Ogino, ShujiNishihara, ReikoLochhead, PaulImamura, YuKuchiba, AyaMorikawa, TeppeiYamauchi, MaiLiao, XiaoyunQian, Zhi RongSun, RuifangSato, KaoriKirkner, Gregory J.Wang, MolinSpiegelman, DonnaMeyerhardt, Jeffrey A.Schernhammer, Eva S.Chan, Andrew T.Giovannucci, EdwardFuchs, Charles S.2019-09-212013Ogino, Shuji, Reiko Nishihara, Paul Lochhead, Yu Imamura, Aya Kuchiba, Teppei Morikawa, Mai Yamauchi, et al. 2012. “Prospective Study of Family History and Colorectal Cancer Risk by Tumor LINE-1 Methylation Level.” JNCI: Journal of the National Cancer Institute 105 (2): 130–40. https://doi.org/10.1093/jnci/djs482.0027-88740198-01571460-2105http://nrs.harvard.edu/urn-3:HUL.InstRepos:41384695Background: Beyond 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. Methods: Using 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. Results: The 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). CONCLUSIONS: This 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. J Natl Cancer Inst 2013;105:130-140en-USJournal Article2019-09-2110.1093/jnci/djs482