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 exon...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.展开更多
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...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.展开更多
基金supported by the National Basic Research Program of China from the National Ministry of Science and Technology(973 Program)to YK(Grant No.2011CB504300)and to HC(Grant No.2012CB910800)the National Natural Science Foundation of China(Grant No.30930102)to YK+3 种基金the National High-tech R&D Program of China(863 ProgramGrant No.2012AA022502)Key Research Program of the Chinese Academy of Sciences of China(Grant No.KJZD-EW-L06-2)to CZthe Open Fund of MOE Key Laboratory of Carcinogenesis and Translational Research(Grant No.2014KAIFANG-4)to JB
文摘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.
基金supported by the grants from the Strategic Priority Research Program of Chinese Academy of Sciences(Grant No.XDB13020500)the National Natural Science Foundation of China(NSFC)(Grant Nos.91131905,31471199,and 91631304)+3 种基金the Key Research Program of Chinese Academy of Sciences(Grant No.KJZD-EW-L14 to CZ)the NSFC(Grant Nos.31440057 and 31701081 to WC)the 111 Project(Grant No.B13003 to WC and DZ)the Innovation Promotion Association of Chinese Academy of Sciences(Grant Nos.2016098 to DZ and 2019103 to AC)。
文摘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.
