期刊
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
卷 105, 期 2, 页码 130-140出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/jnci/djs482
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资金
- National Institute of Health [P01 CA87969, P01 CA55075, P50 CA127003, R01 CA151993, R01 CA137178]
- Bennett Family Fund for Targeted Therapies Research
- National Colorectal Cancer Research Alliance
- Harvard University Knox Memorial Fellowship
- Chief Scientist Office [CAF/10/15] Funding Source: researchfish
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. J Natl Cancer Inst 2013;105:130-140
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