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

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)

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

Fingerprint

Dive into the research topics of 'Prospective study of family history and colorectal cancer risk by tumor LINE-1 methylation level'. Together they form a unique fingerprint.

Cite this