title: Associations of hormone replacement therapy and oral contraceptives with risk of colorectal cancer defined by clinicopathological factors, beta-catenin alterations, expression of cyclin D1, p53, and microsatellite-instability.
abstract: BACKGROUND
  Postmenopausal hormone therapy (HRT) and oral contraceptive (OC) use have in several studies been reported to be associated with a decreased colorectal cancer (CRC) risk. However, data on the association between HRT and OC and risk of different clinicopathological and molecular subsets of CRC are lacking. The aim of this molecular pathological epidemiology study was therefore to evaluate the associations between HRT and OC use and risk of specific CRC subgroups, overall and by tumour site.
  
  
  METHODS
  In the population-based prospective cohort study Mamö Diet and Cancer, including 17035 women, 304 cases of CRC were diagnosed up until 31 December 2008. Immunohistochemical expression of beta-catenin, cyclin D1, p53 and MSI-screening status had previously been assessed in tissue microarrays with tumours from 280 cases. HRT was assessed as current use of combined HRT (CHRT) or unopposed oestrogen (ERT), and analysed among 12583 peri-and postmenopausal women. OC use was assessed as ever vs never use among all women in the cohort. A multivariate Cox regression model was applied to determine hazard ratios for risk of CRC, overall and according to molecular subgroups, in relation to HRT and OC use.
  
  
  RESULTS
  There was no significantly reduced risk of CRC by CHRT or ERT use, however a reduced risk of T-stage 1-2 tumours was seen among CHRT users (HR: 0.24; 95% CI: 0.09-0.77).Analysis stratified by tumour location revealed a reduced overall risk of rectal, but not colon, cancer among CHRT and ERT users, including T stage 1-2, lymph node negative, distant metastasis-free, cyclin D1 - and p53 negative tumours.In unadjusted analysis, OC use was significantly associated with a reduced overall risk of CRC (HR: 0.56; 95% CI: 0.44-0.71), but this significance was not retained in adjusted analysis (HR: 1.05: 95% CI: 0.80-1.37). A similar risk reduction was seen for the majority of clinicopathological and molecular subgroups.
  
  
  CONCLUSIONS
  Our findings provide information on the relationship between use of HRT and OC and risk of clinicopathological and molecular subsets of CRC.
authors.affiliation: Department of Clinical Sciences, Lund, Oncology and Pathology, Lund University, Skåne University Hospital, Lund, Sweden. jenny.brandstedt@med.lu.se.
authors.forename: Jenny
authors.initials: J
authors.lastname: Brändstedt
authors.forename: Sakarias
authors.initials: S
authors.lastname: Wangefjord
authors.forename: Björn
authors.initials: B
authors.lastname: Nodin
authors.forename: Jakob
authors.initials: J
authors.lastname: Eberhard
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.forename: Jonas
authors.initials: J
authors.lastname: Manjer
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000453:epidemiology* / Q000235:genetics / Q000473:pathology; D003278:Contraceptives, Oral, Hormonal / Q000009:adverse effects*; D019938:Cyclin D1 / Q000032:analysis*; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D053842:Microsatellite Instability; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013548:Sweden / Q000453:epidemiology; D013997:Time Factors; D046888:Tissue Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*; D051176:beta Catenin / Q000032:analysis*
chemical_list: D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; C495270:CTNNB1 protein, human; D003278:Contraceptives, Oral, Hormonal; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D019938:Cyclin D1