Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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

BACKGROUND: 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.[1]

References

Prospective study of family history and colorectal cancer risk by tumor LINE-1 methylation level. Ogino, S., Nishihara, R., Lochhead, P., Imamura, Y., Kuchiba, A., Morikawa, T., Yamauchi, M., Liao, X., Qian, Z.R., Sun, R., Sato, K., Kirkner, G.J., Wang, M., Spiegelman, D., Meyerhardt, J.A., Schernhammer, E.S., Chan, A.T., Giovannucci, E., Fuchs, C.S. J. Natl. Cancer Inst. (2013) [Pubmed]

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