Dataset Information

Genomic and Transcriptomic Landscape of Tumor Clonal Evolution in Cholangiocarcinoma.

ABSTRACT: Cholangiocarcinoma remained a severe threat to human health. Deciphering the genomic and/or transcriptomic profiles of tumor has been proved to be a promising strategy for exploring the mechanism of tumorigenesis and development, which could also provide valuable insights into Cholangiocarcinoma. However, little knowledge has been obtained regarding to how the alteration among different omics levels is connected. Here, using whole exome sequencing and transcriptome sequencing, we performed a thorough evaluation for the landscape of genome and transcriptome in cholangiocarcinoma and illustrate the alteration of tumor on different biological levels. Meanwhile, we also identified the clonal structure of each included tumor sample and discovered different clonal evolution patterns related to patients' survival. Furthermore, we extracted subnetworks that were greatly influenced by tumor clonal/subclonal mutations or transcriptome change. The topology relationship between genes affected by genomic/transcriptomic changes in biological interaction networks revealed that alteration of genome and transcriptome was highly correlated, and somatic mutations located on important genes might affect the expression of numerous genes in close range.

SUBMITTER: Chen G

PROVIDER: S-EPMC7083074 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Genomic and Transcriptomic Landscape of Tumor Clonal Evolution in Cholangiocarcinoma.

Chen Geng G Cai Zhixiong Z Dong Xiuqing X Zhao Jing J Lin Song S Hu Xi X Liu Fang-E FE Liu Xiaolong X Zhang Huqing H

Frontiers in genetics 20200313

Cholangiocarcinoma remained a severe threat to human health. Deciphering the genomic and/or transcriptomic profiles of tumor has been proved to be a promising strategy for exploring the mechanism of tumorigenesis and development, which could also provide valuable insights into Cholangiocarcinoma. However, little knowledge has been obtained regarding to how the alteration among different omics levels is connected. Here, using whole exome sequencing and transcriptome sequencing, we performed a tho ...[more]

PMID: 32231683

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Project description:Adaptive evolution is generally assumed to progress through the accumulation of beneficial mutations. However, as deleterious mutations are common in natural populations, they generate a strong selection pressure to mitigate their detrimental effects through compensatory genetic changes. This process can potentially influence directions of adaptive evolution by enabling evolutionary routes that are otherwise inaccessible. Therefore, the extent to which compensatory mutations shape genomic evolution is of central importance. Here, we studied the capacity of the baker's yeast genome to compensate the complete loss of genes during evolution, and explored the long-term consequences of this process. We initiated laboratory evolutionary experiments with over 180 haploid baker's yeast genotypes, all of which initially displayed slow growth owing to the deletion of a single gene. Compensatory evolution following gene loss was rapid and pervasive: 68% of the genotypes reached near wild-type fitness through accumulation of adaptive mutations elsewhere in the genome. As compensatory mutations have associated fitness costs, genotypes with especially low fitnesses were more likely to be subjects of compensatory evolution. Genomic analysis revealed that as compensatory mutations were generally specific to the functional defect incurred, convergent evolution at the molecular level was extremely rare. Moreover, the majority of the gene expression changes due to gene deletion remained unrestored. Accordingly, compensatory evolution promoted genomic divergence of parallel evolving populations. However, these different evolutionary outcomes are not phenotypically equivalent, as they generated diverse growth phenotypes across environments. Taken together, these results indicate that gene loss initiates adaptive genomic changes that rapidly restores fitness, but this process has substantial pleiotropic effects on cellular physiology and evolvability upon environmental change. Our work also implies that gene content variation across species could be partly due to the action of compensatory evolution rather than the passive loss of genes.

Project description:Multiple Myeloma (MM) arises from malignant transformation and deregulated proliferation of clonal plasma cells (PCs) harbouring heterogeneous molecular anomalies. The effect of evolving mutations on clone fitness and their cellular prevalence shapes the progressing myeloma genome and impacts clinical outcomes. Although clonal heterogeneity in MM is well established, which subclonal mutations emerge/persist/perish with progression in MM and which of these can be targeted therapeutically remains an open question. In line with this, we have sequenced pairwise whole exomes of 62 MM patients collected at two time points, i.e., at diagnosis and on progression. Somatic variants were called using a novel ensemble approach where a consensus was deduced from four variant callers (Illumina's Dragen, Strelka2, SomaticSniper and SpeedSeq) and actionable/druggable gene targets were identified. A marked intraclonal heterogeneity was observed. Branching evolution was observed among 72.58% patients, of whom 64.51% had low TMBs (<10) and 61.29% had 2 or more founder clones. The hypermutator patients (with high TMB levels ≥10 to ≤100) showed a significant decrease in their TMBs from diagnosis (median TMB 77.11) to progression (median TMB 31.22). A distinct temporal fall in subclonal driver mutations was identified recurrently across diagnosis to progression e.g., in PABPC1, BRAF, KRAS, CR1, DIS3 and ATM genes in 3 or more patients suggesting such patients could be treated early with target specific drugs like Vemurafenib/Cobimetinib. An analogous rise in driver mutations was observed in KMT2C, FOXD4L1, SP140, NRAS and other genes. A few drivers such as FAT4, IGLL5 and CDKN1A retained consistent distribution patterns at two time points. These findings are clinically relevant and point at consideration of evaluating multi time point subclonal mutational landscapes for designing better risk stratification strategies and tailoring time to time risk adapted combination therapies in future.

Project description:BackgroundAcinetobacter calcoaceticus-A. baumannii (ACB) complex pathogens are known for their prevalence in nosocomial infections and extensive antimicrobial resistance (AMR) capabilities. While genomic studies worldwide have elucidated the genetic context of antibiotic resistance in major international clones (ICs) of clinical Acinetobacter spp., not much information is available from Bangladesh. In this study, we analysed the AMR profiles of 63 ACB complex strains collected from Dhaka, Bangladesh. Following this, we generated draft genomes of 15 of these strains to understand the prevalence and genomic environments of AMR, virulence and mobilization associated genes in different Acinetobacter clones.ResultsAround 84% (n = 53) of the strains were extensively drug resistant (XDR) with two showing pan-drug resistance. Draft genomes generated for 15 strains confirmed 14 to be A. baumannii while one was A. nosocomialis. Most A. baumannii genomes fell under three clonal complexes (CCs): the globally dominant CC1 and CC2, and CC10; one strain had a novel sequence type (ST). AMR phenotype-genotype agreement was observed and the genomes contained various beta-lactamase genes including blaOXA-23 (n = 12), blaOXA-66 (n = 6), and blaNDM-1 (n = 3). All genomes displayed roughly similar virulomes, however some virulence genes such as the Acinetobactin bauA and the type IV pilus gene pilA displayed high genetic variability. CC2 strains carried highest levels of plasmidic gene content and possessed conjugative elements carrying AMR genes, virulence factors and insertion sequences.ConclusionThis study presents the first comparative genomic analysis of XDR clinical Acinetobacter spp. from Bangladesh. It highlights the prevalence of different classes of beta-lactamases, mobilome-derived heterogeneity in genetic architecture and virulence gene variability in prominent Acinetobacter clonal complexes in the country. The findings of this study would be valuable in understanding the genomic epidemiology of A. baumannii clones and their association with closely related pathogenic species like A. nosocomialis in Bangladesh.

Dataset Information

Genomic and Transcriptomic Landscape of Tumor Clonal Evolution in Cholangiocarcinoma.

Publications

Genomic and Transcriptomic Landscape of Tumor Clonal Evolution in Cholangiocarcinoma.

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