Functional mononucleotide repeat polymorphism in the promoter region of HGF is associated with risk and malignant aggressiveness of bladder cancer

Abstract

Increased expression of hepatocyte growth factor (HGF) has been shown to be associated with aggressiveness in several types of cancer. Shorter variants of deoxyadenosine tract element (DATE) located in the HGF promoter region have been reported to enhance the expression of HGF. In this study, we investigated the role of HGF DATE variants in bladder cancer risk, HGF expression and clinicopathological features. The frequency of individuals with a short DATE (<28 repeats) in peripheral blood lymphocytes (PBLs) was significantly higher in bladder cancer patients compared to controls (p<0.001). Somatic mutations were observed in 37 of 70 bladder tumor (BT) tissues and the frequency of mutation to long DATE was significantly higher than that to short DATE (p=0.047). The presence of the short DATE in BT tissue was significantly associated with higher tumor grade (p=0.015). HGF mRNA levels were significantly higher in pT2 tumors than pTa or pT1 tumors (p=0.019), and in grade 3 tumors than grade 1 or 2 tumors (p=0.020). Furthermore, BT tissues with the short DATE showed significantly higher levels of HGF mRNA (p<0.001). In patients who underwent radical cystectomy, those with higher HGF expression had a significantly shorter overall survival than those with lower HGF expression (p=0.012). In conclusion, HGF may be associated with the prognosis of patients who undergo radical cystectomy, and the HGF DATE may affect the risk and aggressiveness of bladder cancer by altering HGF expression.