Tumor LINE-1 Methylation Level and Microsatellite Instability in Relation to Colorectal Cancer Prognosis

Kentaro Inamura, Mai Yamauchi, Reiko Nishihara, Paul Lochhead, Zhi Rong Qian, Aya Kuchiba, Sun A Kim, Kosuke Mima, Yasutaka Sukawa, Seungyoun Jung, Xuehong Zhang, Kana Wu, Eunyoung Cho, Andrew T Chan, Jeffrey A Meyerhardt, Curtis C Harris, Charles S Fuchs, Shuji Ogino

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Abstract

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) (P interaction < .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) (P interaction = .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.

Original languageEnglish
Article numberdju195
JournalJournal of the National Cancer Institute
Volume106
Issue number9
DOIs
Publication statusPublished - Sep 2014

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    Inamura, K., Yamauchi, M., Nishihara, R., Lochhead, P., Qian, Z. R., Kuchiba, A., Kim, S. A., Mima, K., Sukawa, Y., Jung, S., Zhang, X., Wu, K., Cho, E., Chan, A. T., Meyerhardt, J. A., Harris, C. C., Fuchs, C. S., & 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), [dju195]. https://doi.org/10.1093/jnci/dju195