Journal of the National Cancer Institute Advance Access published online on November 25, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn359
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© The Author 2008. Published by Oxford University Press.
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A Cohort Study of Tumoral LINE-1 Hypomethylation and Prognosis in Colon Cancer
Affiliations of authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA (SO, KN, TK, CSF); Department of Pathology (SO), Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (GJK, ATC, ESS, ELG, CSF); Department of Epidemiology, Harvard School of Public Health, Boston, MA (SO, ESS, ELG); Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA (ATC); Ludwig Boltzmann-Institute for Applied Cancer Research, Vienna, Austria (ESS)
Correspondence to: Shuji Ogino, MD, PhD, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 44 Binney St, Rm JF-215C, Boston, MA 02115 (e-mail: shuji_ogino{at}dfci.harvard.edu).
Genome-wide DNA hypomethylation plays has an important role in genomic instability and colorectal carcinogenesis. However, the relationship between cellular DNA methylation level and patient outcome remains uncertain. Using 643 colon cancers in two independent prospective cohorts, we quantified DNA methylation in repetitive long interspersed nucleotide element-1 (LINE-1) elements using pyrosequencing, which is a good indicator of global DNA methylation level. We used Cox proportional hazard models to calculate hazard ratios (HRs) of colon cancer–specific and overall mortality, adjusting for patient and tumoral features, including CpG island methylator phenotype (CIMP). Statistical tests were two-sided. LINE-1 hypomethylation was linearly associated with a statistically significant increase in colon cancer–specific mortality (for a 30% decrease in LINE-1 methylation: multivariable HR = 2.37, 95% confidence interval [CI] = 1.42 to 3.94; Ptrend < .001) and overall mortality (multivariable HR = 1.85, 95% CI = 1.25 to 2.75; Ptrend = .002). The association was consistent across the two independent cohorts and strata of clinical and molecular characteristics, including sex, age, tumor location, stage, and CIMP, microsatellite instability, KRAS, BRAF, p53, and chromosomal instability status. In conclusion, tumoral LINE-1 hypomethylation is independently associated with shorter survival among colon cancer patients.
| CONTEXT AND CAVEATS Prior knowledge DNA hypomethylation is involved in genomic instability and colorectal carcinogenesis, but whether it is associated with the survival of colon cancer patients is unknown. Study design Prospective study of two colon cancer patient populations to evaluate the association between DNA methylation, which was assayed in long interspersed nucleotide element-1 (LINE-1), and survival. Clinical and molecular characteristics of the tumors were included in the analyses. Contribution LINE-1 hypomethylation was associated with higher colon cancer–specific and overall mortality, independent of other tumor characteristics. Implications LINE-1 hypomethylation may be a prognostic indicator of patient survival in colon cancer. Limitations Treatment data were limited for the patients studied. The patients were all health care professionals, and it is unknown whether the findings are applicable to the general population. The mechanism involved is unknown. From the Editors
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Manuscript received April 22, 2008; revised August 29, 2008; accepted September 4, 2008.
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J Natl Cancer Inst 2008 100: 1657.
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