title: Spatial intratumoral heterogeneity and temporal clonal evolution in esophageal squamous cell carcinoma.
abstract: Esophageal squamous cell carcinoma (ESCC) is among the most common malignancies, but little is known about its spatial intratumoral heterogeneity (ITH) and temporal clonal evolutionary processes. To address this, we performed multiregion whole-exome sequencing on 51 tumor regions from 13 ESCC cases and multiregion global methylation profiling for 3 of these 13 cases. We found an average of 35.8% heterogeneous somatic mutations with strong evidence of ITH. Half of the driver mutations located on the branches of tumor phylogenetic trees targeted oncogenes, including PIK3CA, NFE2L2 and MTOR, among others. By contrast, the majority of truncal and clonal driver mutations occurred in tumor-suppressor genes, including TP53, KMT2D and ZNF750, among others. Interestingly, phyloepigenetic trees robustly recapitulated the topological structures of the phylogenetic trees, indicating a possible relationship between genetic and epigenetic alterations. Our integrated investigations of spatial ITH and clonal evolution provide an important molecular foundation for enhanced understanding of tumorigenesis and progression in ESCC.
authors.affiliation: State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Jia-Jie
authors.initials: JJ
authors.lastname: Hao
authors.affiliation: Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California, USA.|Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: De-Chen
authors.initials: DC
authors.lastname: Lin
authors.affiliation: Center for Bioinformatics and Functional Genomics, Biomedical Sciences, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California, USA.
authors.forename: Huy Q
authors.initials: HQ
authors.lastname: Dinh
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Anand
authors.initials: A
authors.lastname: Mayakonda
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Yan-Yi
authors.initials: YY
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chang
authors.affiliation: State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Chen-Chen
authors.initials: CC
authors.lastname: Lu
authors.affiliation: Faculty of Medicine, Kunming University of Science and Technology, Kunming, China.
authors.forename: Zhi-Zhou
authors.initials: ZZ
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Pathology, Linzhou Cancer Hospital, Henan, China.
authors.forename: Jin-Wu
authors.initials: JW
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Qi-Min
authors.initials: QM
authors.lastname: Zhan
authors.affiliation: Department of Cancer Epidemiology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Wen-Qiang
authors.initials: WQ
authors.lastname: Wei
authors.affiliation: Center for Bioinformatics and Functional Genomics, Biomedical Sciences, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California, USA.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Berman
authors.affiliation: State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Wang
authors.affiliation: Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California, USA.|Cancer Science Institute of Singapore, National University of Singapore, Singapore.|National University Cancer Institute, National University Hospital Singapore, Singapore.
authors.forename: H Phillip
authors.identifier: 0000-0001-5839-9913
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D060965:Clonal Evolution / Q000235:genetics*; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D019175:DNA Methylation; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*
chemical_list: D009363:Neoplasm Proteins