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Common Postzygotic Mutational Signatures in Healthy Adult Tissues Related to Embryonic Hypoxia

Genomics, Proteomics & Bioinformatics 2022年第1期20卷 177-191页

作者： Yaqiang Hong Dake Zhang Xiangtian Zhou Aili Chen amir abliz Jian Bai Liang Wang Qingtao Hu Kenan Gong Xiaonan Guan Mengfei Liu Xinchang Zheng Shujuan Lai Hongzhu Qu Fuxin Zhao Shuang Hao Zhen Wu Hong Cai Shaoyan Hu Yue Ma Junting Zhang Yang Ke Qian-Fei Wang Wei Chen Changqing Zeng CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China Beijing Advanced Innovation Centre for Biomedical Engineering Key Laboratory for Biomechanics and Mechanobiology of Ministry of EducationSchool of Biological Science and Medical EngineeringBeihang UniversityBeijing 100191China Tsinghua-Peking Center for Life Sciences School of Life SciencesTsinghua UniversityBeijing 100084China School of Optometry and Ophthalmology and Eye Hospital Wenzhou Medical UniversityWenzhou 325035China The State Key Laboratory of Optometry Ophthalmology and Vision ScienceWenzhou 325035China Key Laboratory of Carcinogenesis and Translational Research(MOE) Laboratory of GeneticsPeking University Cancer Hospital&InstituteBeijing 100142China Skull Base and Brainstem Tumor Division Department of NeurosurgeryBeijing Tian Tan HospitalCapital Medical UniversityBeijing 100050China China National Clinical Research Center for Neurological Diseases Beijing 100050China CAS Key Laboratory of Genome Sciences and Information Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China Department of Hematology and Oncology Children’s Hospital of Soochow UniversitySuzhou 215025China Institute of Biophysics Chinese Academy of SciencesBeijing 100101China Collaborative Innovation Center for Genetics and Development Shanghai 200438China University of Chinese Academy of Sciences Beijing 100049China

Postzygotic mutations are acquired in normal tissues throughout an individual’s lifetime and hold clues for identifying mutagenic factors.Here,we investigated postzygotic mutation spectra of healthy individuals using optimized ultra-deep exome sequencing of the time-series samples from the same volunteer as well as the samples from different individuals.In blood,sperm,and muscle cells,we resolved three common types of mutational signatures.Signatures A and B represent clocklike mutational processes,and the polymorphisms of epigenetic regulation genes influence the proportion of signature B in mutation profiles.Notably,signature C,characterized by C>T transitions at GpCpN sites,tends to be a feature of diverse normal tissues.Mutations of this type are likely to occur early during embryonic development,supported by their relatively high allelic frequencies,presence in multiple tissues,and decrease in occurrence with age.Almost none of the public datasets for tumors feature this signature,except for 19.6%of samples of clear cell renal cell carcinoma with increased activation of the hypoxia-inducible factor 1(HIF-1)signaling pathway.Moreover,the accumulation of signature C in the mutation profile was accelerated in a human embryonic stem cell line with drug-induced activation of HIF-1α.Thus,embryonic hypoxia may explain this novel signature across multiple normal tissues.Our study suggests that hypoxic condition in an early stage of embryonic development is a crucial factor inducing C>T transitions at GpCpN sites;and individuals’genetic background may also influence their postzygotic mutation profiles.

关键词： Postzygotic mutation Mutational signature Healthy individual Embryonic development Hypoxia

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An Old Story Retold: Loss of G1 Control Defines A Distinct Genomic Subtype of Esophageal Squamous Cell Carcinoma

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Genomics, Proteomics & Bioinformatics 2015年第4期13卷 258-270页

作者： Qiyan Wang Jian Bai amir abliz Ying Liu Kenan Gong Jingjing Li Wenjie Shi Yaqi Pan Fangfang Liu Shujuan Lai Haijun Yang Changdong Lu Lixin Zhang Wei Chen Ruiping Xu Hong Cai Yang Ke Changqing Zeng MOE Key Laboratory of Carcinogenesis and Translational Research Laboratory of Genetics Peking UniversityCancer Hospital & Institute Beijing University of Chinese Medicine CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of Genomics Chinese Academy of Sciences University of Chinese Academy of Sciences Anyang Cancer Hospital

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 sam- ples using Sanger sequencing. Whole-genomc 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 signifi- cantly 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 1 1q13.3 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, 7p 11.2, and 3p 12.1, 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.

关键词： Esophageal squamous cell carcinoma Genomic subtype somatic mutation Copy number alteration Cell cycle deregulation

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