Currently, immune checkpoint blockade against members of the B7/CD28 family is being used as a new molecular-targeted therapy, in patients with unresectable advanced or recurrent gastric cancer. Although human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) is a novel molecule of the B7/ CD28 family, the clinical impact of its expression remains uncertain in gastric cancer. Consequently, we examined HHLA2 expression in blood specimens from patients with gastric cancer, and investigated the relationship between its expression and clinicopathological factors to assess its potential power as a prognostic blood predictor. Untreated peripheral blood specimens were obtained from 111 patients with gastric cancer and 20 healthy volunteers. HHLA2 mRNA expression levels were determined using quantitative RT-PCR assay. Blood specimens obtained from patients with gastric cancer had significantly lower copies of HHLA2 mRNA than those obtained from healthy volunteers (P < 0.0001). Furthermore, HHLA2 expression was significantly correlated with the depth of tumor invasion (P = 0.0331), distant metastasis (P < 0.0001), and stage of disease (P = 0.0032). The 5-year survival rate was significantly higher in patients with high HHLA2 expression compared with the patients with low expression (P = 0.0001). These findings demonstrate that assessment of HHLA2 expression levels in the blood could be utilized to predict tumor aggressiveness in patients with gastric cancer.
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