The cellular etiology of chromosome translocations

Roukos, Vassilis; Burman, Bharat; Misteli, Tom

doi:10.1016/j.ceb.2013.02.015

Cited by 34 publications

(22 citation statements)

References 79 publications

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“…Studies of both RET/PTC and NTRK rearrangements have shown that the gene loci participating in the fusions lie in close spatial proximity to one another during interphase in thyroid cells, likely predisposing to recombination of adjacent chromosomal regions after radiation-induced DNA damage (9,10). The spatial organization of the genome is now thought to be a key contributing factor to the generation of chromosomal translocations in cancer (22). The rationale to select RNA-seq rather than whole-exome sequencing as the primary modality to screen for new oncogenic drivers was based on these factors and the consequent prediction that fusion oncogenes were likely to predominate in this particular patient population.…”

Section: Discussionmentioning

confidence: 99%

Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers

Ricarte-Filho¹,

Li²,

et al. 2013

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Exposure to ionizing radiation during childhood markedly increases the risk of developing papillary thyroid cancer. We examined tissues from 26 Ukrainian patients with thyroid cancer who were younger than 10 years of age and living in contaminated areas during the time of the Chernobyl nuclear reactor accident. We identified nonoverlapping somatic driver mutations in all 26 cases through candidate gene assays and next-generation RNA sequencing. We found that 22 tumors harbored fusion oncogenes that arose primarily through intrachromosomal rearrangements. Altogether, 23 of the oncogenic drivers identified in this cohort aberrantly activate MAPK signaling, including the 2 somatic rearrangements resulting in fusion of transcription factor ETS variant 6 (ETV6) with neurotrophic tyrosine kinase receptor, type 3 (NTRK3) and fusion of acylglycerol kinase (AGK) with BRAF. Two other tumors harbored distinct fusions leading to overexpression of the nuclear receptor PPARγ. Fusion oncogenes were less prevalent in tumors from a cohort of children with pediatric thyroid cancers that had not been exposed to radiation but were from the same geographical regions. Radiation-induced thyroid cancers provide a paradigm of tumorigenesis driven by fusion oncogenes that activate MAPK signaling or, less frequently, a PPARγ-driven transcriptional program.

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Section: Discussionmentioning

confidence: 99%

Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers

Ricarte-Filho¹,

Li²,

et al. 2013

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“…Automated analysis of all images was performed based on a modified version of a previously described Acapella 2.6 (PerkinElmer) custom script [30,[33][34][35]. This custom script performed automated nucleus detection based on the maximal projection of the DAPI image (ex.…”

Section: D and 3d Image Analysismentioning

confidence: 99%

Comparative analysis of 2D and 3D distance measurements to study spatial genome organization

Finn

Pegoraro

Shachar

et al. 2016

Preprint

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The spatial organization of eukaryotic genomes is non-random, cell-type specific, and has been linked to cellular function. The investigation of spatial organization has traditionally relied extensively on fluorescence microscopy. The validity of the imaging methods used to probe spatial genome organization often depends on the accuracy and precision of distance measurements. Imaging-based measurements may either use 2 dimensional datasets or 3D datasets including the z-axis information in image stacks. Here we compare the suitability of 2D versus 3D distance measurements in the analysis of various features of spatial genome organization. We find in general good agreement between 2D and 3D analysis with higher convergence of measurements as the interrogated distance increases, especially in flat cells. Overall, 3D distance measurements are more accurate than 2D distances, but are also more prone to noise. In particular, z-stacks are prone to error due to imaging properties such as limited resolution along the z-axis and optical aberrations, and we also find significant deviations from unimodal distance distributions caused by low sampling frequency in z. These deviations can be ameliorated by sampling at much higher frequency in the z-direction. We conclude that 2D distances are preferred for comparative analyses between cells, but 3D distances are preferred when comparing to theoretical models in large samples of cells. In general, 2D distance measurements remain preferable for many applications of analysis of spatial genome organization.

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“…Translocations recur at nonrandom genomic sites, and breakpoints tend to cluster in the translocating genes, often within introns (Zhang and Rowley 2006). The molecular features that determine which regions of the genome are particularly susceptible to breakage and translocation are largely unknown (Roukos et al 2013a). While DNA sequence features such as CpG content, repetitive elements, and secondary non-B DNA structures have been implicated in promoting breakage of some genome regions (Nambiar and Raghavan 2011), large-scale sequencing of translocation junctions indicates considerable sequence diversity over translocation-prone genome regions (Talkowski et al 2011).…”

mentioning

confidence: 99%

Histone modifications predispose genome regions to breakage and translocation

et al. 2015

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Chromosome translocations are well-established hallmarks of cancer cells and often occur at nonrandom sites in the genome. The molecular features that define recurrent chromosome breakpoints are largely unknown. Using a combination of bioinformatics, biochemical analysis, and cell-based assays, we identify here specific histone modifications as facilitators of chromosome breakage and translocations. We show enrichment of several histone modifications over clinically relevant translocation-prone genome regions. Experimental modulation of histone marks sensitizes genome regions to breakage by endonuclease challenge or irradiation and promotes formation of chromosome translocations of endogenous gene loci. Our results demonstrate that histone modifications predispose genome regions to chromosome breakage and translocations.

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The cellular etiology of chromosome translocations

Cited by 34 publications

References 79 publications

Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers

Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers

Comparative analysis of 2D and 3D distance measurements to study spatial genome organization

Histone modifications predispose genome regions to breakage and translocation

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