LINE-1 Extreme Hypomethylator Is a New Distinct Molecular Subtype Associated with Young Age and Poor Prognosis: Bioinformatic Analysis of 1190 Colorectal Cancers.
Shuji Ogino, Charles Fuchs, Curtis Huttenhower. Brigham and Women's Hospital, Boston, MA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Harvard School of Public Health, Boston, MA
Background: Global DNA hypomethylation plays a role in carcinogenesis. LINE-1 constitutes 15-25% of the human genome, and its methylation level correlates with global DNA methylation status. LINE-1 hypomethylation in colon cancer is strongly associated with poor prognosis. However, whether there is a distinct group of LINE-1 hypomethylators remains uncertain.
Design: Utilizing a database of 1190 colorectal cancers with clinical, pathologic and molecular annotations, we quantified LINE-1 methylation by Pyrosequencing. We conducted multivariate linear regression analysis for LINE-1 methylation, using age, sex, body mass index, family history of cancer, smoking status, tumor location, TNM stage, pathologic features, the CpG island methylator phenotype (CIMP), MSI, KRAS, BRAF, and PIK3CA mutations.
Results: Tumor LINE-1 methylation levels ranged from 23.1-90.3 of 0-100 scale (mean 61.4; median 62.3; SD 9.6), and distributed normally, except for extreme hypomethylators [LINE-1 methylation <40; N=27 (2.3%), which were far more than what could be expected by normal distribution]. LINE-1 extreme hypomethylators were significantly associated with young age of onset (p=0.0017), left colon location (p=0.0068), and CIMP-negative (p=0.0067). Residual plot by multivariate linear regression showed that the residuals of the LINE-1 extreme hypomethylators clustered as a distinct group, separate from the main tumor group.
In survival analyses, LINE-1 extreme hypomethylators showed aggressive tumor behavior (multivariate mortality hazard ratio=3.29; 95% CI, 1.62-6.68; p=0.0010; log-rank p=0.0002).
Conclusions: LINE-1 extreme hypomethylators constitute a previously unrecognized subtype of colorectal cancers with young age of onset and aggressive tumor behavior.
Monday, February 28, 2011 11:15 AM
Platform Session: Section E, Monday Morning