A comprehensive genomic characterization of esophageal squamous cell carcinoma: from prognostic analysis to in vivo assay

Background: Esophageal squamous cell carcinoma(ESCC) is a leading cause of cancer death worldwide and is char?acterized by numerous genetic mutations. TNM staging is not sufficient for predicting patient outcomes. Addition?ally, ESCC shows poor responsiveness to chemotherapy and radiation. Thus, there is an urgent need to find efficient therapy targets. Previous ESCC high?throughput genomic studies have lacked intensive survival analysis, particularly for copy number variation(CNV) and the genes involved.Main body: In the study "Genomic Characterization of Esophageal Squamous Cell Carcinoma Reveals Critical Genes Underlying Tumorigenesis and Poor Prognosis" recently published in the American Journal of Human Genetics, we comprehensively analyzed the effects of CNVs, mutations, and relative gene expression on patient outcomes. To validate our findings for our 67 sequencing samples, we collected a 321?patient retrospective cohort with detailed 5?year follow?up information and carried out univariate and multivariate survival analyses. In addition, the biological functions of the survival predictors in ESCC were investigated both in vitro and in vivo.Conclusions: We found the independent ESCC survival predictors and potential therapy targets. Nevertheless, the effects of numerous low?frequency mutations need to be explored using larger sample sequencing. Overall, con?structing multi?gene prognostic signatures will remain a great challenge in the future.

Somatic CDKN2A copy number variations are associated with the prognosis of esophageal squamous cell dysplasia

Background:Somatic copy number variations(SCNVs)in the CDKN2A gene are among the most frequent events in the dysplasia-carcinoma sequence of esophageal squamous cell carcinoma.However,whether CDKN2A SCNVs are useful biomarkers for the risk stratification and management of patients with esophageal squamous cell dysplasia(ESCdys)is unknown.This study aimed to investigate the characteristics and prognostic value of CDKN2A SCNVs in patients with mild or moderate(m/M)ESCdys.Methods:This study conducted a prospective multicenter study of 205 patients with a baseline diagnosis of m/M ESCdys in five high-risk regions of China(Ci County,Hebei Province;Yanting,Sichuan Province;Linzhou,Henan Province;Yangzhong,Jiangsu Province;and Feicheng,Shandong Province)from 2005 to 2019.Genomic DNA was extracted from paraffin biopsy samples and paired peripheral white blood cells from patients,and a quantitative polymerase chain reaction assay,P16-Light,was used to detect CDKN2A copy number.The cumulative regression and progression rates of ESCdys were evaluated using competing risk models.Results:A total of 205 patients with baseline m/M ESCdys were enrolled.The proportion of ESCdys regression was significantly lower in the CDKN2A deletion cohort than in the diploid and amplification cohorts(18.8%[13/69]vs.35.0%[28/80]vs.51.8%[29/56],P<0.001).In the univariable competing risk analysis,the cumulative regression rate was statistically significantly lower(P=0.008),while the cumulative progression rate was higher(P=0.017)in ESCdys patients with CDKN2A deletion than in those without CDKN2A deletion.CDKN2A deletion was also an independent predictor of prognosis in ESCdys(P=0.004)in the multivariable analysis.Conclusion:The results indicated that CDKN2A SCNVs are associated with the prognosis of ESCdys and may serve as potential biomarkers for risk stratification.

Comparative genomic analysis of esophageal squamous cell carcinoma and adenocarcinoma:New opportunities towards molecularly targeted therapy

Esophageal cancer is one of the most lethal cancers worldwide because of its rapid progression and poor prognosis.Esophageal squamous cell carcinoma(ESCC)and esophageal adenocarcinoma(EAC)are two major subtypes of esophageal cancer.ESCC predominantly affects African and Asian populations,which is closely related to chronic smoking and alcohol consumption.EAC typically arises in Barrett’s esophagus with a predilection for Western countries.While surgical operation and chemoradiotherapy have been applied to combat this deadly cancer,molecularly targeted therapy is still at the early stages.With the development of large-scale next-generation sequencing,various genomic alterations in ESCC and EAC have been revealed and their potential roles in the initiation and progression of esophageal cancer have been studied.Potential therapeutic targets have been identified and novel approaches have been developed to combat esophageal cancer.In this review,we comprehensively analyze the genomic alterations in EAC and ESCC and summarize the potential role of the genetic alterations in the development of esophageal cancer.Progresses in the therapeutics based on the different tissue types and molecular signatures have also been reviewed and discussed.

Variation_91720拷贝数变异与食管鳞癌易感性的关联研究

目的探讨PIK3CA基因中Variation_91720拷贝数变异（copy number variation,CNV）与中国西南地区汉族人群食管鳞状细胞癌（esophageal squamous cell carcinoma,ESCC）易感性的关联。方法选取149例中国西南地区ESCC患者和205例年龄、性别相匹配的健康人群作为研究对象,采用基于Taq Man实时定量PCR检测外周血中Variation_91720拷贝数;基于SYBR Green实时定量PCR检测34例ESCC患者癌及癌旁组织中PIK3CA基因mRNA表达量。结果Variation_91720拷贝数在ESCC患者和对照人群中分布有显著差异（P〈0.01）,ESCC患者中Variation_91720拷贝数减少频率显著高于对照人群（P〈0.01,OR=5.617,95%CI=2.750-11.470）,是ESCC发生的危险因素;Variation_91720拷贝数增加显著低于对照人群（P=0.028,OR=0.419,95%CI=0.193-0.911）,是ESCC发生的保护因素。34例ESCC患者中癌组织的PIK3CA基因mRNA表达量显著高于癌旁组织（P=0.038）,基因表达差异与相应的外周血基因组Variation_91720拷贝数变异之间无显著统计学差异（P=0.066）。结论 Variation_91720拷贝数变异与中国西南地区汉族人群ESCC的易感性相关联;其拷贝数减少与增加ESCC的易感性相关而其拷贝数增加与降低ESCC的易感性相关,可能成为ESCC的高危人群筛选和早期诊断生物标记物。