Common Fragile Sites: Genomic Hotspots of DNA Damage and Carcinogenesis

Ma, Ke; Qiu, Li; Mrasek, Kristin; Zhang, Jun; Liehr, Thomas; Quintana, Luciana Gonçalves; Li, Zheng

doi:10.3390/ijms130911974

Cited by 63 publications

(53 citation statements)

References 139 publications

(180 reference statements)

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“…Assuming breakpoints are observed in syntenic canine regions, these particular breakpoints would represent fragile sites in CFA 19 and 36 predisposed to duplication, deletion, and translocation. As canine cells evolve to malignancy, rapidly proliferative cells succumb to inherent genomic fragility, resulting in chromosome breaks and copy number aberrations (Richards 2001; Ma et al 2012; Hosseini et al 2013). …”

Section: Discussionmentioning

confidence: 99%

Canine urothelial carcinoma: genomically aberrant and comparatively relevant

et al. 2015

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Urothelial carcinoma (UC), also referred to as transitional cell carcinoma (TCC), is the most common bladder malignancy in both human and canine populations. In human UC, numerous studies have demonstrated the prevalence of chromosomal imbalances. Although the histopathology of the disease is similar in both species, studies evaluating the genomic profile of canine UC are lacking, limiting the discovery of key comparative molecular markers associated with driving UC pathogenesis. In the present study, we evaluated 31 primary canine UC biopsies by oligonucleotide array comparative genomic hybridization (oaCGH). Results highlighted the presence of three highly recurrent numerical aberrations: gain of dog chromosome (CFA) 13 and 36 and loss of CFA 19. Regional gains of CFA 13 and 36 were present in 97% and 84% of cases, respectively, and losses on CFA 19 were present in 77% of cases. Fluorescence in situ hybridization (FISH), using targeted bacterial artificial chromosome (BAC) clones and custom Agilent SureFISH probes, was performed to detect and quantify these regions in paraffin-embedded biopsy sections and urine-derived urothelial cells. The data indicate that these three aberrations are potentially diagnostic of UC. Comparison of our canine oaCGH data with that of 285 human cases identified a series of shared copy number aberrations. Using an informatics approach to interrogate the frequency of copy number aberrations across both species, we identified those that had the highest joint probability of association with UC. The most significant joint region contained the gene PABPC1, which should be considered further for its role in UC progression. In addition, cross-species filtering of genome-wide copy number data highlighted several genes as high-profile candidates for further analysis, including CDKN2A, S100A8/9, and LRP1B. We propose that these common aberrations are indicative of an evolutionarily conserved mechanism of pathogenesis and harbor genes key to urothelial neoplasia, warranting investigation for diagnostic, prognostic, and therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Canine urothelial carcinoma: genomically aberrant and comparatively relevant

et al. 2015

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“…In contrast, CFSs are clearly associated with cancer breakpoints and their expression linked to carcinogenesis (Arlt et al 2006; Ma et al 2012). Interestingly, some CFSs are also implicated in neurological disorders (Parkinson’s, schizophrenia, and intellectual disability) and a variety of diseases associated with immunodeficiency, bone disorders, and infertility (Table 21.2).…”

Section: 3 Classification Of “Common” Vs “Rare” Fragile Sitesmentioning

confidence: 99%

Fragility Extraordinaire: Unsolved Mysteries of Chromosome Fragile Sites

Feng

Chakraborty

2017

Advances in Experimental Medicine and Biology

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Chromosome fragile sites are a fascinating cytogenetic phenomenon now widely implicated in a slew of human diseases ranging from neurological disorders to cancer. Yet, the paths leading to these revelations were far from direct, and the number of fragile sites that have been molecularly cloned with known disease-associated genes remains modest. Moreover, as more fragile sites were being discovered, research interests in some of the earliest discovered fragile sites ebbed away, leaving a number of unsolved mysteries in chromosome biology. In this review we attempt to recount some of the early discoveries of fragile sites and highlight those phenomena that have eluded intense scrutiny but remain extremely relevant in our understanding of the mechanisms of chromosome fragility. We then survey the literature for disease association for a comprehensive list of fragile sites. We also review recent studies addressing the underlying cause of chromosome fragility while highlighting some ongoing debates. We report an observed enrichment for R-loop forming sequences in fragile site-associated genes than genomic average. Finally, we will leave the reader with some lingering questions to provoke discussion and inspire further scientific inquiries.

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“…9 This usage as a term of increased intensity continues in radiology, 10,11 and is analogous to references to hotspots as areas of increased risk or incidence in epidemiology and other fields. [12][13][14][15][16][17] In contrast, "hotspot" has long been used in genetics to refer to a highly polymorphic area in an organism's genome, 18 where, for instance, cancer-causing mutations are likely to occur, 19,20 or hypervariability allows a pathogen to evade the immune response. 21 This usage is analogous to how "hotspot" is used when referring to areas of frequent emergence of novel pathogens.…”

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confidence: 99%

What is a Hotspot Anyway?

Lessler

Azman

McKay

et al. 2017

The American Society of Tropical Medicine and Hygiene

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The importance of spatial clusters, or “hotspots,” in infectious disease epidemiology has been increasingly recognized, and targeting hotspots is often seen as an important component of disease-control strategies. However, the precise meaning of “hotspot” varies widely in current research and policy documents. Hotspots have been variously described as areas of elevated incidence or prevalence, higher transmission efficiency or risk, or higher probability of disease emergence. This ambiguity has led to confusion and may result in mistaken inferences regarding the best way to target interventions. We surveyed the literature on epidemiologic hotspots, examining the multitude of ways in which the term is used; and highlight the difference in the geographic scale of hotspots and the properties they are supposed to have. In response to the diversity in the term's usage, we advocate the use of more precise terms, such as “burden hotspot,” “transmission hotspot,” and “emergence hotspot,” as well as explicit specification of the spatiotemporal scale of interest. Increased precision in terminology is needed to ensure clear and effective policies for disease control.

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Common Fragile Sites: Genomic Hotspots of DNA Damage and Carcinogenesis

Cited by 63 publications

References 139 publications

Canine urothelial carcinoma: genomically aberrant and comparatively relevant

Canine urothelial carcinoma: genomically aberrant and comparatively relevant

Fragility Extraordinaire: Unsolved Mysteries of Chromosome Fragile Sites

What is a Hotspot Anyway?

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