title: Prospective study of family history and colorectal cancer risk by tumor LINE-1 methylation level.
abstract: 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.
authors.affiliation: Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 450 Brookline Ave, Rm JF-215C, Boston, MA 02215, USA. shuji_ogino@dfci.harvard.edu
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.forename: Reiko
authors.initials: R
authors.lastname: Nishihara
authors.forename: Paul
authors.initials: P
authors.lastname: Lochhead
authors.forename: Yu
authors.initials: Y
authors.lastname: Imamura
authors.forename: Aya
authors.initials: A
authors.lastname: Kuchiba
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.forename: Mai
authors.initials: M
authors.lastname: Yamauchi
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Liao
authors.forename: Zhi Rong
authors.initials: ZR
authors.lastname: Qian
authors.forename: Ruifang
authors.initials: R
authors.lastname: Sun
authors.forename: Kaori
authors.initials: K
authors.lastname: Sato
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kirkner
authors.forename: Molin
authors.initials: M
authors.lastname: Wang
authors.forename: Donna
authors.initials: D
authors.lastname: Spiegelman
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.forename: Eva S
authors.initials: ES
authors.lastname: Schernhammer
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
mesh_terms: D000328:Adult; D015179:Colorectal Neoplasms / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008297:Male; D008487:Medical History Taking; D053842:Microsatellite Instability; D008875:Middle Aged; D016017:Odds Ratio; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors