title: Modulation of age- and cancer-associated DNA methylation change in the healthy colon by aspirin and lifestyle.
abstract: BACKGROUND
  Aberrant DNA methylation in gene promoters is associated with aging and cancer, but the circumstances determining methylation change are unknown. We investigated the impact of lifestyle modulators of colorectal cancer (CRC) risk on the stability of gene promoter methylation in the colonic mucosa.
  
  
  METHODS
  We measured genome-wide promoter CpG methylation in normal colon biopsies (n = 1092) from a female screening cohort, investigated the interaction of lifestyle factors with age-dependent increase in methylation with log-linear multivariable regression, and related their modifying effect to hypermethylation in CRC. All statistical tests were two-sided.
  
  
  RESULTS
  Of 20025 promoter-associated CpGs analyzed, 1713 showed statistically significant age-dependent methylation gains. Fewer CpGs acquired methylation in users of aspirin (≥ 2 years) and hormonal replacement therapy (HRT age ≥ 50 years) compared with nonusers (43 vs 1355; 1 vs1377, respectively), whereas more CpGs were affected in smokers (≥ 20 years) and individuals with a body mass index (BMI) of 25 kg/m(2) and greater compared with control groups (180 vs 39; 554 vs 144, respectively). Fifty percent of the CpGs showing age-dependent methylation were found hypermethylated in CRC (odds ratio [OR] = 20; 95% confidence interval [CI] = 18 to 23; P < 2 × 10(-16)). These loci gained methylation with a higher median rate compared with age-only methylated sites (P = 2 × 10(-76)) and were enriched for polycomb regions (OR = 3.67). Importantly, aspirin (P < .001) and HRT use (P < .001) reduced the methylation rate at these cancer-related genes, whereas smoking (P < .001) and high BMI (P = .004) increased it.
  
  
  CONCLUSIONS
  Lifestyle, including aspirin use, modulates age-associated DNA methylation change in the colonic epithelium and thereby impacts the evolution of cancer methylomes.
authors: Affiliations of authors: Department of Biomedicine, University of Basel, Basel, Switzerland (FN, SW, PU, PS, KT); Department of Epidemiology & Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland (MR); Department of Gastroenterology, Medical Center for Postgraduate Education, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland (PG, JP, JR); FMH Gastroenterology and Internal Medicine, Langenthal, Switzerland (KT).
authors: Faiza
authors: F
authors: Noreen
authors: Affiliations of authors: Department of Biomedicine, University of Basel, Basel, Switzerland (FN, SW, PU, PS, KT); Department of Epidemiology & Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland (MR); Department of Gastroenterology, Medical Center for Postgraduate Education, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland (PG, JP, JR); FMH Gastroenterology and Internal Medicine, Langenthal, Switzerland (KT).
authors: Martin
authors: M
authors: Röösli
authors: Affiliations of authors: Department of Biomedicine, University of Basel, Basel, Switzerland (FN, SW, PU, PS, KT); Department of Epidemiology & Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland (MR); Department of Gastroenterology, Medical Center for Postgraduate Education, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland (PG, JP, JR); FMH Gastroenterology and Internal Medicine, Langenthal, Switzerland (KT).
authors: Pawel
authors: P
authors: Gaj
authors: Affiliations of authors: Department of Biomedicine, University of Basel, Basel, Switzerland (FN, SW, PU, PS, KT); Department of Epidemiology & Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland (MR); Department of Gastroenterology, Medical Center for Postgraduate Education, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland (PG, JP, JR); FMH Gastroenterology and Internal Medicine, Langenthal, Switzerland (KT).
authors: Jakub
authors: J
authors: Pietrzak
authors: Affiliations of authors: Department of Biomedicine, University of Basel, Basel, Switzerland (FN, SW, PU, PS, KT); Department of Epidemiology & Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland (MR); Department of Gastroenterology, Medical Center for Postgraduate Education, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland (PG, JP, JR); FMH Gastroenterology and Internal Medicine, Langenthal, Switzerland (KT).
authors: Stefan
authors: S
authors: Weis
authors: Affiliations of authors: Department of Biomedicine, University of Basel, Basel, Switzerland (FN, SW, PU, PS, KT); Department of Epidemiology & Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland (MR); Department of Gastroenterology, Medical Center for Postgraduate Education, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland (PG, JP, JR); FMH Gastroenterology and Internal Medicine, Langenthal, Switzerland (KT).
authors: Patric
authors: P
authors: Urfer
authors: Affiliations of authors: Department of Biomedicine, University of Basel, Basel, Switzerland (FN, SW, PU, PS, KT); Department of Epidemiology & Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland (MR); Department of Gastroenterology, Medical Center for Postgraduate Education, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland (PG, JP, JR); FMH Gastroenterology and Internal Medicine, Langenthal, Switzerland (KT).
authors: Jaroslaw
authors: J
authors: Regula
authors: Affiliations of authors: Department of Biomedicine, University of Basel, Basel, Switzerland (FN, SW, PU, PS, KT); Department of Epidemiology & Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland (MR); Department of Gastroenterology, Medical Center for Postgraduate Education, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland (PG, JP, JR); FMH Gastroenterology and Internal Medicine, Langenthal, Switzerland (KT). primo.schaer@unibas.ch k.truninger@gastroenterologie-oberaargau.ch.
authors: Primo
authors: P
authors: Schär
authors: Affiliations of authors: Department of Biomedicine, University of Basel, Basel, Switzerland (FN, SW, PU, PS, KT); Department of Epidemiology & Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland (MR); Department of Gastroenterology, Medical Center for Postgraduate Education, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland (PG, JP, JR); FMH Gastroenterology and Internal Medicine, Langenthal, Switzerland (KT).
authors: Kaspar
authors: K
authors: Truninger
mesh_terms: D000367:Age Factors; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D001241:Aspirin / Q000008:administration & dosage*; D015331:Cohort Studies; D003106:Colon / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D055088:Early Detection of Cancer / Q000379:methods; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008019:Life Style; D008403:Mass Screening / Q000379:methods; D008875:Middle Aged; D011401:Promoter Regions, Genetic
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin