title: Early life exposure to famine and colorectal cancer risk: a role for epigenetic mechanisms.
abstract: BACKGROUND
  Exposure to energy restriction during childhood and adolescence is associated with a lower risk of developing colorectal cancer (CRC). Epigenetic dysregulation during this critical period of growth and development may be a mechanism to explain such observations. Within the Netherlands Cohort Study on diet and cancer, we investigated the association between early life energy restriction and risk of subsequent CRC characterized by the (promoter) CpG island methylation phenotype (CIMP).
  
  
  RESULTS
  Information on diet and risk factors was collected by baseline questionnaire (n = 120,856). Three indicators of exposure were assessed: place of residence during the Hunger Winter (1944-45) and World War II years (1940-44), and father's employment status during the Economic Depression (1932-40). Methylation specific PCR (MSP) on DNA from paraffin embedded tumor tissue was performed to determine CIMP status according to the Weisenberger markers. After 7.3 years of follow-up, 603 cases and 4631 sub-cohort members were available for analysis. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals for CIMP+ (27.7%) and CIMP- (72.3%) tumors according to the three time periods of energy restriction, adjusted for age and gender. Individuals exposed to severe famine during the Hunger Winter had a decreased risk of developing a tumor characterized by CIMP compared to those not exposed (HR 0.65, 95%CI: 0.45-0.92). Further categorizing individuals by an index of '0-1' '2-3' or '4-7' genes methylated in the promoter region suggested that exposure to the Hunger Winter was associated with the degree of promoter hypermethylation ('0-1 genes methylated' HR = 1.01, 95%CI:0.74-1.37; '2-3 genes methylated' HR = 0.83, 95% CI:0.61-1.15; '4-7 genes methylated' HR = 0.72, 95% CI:0.49-1.04). No associations were observed with respect to the Economic Depression and WWII years.
  
  
  CONCLUSIONS
  This is the first study indicating that exposure to a severe, transient environmental condition during adolescence and young adulthood may result in persistent epigenetic changes that later influence CRC development.
authors: Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Laura A E
authors: LA
authors: Hughes
authors: Piet A
authors: PA
authors: van den Brandt
authors: Adriaan P
authors: AP
authors: de Bruïne
authors: Kim A D
authors: KA
authors: Wouters
authors: Sarah
authors: S
authors: Hulsmans
authors: Angela
authors: A
authors: Spiertz
authors: R Alexandra
authors: RA
authors: Goldbohm
authors: Anton F P M
authors: AF
authors: de Goeij
authors: James G
authors: JG
authors: Herman
authors: Matty P
authors: MP
authors: Weijenberg
authors: Manon
authors: M
authors: van Engeland
mesh_terms: D000293:Adolescent; D000368:Aged; D002648:Child; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000235:genetics*; D018899:CpG Islands; D004032:Diet; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D013217:Starvation / Q000235:genetics*