LINE-1 Hypomethylation Associated With Poorer Survival in Microsatellite Instability–High vs Microsatellite-Stable Tumors in Colorectal Cancer
In a study reported in the Journal of the National Cancer Institute, Inamura et al found that hypomethylation in long interspersed nucleotide element-1 (LINE-1) is associated with greater colorectal cancer–specific and overall mortality in high-degree microsatellite instability vs microsatellite-stable colorectal cancer.
Study Details
The study involved analysis of colorectal cancer–specific survival in 1,211 cases of colorectal cancer in the Nurses’ Health Study and the Health Professionals Follow-up Study according to LINE-1 hypomethylation status and microsatellite instability status. There were 190 microsatellite instability–high colorectal cancers and 1,021 microsatellite-stable colorectal cancers.
A Cox proportional hazards model was used to compute multivariate colorectal cancer–specific mortality hazard ratios (HRs) for a 10% decrease in LINE-1 methylation level, adjusting for sex, age at diagnosis, year of diagnosis, family history of colorectal cancer, tumor location, tumor differentiation, CpG island methylator phenotype, and KRAS, BRAF, and PIK3CA mutations.
Effect on Colorectal Cancer–Specific Mortality
On multivariate analysis, LINE-1 hypomethylation (10% decrease as a unit) was associated with greater colorectal cancer–specific mortality among all patients (HR = 1.16, P = .02). The association of LINE-1 hypomethylation with higher mortality in microsatellite instability–high cancers (HR = 2.45, P < .001) was stronger than that in microsatellite-stable cancers (HR = 1.10, P = .11; P < .001 for interaction). In microsatellite instability–high cases, the association of LINE-1 hypomethylation with higher mortality in cases with family history of colorectal cancer (HR = 5.13, P < .001) was stronger than that in microsatellite instability–high cases without family history (HR = 1.62, P = .11; P = .02 for interaction).
Overall Mortality
The difference in overall survival according to LINE-1 hypomethylation and microsatellite instability status was significant but not as great as that in colorectal cancer–specific mortality. On multivariate analysis, LINE-1 hypomethylation was associated with nonsignificantly increased overall mortality in all patients (HR = 1.06, P = .18) and in microsatellite-stable cases (HR = 1.02, P = .64) as well as a significant increase in microsatellite instability–high cases (HR = 1.42, P = .004; P = .02 for interaction).
The investigators concluded: “The association of LINE-1 hypomethylation with inferior survival is stronger in [microsatellite instability–high colorectal cancers] than in [microsatellite-stable colorectal cancers]. Tumor LINE-1 methylation level may be a useful prognostic biomarker to identify aggressive carcinomas among [microsatellite instability–high colorectal cancers].”
Shuji Ogino, MD, PhD, of the Dana-Farber Cancer Institute, is the corresponding author for the Journal of the National Cancer Institute article.
The study was supported by the National Institutes of Health and National Colorectal Cancer Research Alliance. Andrew T. Chan, MD, previously served as a consultant for Bayer Healthcare, Millennium Pharmaceuticals, Pozen Inc, and Pfizer Inc.
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