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DNA Methylation Signatures and the Contribution of Age-Associated Methylomic Drift to Carcinogenesis in Early-Onset Colorectal Cancer

1
Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia
2
University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Melbourne 3000, Australia
3
Precision Medicine, Monash Health, Monash University, Clayton, Melbourne 3800, Australia
4
School of Medicine, University of Queensland, Herston, Brisbane 4006, Australia
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Envoi Pathology, Brisbane 4059, Australia
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Melbourne Bioinformatics, The University of Melbourne, Parkville, Melbourne 3010, Australia
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Department of Medicine, The Royal Melbourne Hospital, University of Melbourne, Parkville, Melbourne 3050, Australia
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Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Melbourne 3050, Australia
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Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne 3010, Australia
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Cancer Epidemiology Division, Cancer Council Victoria, Melbourne 3004, Australia
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Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Parkville, Melbourne 3050, Australia
12
Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia
*
Author to whom correspondence should be addressed.
Academic Editor: Ane Etxart
Cancers 2021, 13(11), 2589; https://doi.org/10.3390/cancers13112589
Received: 16 April 2021 / Revised: 14 May 2021 / Accepted: 19 May 2021 / Published: 25 May 2021
(This article belongs to the Section Molecular Cancer Biology)
The role of DNA methylation in the carcinogenesis of colorectal cancer (CRC) diagnosed <50 years of age (early-onset CRC or EOCRC) is currently unknown. In this study, we investigated the genome-wide DNA methylation of 97 tumour and 54 normal colonic mucosa samples from people with EOCRC with the aim of identifying unique DNA methylation signatures and determining the role of ageing-related DNA methylation drift and age-acceleration in EOCRC aetiology. We found extensive DNA methylation alterations associated with EOCRC carcinogenesis, including a unique signature comprising 234 loci compared with CRCs from people >50 years of age. CpGs that undergo ageing-related methylation drift were significantly altered in EOCRC, and accelerated ageing was also evident in normal mucosa from people with EOCRC. Our study is the first study to identify unique DNA methylation changes in EOCRC, contributing novel information that may aid future efforts towards EOCRC prevention.
We investigated aberrant DNA methylation (DNAm) changes and the contribution of ageing-associated methylomic drift and age acceleration to early-onset colorectal cancer (EOCRC) carcinogenesis. Genome-wide DNAm profiling using the Infinium HM450K on 97 EOCRC tumour and 54 normal colonic mucosa samples was compared with: (1) intermediate-onset CRC (IOCRC; diagnosed between 50–70 years; 343 tumour and 35 normal); and (2) late-onset CRC (LOCRC; >70 years; 318 tumour and 40 normal). CpGs associated with age-related methylation drift were identified using a public dataset of 231 normal mucosa samples from people without CRC. DNAm-age was estimated using epiTOC2. Common to all three age-of-onset groups, 88,385 (20% of all CpGs) CpGs were differentially methylated between tumour and normal mucosa. We identified 234 differentially methylated genes that were unique to the EOCRC group; 13 of these DMRs/genes were replicated in EOCRC compared with LOCRCs from TCGA. In normal mucosa from people without CRC, we identified 28,154 CpGs that undergo ageing-related DNAm drift, and of those, 65% were aberrantly methylated in EOCRC tumours. Based on the mitotic-based DNAm clock epiTOC2, we identified age acceleration in normal mucosa of people with EOCRC compared with normal mucosa from the IOCRC, LOCRC groups (p = 3.7 × 10−16) and young people without CRC (p = 5.8 × 10−6). EOCRC acquires unique DNAm alterations at 234 loci. CpGs associated with ageing-associated drift were widely affected in EOCRC without needing the decades-long accrual of DNAm drift as commonly seen in intermediate- and late-onset CRCs. Accelerated ageing in normal mucosa from people with EOCRC potentially underlies the earlier age of diagnosis in CRC carcinogenesis. View Full-Text
Keywords: early onset colorectal cancer; colorectal cancer; DNA methylation; age acceleration; epigenetic drift early onset colorectal cancer; colorectal cancer; DNA methylation; age acceleration; epigenetic drift
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MDPI and ACS Style

Joo, J.E.; Clendenning, M.; Wong, E.M.; Rosty, C.; Mahmood, K.; Georgeson, P.; Winship, I.M.; Preston, S.G.; Win, A.K.; Dugué, P.-A.; Jayasekara, H.; English, D.; Macrae, F.A.; Hopper, J.L.; Jenkins, M.A.; Milne, R.L.; Giles, G.G.; Southey, M.C.; Buchanan, D.D. DNA Methylation Signatures and the Contribution of Age-Associated Methylomic Drift to Carcinogenesis in Early-Onset Colorectal Cancer. Cancers 2021, 13, 2589. https://doi.org/10.3390/cancers13112589

AMA Style

Joo JE, Clendenning M, Wong EM, Rosty C, Mahmood K, Georgeson P, Winship IM, Preston SG, Win AK, Dugué P-A, Jayasekara H, English D, Macrae FA, Hopper JL, Jenkins MA, Milne RL, Giles GG, Southey MC, Buchanan DD. DNA Methylation Signatures and the Contribution of Age-Associated Methylomic Drift to Carcinogenesis in Early-Onset Colorectal Cancer. Cancers. 2021; 13(11):2589. https://doi.org/10.3390/cancers13112589

Chicago/Turabian Style

Joo, Jihoon E., Mark Clendenning, Ee M. Wong, Christophe Rosty, Khalid Mahmood, Peter Georgeson, Ingrid M. Winship, Susan G. Preston, Aung K. Win, Pierre-Antoine Dugué, Harindra Jayasekara, Dallas English, Finlay A. Macrae, John L. Hopper, Mark A. Jenkins, Roger L. Milne, Graham G. Giles, Melissa C. Southey, and Daniel D. Buchanan 2021. "DNA Methylation Signatures and the Contribution of Age-Associated Methylomic Drift to Carcinogenesis in Early-Onset Colorectal Cancer" Cancers 13, no. 11: 2589. https://doi.org/10.3390/cancers13112589

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