Association between genetic variations involved in tumor dormancy related genes and clinical outcomes in Japanese patients with gastric cancer.

Abstract

43 Background: The major cause of cancer-related death is metastatic growth of disseminated tumor cells (DTCs) from the primary tumor despite approximate resection and adjuvant chemotherapy. Tumor dormancy is a stage in cancer progression in which micrometastases or residual tumor remains occult and asymptomatic until clinical appearance. The regulation of whether DTCs keep to a quiescent state or transit into a proliferative state can be explained through the interaction of the DTCs with the microenvironment, blood supply, and immunosurveillance. This suggests that host genetic background may impact this process. We tested our hypothesis whether polymorphisms involved in tumor dormancy related genes could predict clinical outcomes in gastric cancer (GC). Methods: One-hundred and sixty-nine Japanese patients with histolopathologically confirmed localized GC (stage Ib to IV; AJCC-6th) were enrolled from Kitasato East University Hospital and Fukushima Red Cross Hospital between 2002 and 2010. Twenty-four polymorphisms were selected from VEGF pathway genes, microenvironment related genes, and metastasis suppressor genes. Genomic DNA was extracted from blood or tissue, and all samples were analyzed by PCR-based direct DNA-sequencing. Results: The median age was 68 (31-88) years-old, and 64% of patients were males in this cohort. Pathological stages were 17% in stage Ib, 31% in stage II, 36% in stage III, and 17% in stage IV,. Almost all patients received D2 lymphadectomy based surgery and 65% patients received S-1 based adjuvant chemotherapy. The median follow-up periods were 4.0 years. NME1 rs2302254 was associated with significantly shorter disease-free survival (HR 1.555; 95%CI, 1.026-2.359; p=0.032). NME1 rs34214448 (HR 1.732; 95%CI, 1.082-2.770; p=0.036), PAI1 rs1799889 (HR 1.855; 95%CI, 1.032-3.333; p=0.02), and VEGF-A rs699946 (HR 1.678; 95%CI, 1.014-2.778; P=0.042) were associated with significantly shorter overall survival. Conclusions: NME1 rs2302254 may predict early recurrence of Japanese patients with GC. Additionally, survival after recurrence could be influenced by angiogenic factors in a synergic manner.