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Updated: Apr 24, 2026
Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Tumor LINE-1 methylation level and microsatellite instability in relation to colorectal cancer prognosis
Kentaro Inamura1, Mai Yamauchi1, Reiko Nishihara1
1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (KI, MY, RN, PL, ZRQ, AK, SAK, KM, YS, JAM, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI, CCH); Department of Nutrition, Harvard School of Public Health, Boston, MA (RN, AK, KW); Gastrointestinal Research Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK (PL); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA (SJ, XZ, EC, ATC, CSF); Department of Dermatology, The Warren Alpert Medical School of Brown University, Province, RI (EC); Division of Gastroenterology, Massachusetts General Hospital, Boston, MA (ATC); Department of Epidemiology, Harvard School of Public Health, Boston, MA (SO); Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA (SO).
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.
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