Prognostic Impact of Jass's Proposed Molecular Classification of Colorectal Cancer Based on MSI, CIMP, MGMT, KRAS and BRAF Status.
Inti Zlobec, Michel Bihl, Anja Foerster, Alex Rufle, Alessandro Lugli. University Hospital Basel, Switzerland
Background: In 2007, Jeremy Jass proposed a new molecular classification for colorectal cancer based primarily on 5 features: microsatellite instability status (MSI), CpG Island Methylator Phenotype (CIMP), O-6-methylguanine-DNA methyltransferase (MGMT), KRAS and BRAF gene status. The aim of this study was to validate this classification and its impact on prognosis.
Design: 404 patients were included in this study. MSI-H was defined as instability in ≥2 Bethesda-panel markers. CIMP-high was defined as methylation in ≥4/5 loci including CACNA1G, CDKN2A, CRABP1, MLH1, and Neurog1. Mutation of KRAS (codons 12/13) and BRAF (codon V600E) and methylation of MGMT were investigated. The 5 proposed Jass groups were tested; patients were subsequently re-classified based on 10-year overall survival (OS).
Results: CIMP-high was linked to right-sided location (p<0.001), higher tumor grade (p=0.005), BRAF mutation (p<0.001), MSI-H (p<0.001), MGMT methylation (p=0.022), and worse survival (p=0.053). 123 (40.7%) patients could not be assigned to any proposed Jass groups. The frequencies of patients successfully classified did not show the expected trends. After re-classification, BRAF best classified OS, followed by CIMP, KRAS, MSI and MGMT. Six prognostic subgroups were identified, the largest comprised of patients with BRAF WT/CIMP-H or -low (n=39.1%; OS: 38%), the worst OS was observed for patients with BRAF mutation (n=9.9%; OS:10%), independently of CIMP, MSI, or MGMT.
Conclusions: Although MGMT may have limited prognostic value, BRAF, CIMP, KRAS and MSI status may interact with each other to modify clinical outcome. These features will likely play a significant role in a future molecular classification of colorectal cancer.
Monday, February 28, 2011 8:00 AM
Platform Session: Section E, Monday Morning