Prospective study of family history and colorectal cancer risk by tumor LINE-1 methylation level

Shuji Ogino, Reiko Nishihara, Paul Lochhead, Yu Imamura, Aya Kuchiba, Teppei Morikawa, Mai Yamauchi, Xiaoyun Liao, Zhi Rong Qian, Ruifang Sun, Kaori Sato, Gregory J Kirkner, Molin Wang, Donna Spiegelman, Jeffrey A Meyerhardt, Eva S Schernhammer, Andrew T Chan, Edward Giovannucci, Charles S Fuchs

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Abstract

BackgroundBeyond known familial colorectal cancer (CRC) syndromes, the mechanisms underlying the elevated CRC risk associated with CRC family history remain largely unknown. A recent retrospective study suggests familial clustering of CRC with hypomethylation in long interspersed nucleotide element 1 (LINE-1). We tested the hypothesis that CRC family history might confer a higher risk of LINE-1 methylation-low CRC.MethodsUsing the Nurses' Health Study and the Health Professionals Follow-up Study, we prospectively examined the association between CRC family history and the risk of rectal and colon cancer (N = 1224) according to tumor LINE-1 methylation level by duplication method Cox proportional hazards regression. We examined microsatellite instability (MSI) status to exclude the influence of Lynch syndrome. All statistical tests were two-sided.ResultsThe association between CRC family history and non-MSI CRC risk differed statistically significantly by LINE-1 methylation level (P (heterogeneity) = .02). CRC family history was associated with a statistically significantly higher risk of LINE-1 methylation-low non-MSI cancer (multivariable hazard ratio [HR] = 1.68, 95% confidence interval [CI] = 1.19 to 2.38 for 1 vs 0 first-degree relatives with CRC; multivariable HR = 3.48, 95% CI = 1.59 to 7.6 for =2 vs 0 first-degree relatives with CRC; P (trend) <.001). In contrast, CRC family history was not statistically significantly associated with LINE-1 methylation-high non-MSI cancer (P (trend) = .35).ConclusionsThis molecular pathological epidemiology study shows that CRC family history is associated with a higher risk of LINE-1 methylation-low CRC, suggesting previously unrecognized heritable predisposition to epigenetic alterations. Additional studies are needed to evaluate tumor LINE-1 methylation as a molecular biomarker for familial cancer risk assessment.
Original languageEnglish
Pages (from-to)130-140
Number of pages11
JournalJournal of the National Cancer Institute
Volume105
Issue number2
Early online date21 Nov 2012
DOIs
Publication statusPublished - 16 Jan 2013

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Long Interspersed Nucleotide Elements
Methylation
Colorectal Neoplasms
Prospective Studies
Neoplasms
Confidence Intervals
Hereditary Nonpolyposis Colorectal Neoplasms
Microsatellite Instability
Molecular Epidemiology

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Ogino, S., Nishihara, R., Lochhead, P., Imamura, Y., Kuchiba, A., Morikawa, T., ... Fuchs, C. S. (2013). Prospective study of family history and colorectal cancer risk by tumor LINE-1 methylation level. Journal of the National Cancer Institute, 105(2), 130-140. https://doi.org/10.1093/jnci/djs482

Prospective study of family history and colorectal cancer risk by tumor LINE-1 methylation level. / Ogino, Shuji; Nishihara, Reiko; Lochhead, Paul; Imamura, Yu; Kuchiba, Aya; Morikawa, Teppei; Yamauchi, Mai; Liao, Xiaoyun; Qian, Zhi Rong; Sun, Ruifang; Sato, Kaori; Kirkner, Gregory J; Wang, Molin; Spiegelman, Donna; Meyerhardt, Jeffrey A; Schernhammer, Eva S; Chan, Andrew T; Giovannucci, Edward; Fuchs, Charles S.

In: Journal of the National Cancer Institute, Vol. 105, No. 2, 16.01.2013, p. 130-140.

Research output: Contribution to journalArticle

Ogino, S, Nishihara, R, Lochhead, P, Imamura, Y, Kuchiba, A, Morikawa, T, Yamauchi, M, Liao, X, Qian, ZR, Sun, R, Sato, K, Kirkner, GJ, Wang, M, Spiegelman, D, Meyerhardt, JA, Schernhammer, ES, Chan, AT, Giovannucci, E & Fuchs, CS 2013, 'Prospective study of family history and colorectal cancer risk by tumor LINE-1 methylation level', Journal of the National Cancer Institute, vol. 105, no. 2, pp. 130-140. https://doi.org/10.1093/jnci/djs482
Ogino, Shuji ; Nishihara, Reiko ; Lochhead, Paul ; Imamura, Yu ; Kuchiba, Aya ; Morikawa, Teppei ; Yamauchi, Mai ; Liao, Xiaoyun ; Qian, Zhi Rong ; Sun, Ruifang ; Sato, Kaori ; Kirkner, Gregory J ; Wang, Molin ; Spiegelman, Donna ; Meyerhardt, Jeffrey A ; Schernhammer, Eva S ; Chan, Andrew T ; Giovannucci, Edward ; Fuchs, Charles S. / Prospective study of family history and colorectal cancer risk by tumor LINE-1 methylation level. In: Journal of the National Cancer Institute. 2013 ; Vol. 105, No. 2. pp. 130-140.
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title = "Prospective study of family history and colorectal cancer risk by tumor LINE-1 methylation level",
abstract = "BackgroundBeyond known familial colorectal cancer (CRC) syndromes, the mechanisms underlying the elevated CRC risk associated with CRC family history remain largely unknown. A recent retrospective study suggests familial clustering of CRC with hypomethylation in long interspersed nucleotide element 1 (LINE-1). We tested the hypothesis that CRC family history might confer a higher risk of LINE-1 methylation-low CRC.MethodsUsing the Nurses' Health Study and the Health Professionals Follow-up Study, we prospectively examined the association between CRC family history and the risk of rectal and colon cancer (N = 1224) according to tumor LINE-1 methylation level by duplication method Cox proportional hazards regression. We examined microsatellite instability (MSI) status to exclude the influence of Lynch syndrome. All statistical tests were two-sided.ResultsThe association between CRC family history and non-MSI CRC risk differed statistically significantly by LINE-1 methylation level (P (heterogeneity) = .02). CRC family history was associated with a statistically significantly higher risk of LINE-1 methylation-low non-MSI cancer (multivariable hazard ratio [HR] = 1.68, 95{\%} confidence interval [CI] = 1.19 to 2.38 for 1 vs 0 first-degree relatives with CRC; multivariable HR = 3.48, 95{\%} CI = 1.59 to 7.6 for =2 vs 0 first-degree relatives with CRC; P (trend) <.001). In contrast, CRC family history was not statistically significantly associated with LINE-1 methylation-high non-MSI cancer (P (trend) = .35).ConclusionsThis molecular pathological epidemiology study shows that CRC family history is associated with a higher risk of LINE-1 methylation-low CRC, suggesting previously unrecognized heritable predisposition to epigenetic alterations. Additional studies are needed to evaluate tumor LINE-1 methylation as a molecular biomarker for familial cancer risk assessment.",
author = "Shuji Ogino and Reiko Nishihara and Paul Lochhead and Yu Imamura and Aya Kuchiba and Teppei Morikawa and Mai Yamauchi and Xiaoyun Liao and Qian, {Zhi Rong} and Ruifang Sun and Kaori Sato and Kirkner, {Gregory J} and Molin Wang and Donna Spiegelman and Meyerhardt, {Jeffrey A} and Schernhammer, {Eva S} and Chan, {Andrew T} and Edward Giovannucci and Fuchs, {Charles S}",
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T1 - Prospective study of family history and colorectal cancer risk by tumor LINE-1 methylation level

AU - Ogino, Shuji

AU - Nishihara, Reiko

AU - Lochhead, Paul

AU - Imamura, Yu

AU - Kuchiba, Aya

AU - Morikawa, Teppei

AU - Yamauchi, Mai

AU - Liao, Xiaoyun

AU - Qian, Zhi Rong

AU - Sun, Ruifang

AU - Sato, Kaori

AU - Kirkner, Gregory J

AU - Wang, Molin

AU - Spiegelman, Donna

AU - Meyerhardt, Jeffrey A

AU - Schernhammer, Eva S

AU - Chan, Andrew T

AU - Giovannucci, Edward

AU - Fuchs, Charles S

PY - 2013/1/16

Y1 - 2013/1/16

N2 - BackgroundBeyond known familial colorectal cancer (CRC) syndromes, the mechanisms underlying the elevated CRC risk associated with CRC family history remain largely unknown. A recent retrospective study suggests familial clustering of CRC with hypomethylation in long interspersed nucleotide element 1 (LINE-1). We tested the hypothesis that CRC family history might confer a higher risk of LINE-1 methylation-low CRC.MethodsUsing the Nurses' Health Study and the Health Professionals Follow-up Study, we prospectively examined the association between CRC family history and the risk of rectal and colon cancer (N = 1224) according to tumor LINE-1 methylation level by duplication method Cox proportional hazards regression. We examined microsatellite instability (MSI) status to exclude the influence of Lynch syndrome. All statistical tests were two-sided.ResultsThe association between CRC family history and non-MSI CRC risk differed statistically significantly by LINE-1 methylation level (P (heterogeneity) = .02). CRC family history was associated with a statistically significantly higher risk of LINE-1 methylation-low non-MSI cancer (multivariable hazard ratio [HR] = 1.68, 95% confidence interval [CI] = 1.19 to 2.38 for 1 vs 0 first-degree relatives with CRC; multivariable HR = 3.48, 95% CI = 1.59 to 7.6 for =2 vs 0 first-degree relatives with CRC; P (trend) <.001). In contrast, CRC family history was not statistically significantly associated with LINE-1 methylation-high non-MSI cancer (P (trend) = .35).ConclusionsThis molecular pathological epidemiology study shows that CRC family history is associated with a higher risk of LINE-1 methylation-low CRC, suggesting previously unrecognized heritable predisposition to epigenetic alterations. Additional studies are needed to evaluate tumor LINE-1 methylation as a molecular biomarker for familial cancer risk assessment.

AB - BackgroundBeyond known familial colorectal cancer (CRC) syndromes, the mechanisms underlying the elevated CRC risk associated with CRC family history remain largely unknown. A recent retrospective study suggests familial clustering of CRC with hypomethylation in long interspersed nucleotide element 1 (LINE-1). We tested the hypothesis that CRC family history might confer a higher risk of LINE-1 methylation-low CRC.MethodsUsing the Nurses' Health Study and the Health Professionals Follow-up Study, we prospectively examined the association between CRC family history and the risk of rectal and colon cancer (N = 1224) according to tumor LINE-1 methylation level by duplication method Cox proportional hazards regression. We examined microsatellite instability (MSI) status to exclude the influence of Lynch syndrome. All statistical tests were two-sided.ResultsThe association between CRC family history and non-MSI CRC risk differed statistically significantly by LINE-1 methylation level (P (heterogeneity) = .02). CRC family history was associated with a statistically significantly higher risk of LINE-1 methylation-low non-MSI cancer (multivariable hazard ratio [HR] = 1.68, 95% confidence interval [CI] = 1.19 to 2.38 for 1 vs 0 first-degree relatives with CRC; multivariable HR = 3.48, 95% CI = 1.59 to 7.6 for =2 vs 0 first-degree relatives with CRC; P (trend) <.001). In contrast, CRC family history was not statistically significantly associated with LINE-1 methylation-high non-MSI cancer (P (trend) = .35).ConclusionsThis molecular pathological epidemiology study shows that CRC family history is associated with a higher risk of LINE-1 methylation-low CRC, suggesting previously unrecognized heritable predisposition to epigenetic alterations. Additional studies are needed to evaluate tumor LINE-1 methylation as a molecular biomarker for familial cancer risk assessment.

U2 - 10.1093/jnci/djs482

DO - 10.1093/jnci/djs482

M3 - Article

C2 - 23175808

VL - 105

SP - 130

EP - 140

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 2

ER -