Somatic alterations, metabolizing genes and smoking in rectal cancer

Int J Cancer. 2009 Jul 1;125(1):158-64. doi: 10.1002/ijc.24338.


Cigarette smoking has been identified as a risk factor for rectal cancer. Our investigation evaluates associations between active and passive smoking and TP53, KRAS2, and BRAF V600E mutations, microsatellite instability (MSI), and CpG Island Methylator Phenotype (CIMP) in rectal tumors. We examine how genetic variants of GSTM1 and NAT2 alter these associations in a population-based, case-control study of 750 incident rectal cancer cases and 1,201 controls. Detailed tobacco exposure data were collected in an extensive questionnaire. DNA from blood was examined for GSTM1 and NAT2 variants. Tumor DNA was assessed to determine TP53 (exons 5-8), KRAS2 (codons 12-13) and BRAF mutations, MSI (BAT26 and TGFbetaRII analysis), and CIMP (methylation of CpG islands in CDKN2A, MLH1, MINT1, MINT2 and MINT31). Cigarette smoking (>20 pack-years, relative to nonsmokers) was associated with increased risk of TP53 mutations (OR = 1.4, 95% CI 1.02-2.0), BRAF mutations (OR = 4.2, 95% CI 1.3-14.2) and MSI (OR = 5.7, 95% CI 1.1-29.8) in rectal tumors. Long-term environmental tobacco smoke (ETS) exposure of >10 hr/wk was associated with increased risk of KRAS2 mutation (OR = 1.5, 95% CI 1.04-2.2). All smoking indicators were suggestive of increased risk in CIMP+ rectal cancer. GSTM1 and NAT2 were generally not associated with rectal tumor alterations; however, we observed an interaction of ETS and NAT2 in TP53-mutated tumors (p < 0.01). Our investigation shows active smoking is associated with increased risk of TP53, BRAF and MSI+ in rectal tumors and is suggestive of increased risk of CIMP+ tumors. ETS may increase risk of KRAS2 mutations; association with TP53 mutations and ETS may be influenced by NAT2.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adult
  • Aged
  • Arylamine N-Acetyltransferase / genetics
  • Cadherins / genetics
  • Carrier Proteins / genetics
  • Case-Control Studies
  • CpG Islands / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Female
  • Genetic Variation
  • Glutathione Transferase / genetics
  • Humans
  • Inactivation, Metabolic / genetics
  • Male
  • Microsatellite Instability*
  • Middle Aged
  • MutL Protein Homolog 1
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nuclear Proteins / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins p21(ras)
  • Rectal Neoplasms / epidemiology*
  • Rectal Neoplasms / genetics*
  • Rectal Neoplasms / metabolism
  • Risk Factors
  • Smoking / adverse effects*
  • Tobacco Smoke Pollution
  • Tumor Suppressor Protein p53 / genetics*
  • ras Proteins / genetics


  • APBA1 protein, human
  • APBA2 protein, human
  • APBA3 protein, human
  • Adaptor Proteins, Signal Transducing
  • Cadherins
  • Carrier Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • KRAS protein, human
  • MLH1 protein, human
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • TP53 protein, human
  • Tobacco Smoke Pollution
  • Tumor Suppressor Protein p53
  • Arylamine N-Acetyltransferase
  • NAT2 protein, human
  • Glutathione Transferase
  • glutathione S-transferase M1
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MutL Protein Homolog 1
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins