Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
12Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
13Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA
14Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
15Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
16Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, 90220 Oulu, Finland
17Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, MA 02215, USA
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.3 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2021060935925
Language: English
Published: Multidisciplinary Digital Publishing Institute, 2021
Publish Date: 2021-06-09
Description:

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-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.

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Series: Cancers
ISSN: 2072-6694
ISSN-E: 2072-6694
ISSN-L: 2072-6694
Volume: 13
Issue: 9
Article number: 2016
DOI: 10.3390/cancers13092016
OADOI: https://oadoi.org/10.3390/cancers13092016
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Subjects:
Funding: This work was supported by U.S. National Institutes of Health (NIH) grants (P01 CA87969; UM1 CA186107; P01 CA55075; UM1 CA167552; U01 CA167552; R35 CA253185 to A.T.C.; R37 CA246175 to Y.C.; R35 CA197735 to S.O.; R01 CA151993 to S.O.); by a Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant (SU2C-AACR-DT22-17 to M.G.), administered by the American Association for Cancer Research, a scientific partner of SU2C; and by grants from the Project P Fund, The Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance and SU2C. X.Z. was supported by the American Cancer Society Research Scholar Grant (RSG NEC-130476). R.Z. was supported by a fellowship grant from Huazhong University of Science and Technology. K.F. was supported by fellowship grants from the Uehara Memorial Foundation and Grant of The Clinical Research Promotion Foundation (2018). K.A. and T.U. were supported by a grant from the Overseas Research Fellowship (201860083 to K.A.; 201960541 to T.U.) from the Japan Society for the Promotion of Science. K.H. was supported by fellowship grants from the Uehara Memorial Foundation and the Mitsukoshi Health and Welfare Foundation. A.T.C. is a Stuart and Suzanne Steele MGH Research Scholar. M.G. is supported by an ASCO Conquer Cancer Foundation Career Development Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Copyright information: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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