Urinary kallikrein 10 predicts the incurability of gastric cancer

// Takaya Shimura 1 , Masahide Ebi 1, 2 , Tomonori Yamada 3 , Tamaki Yamada 4 , Takahito Katano 1 , Yu Nojiri 1, 3 , Hiroyasu Iwasaki 1, 3 , Satoshi Nomura 1 , Noriyuki Hayashi 1 , Yoshinori Mori 1 , Hiromi Kataoka 1 , Marsha A. Moses 5, 6 , Takashi Joh 1 1 Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan 2 Department of Gastroenterology, Aichi Medical University, Nagakute, Japan 3 Department of Gastroenterology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan 4 Okazaki Public Health Center, Okazaki, Japan 5 Vascular Biology Program, Boston Children’s Hospital, Boston, MA, USA 6 Department of Surgery, Harvard Medical School and Boston Children’s Hospital, Boston, MA, USA Correspondence to: Takaya Shimura, email: tshimura@med.nagoya-cu.ac.jp Keywords: biomarker, gastric cancer, inoperability, kallikrein 10, urine Received: November 08, 2016      Accepted: February 22, 2017      Published: March 22, 2017 ABSTRACT The current imaging modalities are not sufficient to identify inoperable tumor factors, including distant metastasis and local invasion. Hence, we conducted this study using urine samples to discover non-invasive biomarkers for the incurability of gastric cancer (GC). Urine samples from 111 GC patients were analyzed in this study. The GC cohort was categorized and analyzed according to disease stage and operability. In the discovery phase, protease protein array analysis identified 3 potential candidate proteins that were elevated in the urine of advanced GC patients compared to early GC patients. Among them, urinary kallikrein 10 (KLK10) was positively associated with tumor stage progression. Moreover, the urinary level of KLK10 (uKLK10) was significantly elevated in the urine of patients with inoperable GC compared to operable GC patients (median, 118 vs. 229; P =0.014). The combination of uKLK10, tumor location and tumor size distinguished operability of GC with an area under the curve of 0.859, 82.4% sensitivity and 86.2% specificity. Disease-free survival (DFS) was significantly shorter in GC patients with high uKLK10 compared to those with low uKLK10 (hazard ratio: 3.30 [95% confidence interval, 1.58-6.90] P <0.001). Immunohistochemical analyses also demonstrated a positive correlation between tumor stage and KLK10 expression in GC tissues (r=0.426, P <0.001). In addition, GC patients with high expression of pathological KLK10 (pKLK10) showed a significantly shorter DFS compared to those with low pKLK10 (hazard ratio: 3.79 [95% confidence interval, 1.27-11.24] P =0.010). uKLK10 is a promising non-invasive biomarker for the inoperability and incurability of GC.