LINE-1 Hypomethylation and Patient Prognosis in 1253 Colorectal Cancers
Shuji Ogino, Yu Imamura, Charles Fuchs. Brigham and Women's Hospital, Boston, MA; Dana-Farber Cancer Institute, Boston, MA
Background: Long interspersed nucleotide element-1 (LINE-1) repetitive elements occupy ∼17% of nucleotides in the human genome. LINE-1 hypomethylation has been associated with global DNA hypomethylation, chromosomal instability, and carcinogenesis. We hypothesized that LINE-1 hypomethylation in colorectal cancer might predict aggressive tumor behavior.
Design: We quantified LINE-1 methylation by PCR-pyrosequencing in 1253 colorectal cancers. Kaplan-Meier method and Cox proportional hazards model were used to assess mortalities, according to LINE-1 methylation level. Multivariate analysis was adjusted for potential confounders including stage and status of MSI, KRAS and BRAF.
Results: LINE-1 hypomethylation in 978 colon cancers was associated with low colon cancer-specific and overall survival in Kaplan-Meier analyses.
In multivariate Cox regression analyses, LINE-1 hypomethylation in colon cancer was independently and linearly associated with an increase in colon cancer-specific and overall mortality.
|LINE-1 methylation level||N||Multivariate HR for cancer-specific mortality (95% CI)||Multivariate HR for overall mortality (95% CI)|
|>=75%||84||1 (reference)||1 (reference)|
|60%-75%||546||1.42 (0.81-2.48)||1.46 (0.98-2.20)|
|45%-60%||309||1.85 (1.04-3.31)||1.61 (1.05-2.46)|
|<45%||39||3.85 (1.86-7.96)||2.81 (1.59-4.98)|
|P value for trend||0.001||0.018|