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CNV instability associated with DNA replication dynamics: evidence for replicative mechanisms in CNV mutagenesis.

ABSTRACT: Copy number variation (CNV) in the human genome is of vital importance to human health and evolution of our species. However, much of the molecular basis of CNV mutagenesis remains to be elucidated. Considering the DNA replication model of 'fork stalling and template switching' for CNV formation, we hypothesized that replication fork progression could be important for CNV mutagenesis. However, molecular assays of replication fork progression at the genome level are technically challenging. Instead, we conducted an estimation of DNA replication dynamics, as the statistic R, using the readily available data of replication timing. Small R-values can reflect 'slowed' replication, which could result from less fork initiation, reduced fork speed or fork barriers. We generated genome-wide profiles of R in the genomes of human, mouse and Drosophila. Intriguingly, the CNV breakpoints in all three genomes showed significantly biased distributions toward the genomic regions with small R-values, suggesting potential replication stress-induced CNV instability. Notably, among the human CNVs with distinct breakpoint junction characteristics, the homology-mediated and VNTR-mediated CNVs contribute the most to the correlation between CNV instability and the statistic R, consistent with the recent findings in the C. elegans and yeast genomes of repeat-induced DNA replication error and consequent CNV formation. The statistic R may reflect both replication stress and the effect of local genome architecture on fork progression. Our concordant observations suggest an important role for DNA replicative mechanisms in CNV mutagenesis and genome instability.

SUBMITTER: Chen L

PROVIDER: S-EPMC4381758 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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CNV instability associated with DNA replication dynamics: evidence for replicative mechanisms in CNV mutagenesis.

Chen Lu L Zhou Weichen W Zhang Cheng C Lupski James R JR Jin Li L Zhang Feng F

Human molecular genetics 20141114 6

Copy number variation (CNV) in the human genome is of vital importance to human health and evolution of our species. However, much of the molecular basis of CNV mutagenesis remains to be elucidated. Considering the DNA replication model of 'fork stalling and template switching' for CNV formation, we hypothesized that replication fork progression could be important for CNV mutagenesis. However, molecular assays of replication fork progression at the genome level are technically challenging. Inste ...[more]

PMID: 25398944

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Project description:In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes. However, it is recognized that many tumors exhibit genomic instability but lack BRCA inactivation. We sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors. Methods: Using multi-omics data from two independent consortia, we analyzed data from dozens of tumor types to identify patient cohorts characterized by poor outcomes, genomic instability, and wildtype BRCA genes. We developed several novel metrics to identify the genetic underpinnings of genomic instability in tumors with wildtype BRCA. Associated clinical data was mined to analyze patient responses to standard of care therapies and potential differences in metastatic dissemination. Results: Systematic analysis of the DNA repair landscape revealed that defective single-strand break repair, translesion synthesis, and non-homologous end-joining effectors drive genomic instability in tumors with wildtype BRCA and BRCA-related genes. Importantly, we find that loss of these effectors promotes replication stress, therapy resistance, and increased primary carcinoma to brain metastasis. Conclusions: Our results have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by the accumulation of intra-chromosomal, gene-level gain and loss events at replication stress sensitive (RSS) genome sites. We find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Clinically, we find that RIN drives therapy resistance and distant metastases across multiple tumor types.

Dataset Information

CNV instability associated with DNA replication dynamics: evidence for replicative mechanisms in CNV mutagenesis.

Publications

CNV instability associated with DNA replication dynamics: evidence for replicative mechanisms in CNV mutagenesis.

Similar Datasets

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