C

C. significantly lower overall mortality, determined by Kaplan-Meier analysis (p=0.0047), univariate Cox regression (HR 0.55; 95% confidence interval [CI], 0.37-0.84; p=0.0053) and multivariate analysis (adjusted HR 0.43; 95% CI, 0.27-0.69; p=0.0004). Patients with O6-Benzylguanine PPARG-positive tumors experienced a lower colorectal cancer-specific mortality (HR 0.65; 95% CI, 0.40-1.07; p=0.092), which became significant in multivariate analysis (adjusted HR 0.44; 95% CI, 0.25-0.79; p=0.0054). The relationship between PPARG and lower mortality did not appear to be significantly altered by tumor stage or the other clinical and molecular variables examined (all O6-Benzylguanine Pinteraction>0.05). == Conclusions == Tumor expression of PPARG is usually independently associated with longer survival of patients. PPARG expression appears to mark an indolent subset of colorectal cancers. == INTRODUCTION == PPARG (the official symbol for peroxisome proliferator-activated receptor-) is usually a member of the nuclear hormone receptor PPAR superfamily.1,2Ligands for PPARG include naturally occurring fatty acids and the thiazolidinedione (TZD) class of antidiabetic drugs. PPARG plays an important role in adipose cell differentiation, modulation of metabolism and inflammatory response, and cellular apoptosis.1,3-5PPARG O6-Benzylguanine interacts with and/or regulates multiple signaling pathways, including those related to p53, p21, BCL2, NF-kappa-, STAT, cyclin D1 and cyclooxygenase-2 (COX-2).1-7Nonetheless, with regard to the role of PPARG in cancer, debate has still continued as to whether PPARG is usually pro-oncogenic or anti-neoplastic.2,8-13In O6-Benzylguanine fact, the effect of PPARG is likely multifaceted and tissue-specific. Experimental studies have suggested the role of PPARG in cell cycle regulation and cellular differentiation in colonic epithelium, supporting its anti-neoplastic effect.8,9,13,14PPARG expression has been examined in human colon cancer tissue.15-17Although two previous studies (N=8615and N=9916) did not demonstrate a prognostic value of tumoral PPARG status, these studies were limited by the small sample sizes. Thus, clinical significance of PPARG expression in human colorectal cancer remains uncertain. We therefore examined the prognostic role of PPARG expression in a large number (N=470) of stage I-IV colorectal cancer patients identified in two impartial, prospective cohort studies. Since we concurrently assessed other related molecular variables [including fatty acid synthase (FASN), COX-2, p53, p21,KRAS, BRAF, PIK3CA, LINE-1 hypomethylation, microsatellite instability (MSI), and the CpG island methylator phenotype (CIMP)], we could evaluate the impartial effect of PPARG on patient survival after controlling for these molecular events. In particular, it is important to control for the effect of MSI, CIMP and LINE-1 hypomethylation (and related molecular events such asKRAS, BRAFandPIK3CAmutations), because these molecular characteristics refect genomic and epigenomic status of cancer cells, and have been related with patient survival in colon cancer.18-25 == MATERIALS AND METHODS == == Study Population == We utilized the databases of two independent prospective cohort studies; the Nurses’ Health Study (N = 121,700 women followed since 1976),26,27and the Health Professionals Follow-up Study (N = 51,500 men followed since 1986).27Every 2 years, participants have been sent follow-up questionnaires to update information on potential risk factors and to identify newly diagnosed cancer and other diseases in themselves and their first degree relatives. We calculated body mass index O6-Benzylguanine (BMI, kg/m2), using self-reported height from the baseline questionnaire and weight from the biennial questionnaire that immediately preceded the diagnosis of colorectal cancer. In validation studies in both cohorts, self-reported anthropometric steps were well correlated with measurements by trained professionals (r >0.96).28On each biennial follow-up questionnaire, participants were asked whether they had a diagnosis of colorectal cancer during the previous 2 years. When a participant (or next of kin for decedents) reported colorectal CACNG4 cancer, we sought permission to obtain medical records. Study physicians, while blinded to exposure data, reviewed all records related to colorectal cancer, and recorded AJCC (American Joint Committee on Cancer) tumor stage and.