Loss of PPARG Expression Is Common in CpG Island Methylator Phenotype-Low (CIMP-Low) Colorectal Cancer
K Shima, K Nosho, L Chen, CS Fuchs, S Ogino. Dana-Farber Cancer Institute, Boston, MA; Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Background: The CpG island methylator phenotype (CIMP) is a distinct phenotype characterized by widespread CpG island methylation and silencing of many tumor suppressor genes (including MLH1), and is a major cause of microsatellite instability (MSI) in colon cancer. The nuclear receptor peroxisome proliferator-activated receptor-γ (PPARG) plays an important role in energy metabolism and inflammatory response, and loss of its expression predicts poor prognosis in colorectal cancer. However, the relationship between PPARG expression and epigenetic alterations remains uncertain.
Design: Among 534 colorectal cancers, loss of PPARG expression was detected in 419 (78%) tumors by immunohistochemistry.
We quantified DNA methylation in 8 CIMP-specific markers (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, SOCS1); 8 other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, WRN) by MethyLight (real-time PCR); and LINE-1 methylation by Pyrosequencing. Multivariate logistic regression was used to assess independent relations between PPARG loss and epigenetic events.
Results: Compared to CIMP-high and CIMP-0 (≥ 6/8 and 0/8 methylated CIMP markers, respectively), PPARG loss was significantly associated with CIMP-low (1/8-5/8 methylated CIMP markers) [vs. CIMP-0; multivariate odds ratio (OR), 2.46; 95% CI, 1.48-4.09; p=0.0005].
PPARG loss was not significantly associated with body mass index, LINE-1 methylation, MSI, KRAS, BRAF, PIK3CA, p53, β-catenin and cyclooxygenase-2, but inversely associated with fatty acid synthase overexpression (multivariate OR, 0.41; 95% CI, 0.22-0.74; p=0.0032).
Conclusions: PPARG loss is independently associated with CIMP-low in colorectal cancer. Our data provide evidence supporting a molecular difference between CIMP-low, CIMP-0 (CIMP-negative) and CIMP-high.
Tuesday, March 23, 2010 1:00 PM
Poster Session IV # 76, Tuesday Afternoon