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Lymphatic spread is the main mode of progression of esophageal squamous cell carcinoma (ESCC). Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid mediator, which produced by sphingosine kinase 1 (SphK1) activated by phosphorylation. The SphK1-S1P axis has a crucial role in lymphangiogenesis. However, the significance of phospho-SphK1 (pSphK1) in the progression of ESCC has not been fully investigated.We evaluated pSphK1 expression in 92 surgically resected tumor tissues of ESCC by the immunohistochemistry. Fifty-nine (64%) patients with moderate or strong expression and 33 (36%) with negative or weak expression were classified in the pSphK1-high and pSphK1-low groups, respectively.Higher pathological N category (pN) was more frequently observed in the pSphK1-high group (P 0.01). The median number of lymph node metastasis (pSphK1-high: 2 versus pSphK1-low: 0; P 0.01), the proportion of patients with lymphatic invasion (69% versus 18%; P 0.01) and that with intramural metastasis (27% versus 3%; P 0.01) were significantly higher in the pSphK1-high group. The presence of lymphatic invasion (odds ratio [OR] 5.63; P 0.01) and pN1-3 (OR 3.26; P = 0.04) were independently associated with high pSphK1 expression. The 5-y overall survival rate of the pSphK1-high group was significantly lower than that of the pSphK1-low group (50.8% versus 67.3%; P = 0.01). High pSphK1 expression was not identified as a significant independent prognostic factor.We provide the first evidence of the association between high expression of pSphK1 and both lymphatic spread and patient outcomes in ESCC.

Recent progress in genomic analysis using next-generation sequencing technology has enabled the comprehensive detection of mutations and tumor mutation burden (TMB) in patients. A high TMB (TMB-H) tumor is defined as one with high somatic mutational rates, which correlates with clinical responses to certain treatments such as immunotherapies. We determined TMB in lung adenocarcinoma and clarified the characteristics of patients with TMB-H in relation to common driver mutations and smoking history.Genomic aberrations and TMB were determined in Japanese patients with lung adenocarcinoma (n = 100) using next-generation sequencing of 415 known cancer genes. TMB-H was defined as20 mutations per megabase (Mb) of sequenced DNA.The median TMB was 13.5 (5-33) mutations/Mb. Ten of 100 (10%) patients showed TMB-H, and the others showed low TMB (TMB-L). Only two of 10 (20%) patients with TMB-H had one of the common driver mutations (ALK and ERBB2 mutation), whereas 57 of 90 (63%) patients with TMB-L had one of the driver mutations, including ALK, EGFR, ERBB2, ROS, RET, and MET (P 0.05). Notably, no EGFR mutation was observed in patients with TMB-H. Eight of 10 (80%) patients with TMB-H had recent smoking history, whereas only 17 of 90 (19%) patients with TMB-L had recent smoking history (P 0.001).We found that TMB-H is associated with smoking history, whereas TMB-L is associated with the common driver mutations in lung adenocarcinoma, which may impact treatment strategies for these patients.