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

doi:10.1093/jnci/dju195

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

Department of Nutritional Science & Food Management

Research output: Contribution to journal › Article › peer-review

67 Scopus citations

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 language	English
Journal	Journal of the National Cancer Institute
Volume	106
Issue number	9
DOIs	https://doi.org/10.1093/jnci/dju195
State	Published - 1 Sep 2014

Bibliographical note

Publisher Copyright:
© The Author 2014. Published by Oxford University Press. All rights reserved.

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10.1093/jnci/dju195

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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). https://doi.org/10.1093/jnci/dju195

@article{bb511c7a93534ac4ac4590d905937446,

title = "Tumor LINE-1 methylation level and microsatellite instability in relation to colorectal cancer prognosis",

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) (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.",

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

year = "2014",

month = sep,

day = "1",

doi = "10.1093/jnci/dju195",

language = "English",

volume = "106",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "9",

}

Inamura, K, Yamauchi, M, Nishihara, R, Lochhead, P, Qian, ZR, Kuchiba, A, Kim, SA, Mima, K, Sukawa, Y, Jung, S, Zhang, X, Wu, K, Cho, E, Chan, AT, Meyerhardt, JA, Harris, CC, Fuchs, CS & Ogino, S 2014, 'Tumor LINE-1 methylation level and microsatellite instability in relation to colorectal cancer prognosis', Journal of the National Cancer Institute, vol. 106, no. 9. https://doi.org/10.1093/jnci/dju195

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

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 - https://www.scopus.com/pages/publications/84929455916

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 -

Tumor LINE-1 methylation level and microsatellite instability in relation to colorectal cancer prognosis

Abstract

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