TY - JOUR
T1 - Tumor LINE-1 methylation level and microsatellite instability in relation to colorectal cancer prognosis
AU - Inamura, Kentaro
AU - Yamauchi, Mai
AU - Nishihara, Reiko
AU - Lochhead, Paul
AU - Qian, Zhi Rong
AU - Kuchiba, Aya
AU - Kim, Sun A.
AU - Mima, Kosuke
AU - Sukawa, Yasutaka
AU - Jung, Seungyoun
AU - Zhang, Xuehong
AU - Wu, Kana
AU - Cho, Eunyoung
AU - Chan, Andrew T.
AU - Meyerhardt, Jeffrey A.
AU - Harris, Curtis C.
AU - Fuchs, Charles S.
AU - Ogino, Shuji
N1 - Publisher Copyright:
© The Author 2014. Published by Oxford University Press. All rights reserved.
PY - 2014/9/1
Y1 - 2014/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84929455916&partnerID=8YFLogxK
U2 - 10.1093/jnci/dju195
DO - 10.1093/jnci/dju195
M3 - Article
C2 - 25190725
AN - SCOPUS:84929455916
SN - 0027-8874
VL - 106
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 9
ER -