[702] 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 and Colon Cancer Mortality
LINE-1 methylation levelNMultivariate HR for cancer-specific mortality (95% CI)Multivariate HR for overall mortality (95% CI)
>=75%841 (reference)1 (reference)
60%-75%5461.42 (0.81-2.48)1.46 (0.98-2.20)
45%-60%3091.85 (1.04-3.31)1.61 (1.05-2.46)
<45%393.85 (1.86-7.96)2.81 (1.59-4.98)
P value for trend 0.0010.018
CI, confidential interval; HR, hazard ratio. P for trend was calculated using raw LINE-1 methylation value in each tumor to assess significance of the linear relationship with mortality.

In contrast, LINE-1 hypomethylation was not significantly associated with prognosis in 275 rectal cancers (P = 0.48).
Conclusions: Tumor LINE-1 hypomethylation is associated with poor prognosis in colon cancer (independent of stage and other molecular factors examined), but not in rectal cancer. Our findings support tumor LINE-1 methylation as a prognostic biomarker in colon cancer.
Category: Gastrointestinal

Monday, March 4, 2013 1:00 PM

Poster Session II # 133, Monday Afternoon


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