title: An Old Story Retold: Loss of G1 Control Defines A Distinct Genomic Subtype of Esophageal Squamous Cell Carcinoma.
abstract: Esophageal squamous cell carcinoma (ESCC) has a high mortality rate. To determine the molecular basis of ESCC development, this study sought to identify characteristic genome-wide alterations in ESCC, including exonic mutations and structural alterations. The clinical implications of these genetic alterations were also analyzed. Exome sequencing and verification were performed for nine pairs of ESCC and the matched blood samples, followed by validation with additional samples using Sanger sequencing. Whole-genome SNP arrays were employed to detect copy number alteration (CNA) and loss of heterozygosity (LOH) in 55 cases, including the nine ESCC samples subjected to exome sequencing. A total of 108 non-synonymous somatic mutations (NSSMs) in 102 genes were verified in nine patients. The chromatin modification process was found to be enriched in our gene ontology (GO) analysis. Tumor genomes with TP53 mutations were significantly more unstable than those without TP53 mutations. In terms of the landscape of genomic alterations, deletion of 9p21.3 covering CDKN2A/2B (30.9%), amplification of 11q13.3 covering CCND1 (30.9%), and TP53 point mutation (50.9%) occurred in two-thirds of the cases. These results suggest that the deregulation of the G1 phase during the cell cycle is a key event in ESCC. Furthermore, six minimal common regions were found to be significantly altered in ESCC samples and three of them, 9p21.3, 7p11.2, and 3p12.1, were associated with lymph node metastasis. With the high correlation of TP53 mutation and genomic instability in ESCC, the amplification of CCND1, the deletion of CDKN2A/2B, and the somatic mutation of TP53 appear to play pivotal roles via G1 deregulation and therefore helps to classify this cancer into different genomic subtypes. These findings provide clinical significance that could be useful in future molecular diagnoses and therapeutic targeting.
authors.affiliation: MOE Key Laboratory of Carcinogenesis and Translational Research, Laboratory of Genetics, Peking University, Cancer Hospital & Institute, Beijing 100142, China; Beijing University of Chinese Medicine, Beijing 100029, China.
authors.forename: Qiyan
authors.initials: Q
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Bai
authors.affiliation: MOE Key Laboratory of Carcinogenesis and Translational Research, Laboratory of Genetics, Peking University, Cancer Hospital & Institute, Beijing 100142, China.
authors.forename: Amir
authors.initials: A
authors.lastname: Abliz
authors.affiliation: MOE Key Laboratory of Carcinogenesis and Translational Research, Laboratory of Genetics, Peking University, Cancer Hospital & Institute, Beijing 100142, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Kenan
authors.initials: K
authors.lastname: Gong
authors.affiliation: MOE Key Laboratory of Carcinogenesis and Translational Research, Laboratory of Genetics, Peking University, Cancer Hospital & Institute, Beijing 100142, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Shi
authors.affiliation: MOE Key Laboratory of Carcinogenesis and Translational Research, Laboratory of Genetics, Peking University, Cancer Hospital & Institute, Beijing 100142, China.
authors.forename: Yaqi
authors.initials: Y
authors.lastname: Pan
authors.affiliation: MOE Key Laboratory of Carcinogenesis and Translational Research, Laboratory of Genetics, Peking University, Cancer Hospital & Institute, Beijing 100142, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Liu
authors.affiliation: CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Shujuan
authors.initials: S
authors.lastname: Lai
authors.affiliation: Anyang Cancer Hospital, Anyang 455000, China.
authors.forename: Haijun
authors.initials: H
authors.lastname: Yang
authors.affiliation: Anyang Cancer Hospital, Anyang 455000, China.
authors.forename: Changdong
authors.initials: C
authors.lastname: Lu
authors.affiliation: Anyang Cancer Hospital, Anyang 455000, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Anyang Cancer Hospital, Anyang 455000, China.
authors.forename: Ruiping
authors.initials: R
authors.lastname: Xu
authors.affiliation: MOE Key Laboratory of Carcinogenesis and Translational Research, Laboratory of Genetics, Peking University, Cancer Hospital & Institute, Beijing 100142, China. Electronic address: drhcai@gmail.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Cai
authors.affiliation: MOE Key Laboratory of Carcinogenesis and Translational Research, Laboratory of Genetics, Peking University, Cancer Hospital & Institute, Beijing 100142, China. Electronic address: keyang@bjmu.edu.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ke
authors.affiliation: CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: czeng@big.ac.cn.
authors.forename: Changqing
authors.initials: C
authors.lastname: Zeng
mesh_terms: D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D002453:Cell Cycle; D019938:Cyclin D1 / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000235:genetics*; D000077277:Esophageal Squamous Cell Carcinoma; D004947:Esophagus / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D018628:Gene Dosage / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics; D023281:Genomics; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C530104:CCND1 protein, human; C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1
keywords: Cell cycle deregulation; Copy number alteration; Esophageal squamous cell carcinoma; Genomic subtype; Somatic mutation