Abstract 2178: Spectrum of pathogenic germline mutations in Chinese esophageal squamous cell carcinoma patients through next-generation sequencing

Abstract

Abstract Background: Esophageal Squamous Cell Carcinoma (ESCC) is one of the leading cause of cancer death in China, while the nature of genetic factors related to ESCC has not been well-studied. The purpose of this study is to assess the inherited genetic factors regarding pathogenic germline mutations in Chinese ESCC population. Methods: Tumor tissue samples from Chinese patients with ESCC were analyzed using next generation sequencing (NGS) (panel on 381/733-gene). MSI was evaluated by NGS of 500 known MSI loci. PD-L1 expression was evaluated using immunohistochemistry (Dako 22C3). TMB was defined as total number of somatic non-synonymous mutations in coding region. Results: Genomic profiling of DNA of 271 ESCC patients were analyzed using NGS, of which 251 (92.6%) harbored 354 pathogenic or very likely pathogenic germline mutations in 94 genes. In ESCC patients with germline mutations, the most frequently germline mutated genes were CYP2C19 (54.18%), followed by UGT1A1 (41.04%), RAC1 (35.06%), VEGFA (34.66%), DPYD (33.47%), CD74 (31.47%), MGMT (31.08%), CYP2D6 (29.88%), BCL2L11 (12.35%), FANCA (7.97%), ALK (7.57%), APC (7.17%), and BARD1 (5.98%). Of all the 94 germline mutated genes, 26.6% (n=25) lay in the DNA damage repair (DDR) pathways. The most frequently germline mutated DDR genes were FANCA (7.97%), followed by BARD1 (5.98%), FANCG (5.98%), BLM (5.58%), BRCA2 (5.18%), BRCA1 (4.78%), FANCD2 (4.78%), POLD1 (3.98%), ATM (3.59%), and POLE (3.58%). MSI status analysis was performed in 246 of 251 ESCC patients with germline mutated genes, and the results showed that all the patients with germline mutated genes were determined to be MSS. In addition, among 251 ESCC patients with germline mutated genes, 163 of them were tested for PD-L1. The results showed that 45 (27.6%) of the ESCC patients were PD-L1 positive (CPS≥10) and 118 (72.4%) were PD-L1 negative. Of the 247 ESCC patients with germline mutations that could be evaluated for TMB, 60 (24.29%) patients had TMB≥10Muts/Mb. Conclusions: As the first study to explore the pathogenic germline mutation profile of Chinese ESCC patients, our study provides valuable clues for the assessment and clinical management of genetic susceptibility to ESCC patients. Citation Format: Ruijun Cai, Yating Zheng, Wenzhuan Xie, Mengli Huang. Spectrum of pathogenic germline mutations in Chinese esophageal squamous cell carcinoma patients through next-generation sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2178.