MET and HGF predict outcome in colorectal cancer

Abstract

Abstract Introduction: MET, a receptor tyrosine kinase, and its ligand, hepatocyte growth factor (HGF), are critical in cellular proliferation, motility, and invasion. We hypothesize that elevated MET and HGF gene expression predicts metastatic spread and poor survival in colorectal (CR) cancer patients. Methods: In 60 primary CR adenocarcinomas, MET and HGF mRNA was quantified with Real-Time RT-PCR. Using random primed cDNA and gene-specific PCR, specimen threshold cycle was measured and standard curves generated. Tumor mRNA levels were extrapolated, normalized to 18S RNA and compared to pooled matched normal mucosa. Median follow-up for survival analysis was 6 years. Results: When compared with normal tissue, a > 2 fold elevation in MET mRNA was seen in 69% of tumors with 48% having > 10 fold increases. Elevated HGF mRNA was noted in 47% of tumors with 19% having a > 10 fold increase. MET and HGF mRNA levels were correlated (p = 0.01). 33 patients had low expression of both genes (LOW MET/HGF) while 27 patients had high expression of both (HIGH MET/HGF). HIGH MET/HGF was associated with nodal and distant metastases (Table). Further, HIGH MET/HGF gene expression predicted poor survival (RR = 2.3, p Factor High MET/HGF n (%) Low MET/HGF n (%) p Value Relative Risk All patients 27 (100) 33 (100) — — Grade 1 1 (4) 1 (3) 0.57 — 2 23 (85) 24 (72) 3 3 (11) 8 (24) T stage 1 1 (4) 1 (3) 0.96 — 2 5 (19) 8 (24) 3 18 (67) 21 (64) 4 3 (11) 3 (9) N stage 0 9 (33) 21 (64) 0.02 1.9 1/2 18 (67) 12 (36) M stage 0 15 (56) 26 (79) 0.05 2.1 1 12 (44) 7 (21) AJCC stage 1/2 5 (19) 18 (55) 0.004 1.8 3/4 22 (81) 15 (45) Conclusions: Over-expression of MET and HGF identifies a metastatic phenotype. These molecular markers may be exploited for identifying tumors with aggressive biology and are potential therapeutic targets.