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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Long Interspersed Nucleotide Elements
Microsatellite Instability
Methylation
Colorectal Neoplasms
Neoplasms
Microsatellite Repeats
Confidence Intervals
Survival
Mortality
N-methylsuccinimide
CpG Islands
Health
Chi-Square Distribution
Proportional Hazards Models

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Inamura, K., Yamauchi, M., Nishihara, R., Lochhead, P., Qian, Z. R., Kuchiba, A., ... 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

Tumor LINE-1 Methylation Level and Microsatellite Instability in Relation to Colorectal Cancer Prognosis. / Inamura, Kentaro; Yamauchi, Mai; Nishihara, Reiko; Lochhead, Paul; Qian, Zhi Rong; Kuchiba, Aya; Kim, Sun A; Mima, Kosuke; Sukawa, Yasutaka; Jung, Seungyoun; Zhang, Xuehong; Wu, Kana; Cho, Eunyoung; Chan, Andrew T; Meyerhardt, Jeffrey A; Harris, Curtis C; Fuchs, Charles S; Ogino, Shuji.

In: Journal of the National Cancer Institute, Vol. 106, No. 9, dju195, 09.2014.

Research output: Contribution to journalArticle

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, dju195. https://doi.org/10.1093/jnci/dju195
Inamura, Kentaro ; Yamauchi, Mai ; Nishihara, Reiko ; Lochhead, Paul ; Qian, Zhi Rong ; Kuchiba, Aya ; Kim, Sun A ; Mima, Kosuke ; Sukawa, Yasutaka ; Jung, Seungyoun ; Zhang, Xuehong ; Wu, Kana ; Cho, Eunyoung ; Chan, Andrew T ; Meyerhardt, Jeffrey A ; Harris, Curtis C ; Fuchs, Charles S ; Ogino, Shuji. / Tumor LINE-1 Methylation Level and Microsatellite Instability in Relation to Colorectal Cancer Prognosis. In: Journal of the National Cancer Institute. 2014 ; Vol. 106, No. 9.
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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) (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.",
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",
note = "{\circledC} The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. Affiliations of Authors - Department 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).",
year = "2014",
month = "9",
doi = "10.1093/jnci/dju195",
language = "English",
volume = "106",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
publisher = "Oxford University Press",
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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 - © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. Affiliations of Authors - Department 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).

PY - 2014/9

Y1 - 2014/9

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) (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.

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) (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.

U2 - 10.1093/jnci/dju195

DO - 10.1093/jnci/dju195

M3 - Article

C2 - 25190725

VL - 106

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 9

M1 - dju195

ER -