Dataset Information

A Gene Gravity Model for the Evolution of Cancer Genomes: A Study of 3,000 Cancer Genomes across 9 Cancer Types.

ABSTRACT: Cancer development and progression result from somatic evolution by an accumulation of genomic alterations. The effects of those alterations on the fitness of somatic cells lead to evolutionary adaptations such as increased cell proliferation, angiogenesis, and altered anticancer drug responses. However, there are few general mathematical models to quantitatively examine how perturbations of a single gene shape subsequent evolution of the cancer genome. In this study, we proposed the gene gravity model to study the evolution of cancer genomes by incorporating the genome-wide transcription and somatic mutation profiles of ~3,000 tumors across 9 cancer types from The Cancer Genome Atlas into a broad gene network. We found that somatic mutations of a cancer driver gene may drive cancer genome evolution by inducing mutations in other genes. This functional consequence is often generated by the combined effect of genetic and epigenetic (e.g., chromatin regulation) alterations. By quantifying cancer genome evolution using the gene gravity model, we identified six putative cancer genes (AHNAK, COL11A1, DDX3X, FAT4, STAG2, and SYNE1). The tumor genomes harboring the nonsynonymous somatic mutations in these genes had a higher mutation density at the genome level compared to the wild-type groups. Furthermore, we provided statistical evidence that hypermutation of cancer driver genes on inactive X chromosomes is a general feature in female cancer genomes. In summary, this study sheds light on the functional consequences and evolutionary characteristics of somatic mutations during tumorigenesis by propelling adaptive cancer genome evolution, which would provide new perspectives for cancer research and therapeutics.

SUBMITTER: Cheng F

PROVIDER: S-EPMC4564226 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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A Gene Gravity Model for the Evolution of Cancer Genomes: A Study of 3,000 Cancer Genomes across 9 Cancer Types.

Cheng Feixiong F Liu Chuang C Lin Chen-Ching CC Zhao Junfei J Jia Peilin P Li Wen-Hsiung WH Li Wen-Hsiung WH Zhao Zhongming Z

PLoS computational biology 20150909 9

Cancer development and progression result from somatic evolution by an accumulation of genomic alterations. The effects of those alterations on the fitness of somatic cells lead to evolutionary adaptations such as increased cell proliferation, angiogenesis, and altered anticancer drug responses. However, there are few general mathematical models to quantitatively examine how perturbations of a single gene shape subsequent evolution of the cancer genome. In this study, we proposed the gene gravit ...[more]

PMID: 26352260

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Project description:BackgroundIn gene-dense genomes, mobile elements are confronted with highly selective pressure to amplify without causing excessive damage to the host. The targeting of tRNA genes as potentially safe integration sites has been developed by retrotransposons in various organisms such as the social amoeba Dictyostelium discoideum and the yeast Saccharomyces cerevisiae. In D. discoideum, tRNA gene-targeting retrotransposons have expanded to approximately 3 % of the genome. Recently obtained genome sequences of species representing the evolutionary history of social amoebae enabled us to determine whether the targeting of tRNA genes is a generally successful strategy for mobile elements to colonize compact genomes.ResultsDuring the evolution of dictyostelids, different retrotransposon types independently developed the targeting of tRNA genes at least six times. DGLT-A elements are long terminal repeat (LTR) retrotransposons that display integration preferences ~15 bp upstream of tRNA gene-coding regions reminiscent of the yeast Ty3 element. Skipper elements are chromoviruses that have developed two subgroups: one has canonical chromo domains that may favor integration in centromeric regions, whereas the other has diverged chromo domains and is found ~100 bp downstream of tRNA genes. The integration of D. discoideum non-LTR retrotransposons ~50 bp upstream (TRE5 elements) and ~100 bp downstream (TRE3 elements) of tRNA genes, respectively, likely emerged at the root of dictyostelid evolution. We identified two novel non-LTR retrotransposons unrelated to TREs: one with a TRE5-like integration behavior and the other with preference ~4 bp upstream of tRNA genes.ConclusionsDictyostelid retrotransposons demonstrate convergent evolution of tRNA gene targeting as a probable means to colonize the compact genomes of their hosts without being excessively mutagenic. However, high copy numbers of tRNA gene-associated retrotransposons, such as those observed in D. discoideum, are an exception, suggesting that the targeting of tRNA genes does not necessarily favor the amplification of position-specific integrating elements to high copy numbers under the repressive conditions that prevail in most host cells.

Dataset Information

A Gene Gravity Model for the Evolution of Cancer Genomes: A Study of 3,000 Cancer Genomes across 9 Cancer Types.

Publications

A Gene Gravity Model for the Evolution of Cancer Genomes: A Study of 3,000 Cancer Genomes across 9 Cancer Types.

Similar Datasets

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