Whole blood DNA methylation aging markers predict colorectal cancer survival: a prospective cohort study
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RESEARCH
Whole blood DNA methylation aging markers predict colorectal cancer survival: a prospective cohort study Xīn Gào1* , Yan Zhang1,5, Daniel Boakye1, Xiangwei Li1,3, Jenny Chang‑Claude2, Michael Hoffmeister1 and Hermann Brenner1,4,5
Abstract Background: Blood DNA methylation-based aging algorithms predict mortality in the general population. We inves‑ tigated the prognostic value of five established DNA methylation aging algorithms for patients with colorectal cancer (CRC). Methods: AgeAccelHorvath, AgeAccelHannum, DNAmMRscore, AgeAccelPheno and AgeAccelGrim were con‑ structed using whole blood epi-genomic data from 2206 CRC patients. After a median follow-up of 6.2 years, 1079 deaths were documented, including 596 from CRC. Associations of the aging algorithms with survival outcomes were evaluated using the Cox regression and survival curves. Harrell’s C-statistics were computed to investigate predictive performance. Results: Adjusted hazard ratios (95% confidence intervals) of all-cause mortality for patients in the third compared to the first tertile were 1.66 (1.32, 2.09) for the DNAmMRscore, 1.35 (1.14, 1.59) for AgeAccelPheno and 1.65 (1.37, 2.00) for AgeAccelGrim, even after adjustment for age, sex and stage. AgeAccelHorvath and AgeAccelHannum were not associated with all-cause or CRC-specific mortality. In stage-specific analyses, associations were much stronger for patients with early or intermediate stage cancers (stages I, II and III) than for patients with metastatic (stage IV) can‑ cers. Associations were weaker and less often statistically significant for CRC-specific mortality. Adding DNAmMRscore, AgeAccelPheno or AgeAccelGrim to models including age, sex and tumor stage improved predictive performance moderately. Conclusions: DNAmMRscore, AgeAccelPheno and AgeAccelGrim could serve as non-invasive CRC prognostic biomarkers independent of other commonly used markers. Further research should aim for tailoring and refining such algorithms for CRC patients and to explore their value for enhanced prediction of treatment success and treatment decisions. Keywords: DNA methylation, Aging, Whole blood, Colorectal cancer, Prognosis, Mortality
*Correspondence: [email protected] 1 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany Full list of author information is available at the end of the article
Introduction Colorectal cancer (CRC) is one of the leading causes of cancer death, accounting for approximately 9% of the total cancer deaths globally [1]. While declines in CRC mortality rates occurred in Western countries in recent years, CRC mortality rates continue to increase in many middle- and low-income countries [2]. Besides enhanced early detection, enhanced prediction of patients’
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