Deng Jiaying, Weng Xiaoling, Ye Junyi, Zhou Daizhan, Liu Yun, Zhao Kuaile
Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Front Genet. 2019 Feb 18;10:47. doi: 10.3389/fgene.2019.00047. eCollection 2019.
Esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis and occurs with high frequency in China. The germline mutation profile in ESCC remains unclear, and therefore, the discovery of oncogenic alterations in ESCC is urgently needed. This study investigates the germline mutation profile and reveals associations among genotype-environment interactions in ESCC. Whole exome sequencing and follow-up analysis were performed in 77 matched tumor-normal ESCC specimens to examine the germline profiles. Additionally, associations among genotype-environment interactions were investigated. We identified 84 pathogenic/likely pathogenic mutations and 51 rare variants of uncertain significance (VUS). Twenty VUS with InterVar evidence of a score of moderate pathogenicity (PM) 2/PM2+ supporting pathogenicity (PP) 1 were found to have pathogenic significance. CYP21A2 was the most frequently mutated gene, and the p.Gln319 variant was identified in 6.5% (5/77) of patients. The TP53 p.V197E mutation, located within the DNA binding domain, was found in 1.3% (1/77) of patients. In total, the 11.7% (9/77) of individuals with homologous recombination (HR) VUS were more likely to have well-differentiated tumors than those without ( = 0.003). The degree of lymph node metastasis was correlated with homologous recombination deficiency (HRD) and VUS group ( < 0.05). Moreover, the 10.4% (8/77) of individuals with mismatch repair (MMR) VUS had a higher tumor mutational burden (TMB), although the correlation was not significant. Our study identified the germline mutation profiles in ESCC, providing novel insights into the molecular pathogenesis of this disease. Our results may also serve as a useful resource for the exploration of the underlying mechanism of ESCC and may provide information for the prevention, diagnosis and risk management of ESCC.
食管鳞状细胞癌（ESCC）预后较差，在中国发病率较高。ESCC的种系突变谱仍不清楚，因此，迫切需要发现ESCC中的致癌改变。本研究调查了ESCC的种系突变谱，并揭示了基因型-环境相互作用之间的关联。对77对匹配的ESCC肿瘤-正常标本进行了全外显子测序和后续分析，以检查种系谱。此外，还研究了基因型-环境相互作用之间的关联。我们鉴定出84个致病/可能致病的突变和51个意义未明的罕见变异（VUS）。发现20个具有InterVar证据、中等致病性（PM）评分为2/PM2+支持致病性（PP）评分为1的VUS具有致病意义。CYP21A2是最常发生突变的基因，在6.5%（5/77）的患者中鉴定出p.Gln319变异。在1.3%（1/77）的患者中发现了位于DNA结合域内的TP53 p.V197E突变。总体而言，具有同源重组（HR）VUS的个体中有11.7%（9/77）比没有HR VUS的个体更有可能患有高分化肿瘤（P = 0.003）。淋巴结转移程度与同源重组缺陷（HRD）和VUS组相关（P < 0.05）。此外，具有错配修复（MMR）VUS的个体中有10.4%（8/77）的肿瘤突变负担（TMB）较高，尽管相关性不显著。我们的研究确定了ESCC中的种系突变谱，为该疾病的分子发病机制提供了新的见解。我们的结果也可能作为探索ESCC潜在机制的有用资源，并可能为ESCC的预防、诊断和风险管理提供信息。
