Tumor LINE-1 methylation level and microsatellite instability in relation to colorectal cancer prognosis
Journal of the National Cancer Institute
© The Author 2014. Published by Oxford University Press. All rights reserved. Background: Hypomethylation in long interspersed nucleotide element-1 (LINE-1) and high-degree microsatellite instability (MSI-high) in colorectal cancer (CRC) have been associated with inferior and superior survival, respectively; however, it remains uncertain whether the prognostic association of LINE-1 hypomethylation differs by MSI status. We hypothesized that the adverse prognostic association of LINE-1 hypomethylation might be stronger in MSI-high CRCs than in microsatellite stable (MSS) CRCs.Methods: Utilizing 1211 CRCs in the Nurses' Health Study and the Health Professionals Follow-up Study, we examined patient survival according to LINE-1 hypomethylation status in strata of MSI status. A Cox proportional hazards model was used to compute multivariable CRC-specific mortality hazard ratios (HRs) for a 10% decrease in LINE-1 methylation level (range = 23.1-93.1%), adjusting for potential confounders, including CpG island methylator phenotype, and KRAS, BRAF, and PIK3CA mutations. Statistical tests (log-rank test, chi-square test, and likelihood ratio test) were two-sided.Results: In MSI-high cancers, the association of LINE-1 hypomethylation with higher mortality (HR = 2.45, 95% confidence interval [CI] = 1.64 to 3.66, P <.001) was stronger than that in MSS cancers (HR = 1.10, 95% CI = 0.98 to 1.24, P =.11) (Pinteraction <.001, between LINE-1 and MSI statuses). In MSI-high cases with CRC family history, the association of LINE-1 hypomethylation with higher mortality (HR = 5.13, 95% CI = 1.99 to 13.2; P <.001) was stronger than that in MSI-high cases without CRC family history (HR = 1.62, 95% CI = 0.89 to 2.94, P =.11) (Pinteraction =.02, between LINE-1 and CRC family history statuses).Conclusions: The association of LINE-1 hypomethylation with inferior survival is stronger in MSI-high CRCs than in MSS CRCs. Tumor LINE-1 methylation level may be a useful prognostic biomarker to identify aggressive carcinomas among MSI-high CRCs.
Inamura, K., Yamauchi, M., Nishihara, R., Lochhead, P., Qian, Z., Kuchiba, A., Kim, S., Mima, K., Sukawa, Y., Jung, S., Zhang, X., Wu, K., Cho, E., Chan, A., Meyerhardt, J., Harris, C., Fuchs, C., & Ogino, S. (2014). Tumor LINE-1 methylation level and microsatellite instability in relation to colorectal cancer prognosis. Journal of the National Cancer Institute, 106 (9). http://dx.doi.org/10.1093/jnci/dju195