Dataset Information

Single-molecule analysis of genome rearrangements in cancer.

ABSTRACT: Rearrangements of the genome can be detected by microarray methods and massively parallel sequencing, which identify copy-number alterations and breakpoint junctions, but these techniques are poorly suited to reconstructing the long-range organization of rearranged chromosomes, for example, to distinguish between translocations and insertions. The single-DNA-molecule technique HAPPY mapping is a method for mapping normal genomes that should be able to analyse genome rearrangements, i.e. deviations from a known genome map, to assemble rearrangements into a long-range map. We applied HAPPY mapping to cancer cell lines to show that it could identify rearrangement of genomic segments, even in the presence of normal copies of the genome. We could distinguish a simple interstitial deletion from a copy-number loss at an inversion junction, and detect a known translocation. We could determine whether junctions detected by sequencing were on the same chromosome, by measuring their linkage to each other, and hence map the rearrangement. Finally, we mapped an uncharacterized reciprocal translocation in the T-47D breast cancer cell line to about 2?kb and hence cloned the translocation junctions. We conclude that HAPPY mapping is a versatile tool for determining the structure of rearrangements in the human genome.

SUBMITTER: Pole JC

PROVIDER: S-EPMC3141271 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Single-molecule analysis of genome rearrangements in cancer.

Pole Jessica C M JC McCaughan Frank F Newman Scott S Howarth Karen D KD Dear Paul H PH Edwards Paul A W PA

Nucleic acids research 20110427 13

Rearrangements of the genome can be detected by microarray methods and massively parallel sequencing, which identify copy-number alterations and breakpoint junctions, but these techniques are poorly suited to reconstructing the long-range organization of rearranged chromosomes, for example, to distinguish between translocations and insertions. The single-DNA-molecule technique HAPPY mapping is a method for mapping normal genomes that should be able to analyse genome rearrangements, i.e. deviatio ...[more]

PMID: 21525129

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Project description:Understanding mechanisms of cancer breakpoint mutagenesis is a difficult task and predictive models of cancer breakpoint formation have to this time failed to achieve even moderate predictive power. Here we take advantage of a machine learning approach that can gather important features from big data and quantify contribution of different factors. We performed comprehensive analysis of almost 630,000 cancer breakpoints and quantified the contribution of genomic and epigenomic features-non-B DNA structures, chromatin organization, transcription factor binding sites and epigenetic markers. The results showed that transcription and formation of non-B DNA structures are two major processes responsible for cancer genome fragility. Epigenetic factors, such as chromatin organization in TADs, open/closed regions, DNA methylation, histone marks are less informative but do make their contribution. As a general trend, individual features inside the groups show a relatively high contribution of G-quadruplexes and repeats and CTCF, GABPA, RXRA, SP1, MAX and NR2F2 transcription factors. Overall, the cancer breakpoint landscape can be represented by well-predicted hotspots and poorly predicted individual breakpoints scattered across genomes. We demonstrated that hotspot mutagenesis has genomic and epigenomic factors, and not all individual cancer breakpoints are just random noise but have a definite mutation signature. Besides we found a long-range action of some features on breakpoint mutagenesis. Combining omics data, cancer-specific individual feature importance and adding the distant to local features, predictive models for cancer breakpoint formation achieved 70-90% ROC AUC for different cancer types; however precision remained low at 2% and the recall did not exceed 50%. On the one hand, the power of models strongly correlates with the size of available cancer breakpoint and epigenomic data, and on the other hand finding strong determinants of cancer breakpoint formation still remains a challenge. The strength of predictive signals of each group and of each feature inside a group can be converted into cancer-specific breakpoint mutation signatures. Overall our results add to the understanding of cancer genome rearrangement processes.

Dataset Information

Single-molecule analysis of genome rearrangements in cancer.

Publications

Single-molecule analysis of genome rearrangements in cancer.

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