Abstract
Esophageal squamous cell cancer (ESCC) is the eighth most common cancer around the world. Several reports have focused on somatic mutations and common germline mutations in ESCC. However, the contributions of pathogenic germline alterations in cancer susceptibility genes (CSGs), highly frequently mutated CSGs, and pathogenically mutated CSG-related pathways in ESCC remain unclear. We obtained data on 571 ESCC cases from public databases and East Asian from the 1000 Genomes Project database and the China Metabolic Analytics Project database to characterize pathogenic mutations. We detected 157 mutations in 75 CSGs, accounting for 25.0% (143/571) of ESCC cases. Six genes had more than five mutations: TP53 (n = 15 mutations), GJB2 (n = 8), BRCA2 (n = 6), RECQL4 (n = 6), MUTYH (n = 6), and PMS2 (n = 5). Our results identified significant differences in pathogenic germline mutations of TP53, BRCA2, and RECQL4 between the ESCC and control cohorts. Moreover, we identified 84 double-hit events (16 germline/somatic double-hit events and 68 somatic/somatic double-hit events) occurring in 18 tumor suppressor genes from 83 patients. Patients who had ESCC with germline/somatic double-hit events were diagnosed at younger ages than patients with the somatic/somatic double-hit events, though the correlation was not significant. Fanconi anemia was the most enriched pathway of pathogenically mutated CSGs, and it appeared to be a primary pathway for ESCC predisposition. The results of this study identified the underlying roles that pathogenic germline mutations in CSGs play in ESCC pathogenesis, increased our awareness about the genetic basis of ESCC, and provided suggestions for using highly mutated CSGs and double-hit features in the early discovery, prevention, and genetic counseling of ESCC.
Highlights
Esophageal squamous cell cancer (ESCC) is one of the most common cancers in the world, and it is especially common in Asian countries, North America, and the eastern corridor of Africa [1]
We identified 16 potential germline/somatic double-hit events (Figure 2, Supplementary Table 11, Supplementary Figures 5, 6) in 16 patients with ESCC, and we identified 68 potential somatic/somatic double-hit events (Figure 2, Supplementary Table 12) in 67 cases
We reported the profile of pathogenic germline mutations of a larger ESCC cohort comparing with previous studies [17, 19]
Summary
Esophageal squamous cell cancer (ESCC) is one of the most common cancers in the world, and it is especially common in Asian countries, North America, and the eastern corridor of Africa [1]. In 2018, several pan-cancer studies focused on pathogenic germline mutations to explore hereditary factors in cancers; 871 rare cancer predisposition mutations and copy number variations (CNVs) were observed in 8% of 10,389 cases, and 7.6% of the 914 patients with pediatric cancers had tumors that harbored pathogenic mutations in cancer predisposition genes [17, 18]. On the basis of these findings, double-hit events in some studies were used to identify cancer predisposition genes [22, 23]. These studies demonstrated the significance of pathogenic germline mutations and doublehit events in genetic testing and risk assessment for cancer. We discovered significantly different pathogenic germline mutations of TP53, BRCA2, and RECQL4 in ESCC cohorts, and we clarified the association between double-hit events and diagnosis age in patients with ESCC. Results of this study will improve genetic testing for relatives of patients with ESCC and facilitate the implementation of organizational or institutional measures for the ESCC prevention and surveillance
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