title: Postmenopausal hormone therapy and colorectal cancer risk in relation to somatic KRAS mutation status among older women.
abstract: BACKGROUND
  Postmenopausal hormone (PMH) therapy represents a controversial colorectal cancer (CRC) preventive intervention. Because colorectal carcinogenesis is a heterogeneous process, we evaluated associations between PMH therapy and incident CRC in relation to KRAS mutation status in a population-based cohort of older women [Iowa Women's Health Study (IWHS)].
  
  
  METHODS
  The IWHS enrolled 41,836 randomly selected women, ages 55 to 69 years, in 1986. PMH therapy and other exposure data were recorded at baseline. Tissue samples from prospectively identified CRC cases (n = 507) were analyzed for somatic KRAS mutations (exon 2, codons 12 and 13). Multivariable Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI).
  
  
  RESULTS
  PMH therapy (ever vs. never) was inversely associated with KRAS mutation-negative (RR = 0.83; 95% CI, 0.66-1.06; P = 0.14) and KRAS mutation-positive (RR = 0.82; 95% CI, 0.58-1.16; P = 0.27) tumors, although the observed risk estimates were not statistically significant. When anatomic subsite was additionally considered, the strongest association was found for KRAS mutation-negative, distal colorectal tumors (RR = 0.64; 95% CI, 0.43-0.96; P = 0.03).
  
  
  CONCLUSIONS
  To our knowledge, we provide the first report of KRAS-defined CRC risks associated with PMH therapy. These data suggest that PMH therapy may reduce CRC risk through mechanisms beyond KRAS mutation status but might provide greater benefits for KRAS mutation-negative than mutation-positive tumors (at least in the distal colorectum).
  
  
  CONCLUSIONS
  Findings from this prospective cohort study provide novel insights about the molecular biology of PMH therapy-related CRC risk reduction.
authors.affiliation: Division of Gastroenterology & Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. limburg.paul@mayo.edu
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Limburg
authors.forename: David
authors.initials: D
authors.lastname: Limsui
authors.forename: Robert A
authors.initials: RA
authors.lastname: Vierkant
authors.forename: Lori S
authors.initials: LS
authors.lastname: Tillmans
authors.forename: Alice H
authors.initials: AH
authors.lastname: Wang
authors.forename: Charles F
authors.initials: CF
authors.lastname: Lynch
authors.forename: Kristin E
authors.initials: KE
authors.lastname: Anderson
authors.forename: Amy J
authors.initials: AJ
authors.lastname: French
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Harnack
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.forename: Susan L
authors.initials: SL
authors.lastname: Slager
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Smyrk
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: James R
authors.initials: JR
authors.lastname: Cerhan
mesh_terms: D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics*; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007484:Iowa / Q000453:epidemiology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D017698:Postmenopause / Q000187:drug effects*; D011379:Prognosis; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012307:Risk Factors; D018426:SEER Program; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins