Ping Yuan1,2, Wenqing Rao1, Zheng Lin1, Shuang Liu1, Xiuquan Lin1, Chaofeng Wu1, Xu Lin3, Zhijian Hu4,5, Weimin Ye6,7,8. 1. Department of Epidemiology and Health Statistics, The School of Public Health, Fujian Medical University, Fuzhou, Fujian, China. 2. Key Laboratory of Ministry of Education for Gastrointestinal Cancer, The School of Basic Medical Sciences, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou, 350122, Fujian, China. 3. Key Laboratory of Ministry of Education for Gastrointestinal Cancer, The School of Basic Medical Sciences, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou, 350122, Fujian, China. linxu70@126.com. 4. Department of Epidemiology and Health Statistics, The School of Public Health, Fujian Medical University, Fuzhou, Fujian, China. hzj99955888@126.com. 5. Key Laboratory of Ministry of Education for Gastrointestinal Cancer, The School of Basic Medical Sciences, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou, 350122, Fujian, China. hzj99955888@126.com. 6. Department of Epidemiology and Health Statistics, The School of Public Health, Fujian Medical University, Fuzhou, Fujian, China. ywm@fjmu.edu.cn. 7. Key Laboratory of Ministry of Education for Gastrointestinal Cancer, The School of Basic Medical Sciences, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou, 350122, Fujian, China. ywm@fjmu.edu.cn. 8. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77, Stockholm, Sweden. ywm@fjmu.edu.cn.
Abstract
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has a poor prognosis and occurs with high frequency in China. In particular, Fujian is one of the high-incidence areas of ESCC in China and the somatic mutation profile of ESCC there remains unclear. PATIENTS AND METHODS: Whole-exome sequencing (WES) was performed in 49 matched ESCC tumor-normal specimens to examine the somatic mutation profiles. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between mutational profile and survival were derived from Cox regression model. RESULTS: We constructed a preliminary somatic mutation profiling of ESCC in Fujian. Exome sequencing data showed that the main base substitutions in ESCC were C > T transformation (close to 50%), C > A and T > C transversion. The study identified 21 significantly mutated genes, including 8 driver genes and 11 predicted driver genes. Among the 19 driver or predicted driver genes, 9 are novel (OBSCN, PKHD1L1, FSIP2, HRNR, CUBN, CELSR3, SCN7A, TULP4, SRRM2) and 10 have been previously reported. Three mutational signatures were identified to be prevalent in ESCC including Signature_15, Signature_4 and Signature_6, of which Signature_15 was related to prognosis of ESCC (HR 2.81, 95% CI 1.30-6.05; p = 0.008). Survival analysis showed that SCN7A was correlated to overall survival with an HR of 2.76 (95% CI 0.96-7.90, p = 0.058). After controlling for confounding factors such as age, gender, stage and location, the correlation between SCN7A and survival was statistically significant based on multivariate COX regression analysis (HR 4.76, 95% CI 1.20-18.85; p = 0.026, padjust = 0.053). The tumor vascular invasion was associated with SCN7A of ESCC patients (p = 0.028). CONCLUSION: In summary, this study provided comprehensive analysis of the somatic mutation profiles of ESCC, and identified SCN7A and Signature_15 for the prognosis of ESCC for the first time. The findings might serve as a conceptual basis for molecular diagnosis and prevention of ESCC.
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has a poor prognosis and occurs with high frequency in China. In particular, Fujian is one of the high-incidence areas of ESCC in China and the somatic mutation profile of ESCC there remains unclear. PATIENTS AND METHODS: Whole-exome sequencing (WES) was performed in 49 matched ESCC tumor-normal specimens to examine the somatic mutation profiles. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between mutational profile and survival were derived from Cox regression model. RESULTS: We constructed a preliminary somatic mutation profiling of ESCC in Fujian. Exome sequencing data showed that the main base substitutions in ESCC were C > T transformation (close to 50%), C > A and T > C transversion. The study identified 21 significantly mutated genes, including 8 driver genes and 11 predicted driver genes. Among the 19 driver or predicted driver genes, 9 are novel (OBSCN, PKHD1L1, FSIP2, HRNR, CUBN, CELSR3, SCN7A, TULP4, SRRM2) and 10 have been previously reported. Three mutational signatures were identified to be prevalent in ESCC including Signature_15, Signature_4 and Signature_6, of which Signature_15 was related to prognosis of ESCC (HR 2.81, 95% CI 1.30-6.05; p = 0.008). Survival analysis showed that SCN7A was correlated to overall survival with an HR of 2.76 (95% CI 0.96-7.90, p = 0.058). After controlling for confounding factors such as age, gender, stage and location, the correlation between SCN7A and survival was statistically significant based on multivariate COX regression analysis (HR 4.76, 95% CI 1.20-18.85; p = 0.026, padjust = 0.053). The tumor vascular invasion was associated with SCN7A of ESCC patients (p = 0.028). CONCLUSION: In summary, this study provided comprehensive analysis of the somatic mutation profiles of ESCC, and identified SCN7A and Signature_15 for the prognosis of ESCC for the first time. The findings might serve as a conceptual basis for molecular diagnosis and prevention of ESCC.
Authors: Melina Arnold; Christian C Abnet; Rachel E Neale; Jerome Vignat; Edward L Giovannucci; Katherine A McGlynn; Freddie Bray Journal: Gastroenterology Date: 2020-04-02 Impact factor: 22.682