Journal article

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

Jihoon E Joo, Mark Clendenning, Ee Ming Wong, Christophe Rosty, Khalid Mahmood, Peter Georgeson, Ingrid M Winship, Susan G Preston, Aung Ko Win, Pierre-Antoine Dugue, Harindra Jayasekara, Dallas English, Finlay A Macrae, John L Hopper, Mark A Jenkins, Roger L Milne, Graham G Giles, Melissa C Southey, Daniel D Buchanan

CANCERS | MDPI | Published : 2021

Abstract

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 gr..

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Grants

Awarded by Australian National Health, and Medical Research Council


Awarded by National Cancer Institute of the National Institutes of Health


Awarded by Australasian Colorectal Cancer Family Registry


Awarded by CCFR


Funding Acknowledgements

Melbourne Collaborative Cohort Study (MCCS) cohort recruitment was funded by VicHealth and Cancer Council Victoria. TheMCCS was further augmented by Australian National Health, and Medical Research Council grants 209057, 396414, and 1074383 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health andWelfare, including the National Death Index and the Australian Cancer Database (ACD). New SouthWales (NSW) cancer registry data were obtained via the ACD with the assistance of the NSWMinistry of Health. The Colon Cancer Family Registry (CCFR) was supported by the National Cancer Institute of the National Institutes of Health under Award Number U01CA167551 and through a cooperative agreementwith theAustralasian Colorectal Cancer Family Registry (NCI/NIH U01 CA074778 and U01/U24 CA097735) and by the Victorian Cancer Registry, Australia. This research was performed under CCFR approved project C-AU-0312-01. DDB is supported by an NHMRC R.D. Wright Career Development Fellowship, an NHMRC Emerging Leadership Investigator grant, and by funding fromthe University ofMelbourne Research atMelbourne Accelerator Program(R@MAP).P.G.is supported by an Australian Government Research Training Program Scholarship. A.K.W. is an NHMRC Career Development Fellow. J.L.H. is an NHMRC Senior Principal Research Fellow. M.A.J. is an NHMRC Senior Research Fellow.