DNA breaks at fragile sites generate oncogenic RET/PTC rearrangements in human thyroid cells

Autor: Sreemanta Pramanik, Manoj Gandhi, Yuri E. Nikiforov, Laura W. Dillon, Levi C. T. Pierce, Yuh-Hwa Wang
Rok vydání: 2010
Předmět:
Cancer Research
endocrine system diseases
Molecular Sequence Data
Population
Thyroid Gland
Fragile site
RET/PTC rearrangement
Biology
medicine.disease_cause
papillary thyroid carcinomas
Biochemistry
Translocation
Genetic
Article
Cell Line
03 medical and health sciences
0302 clinical medicine
Aphidicolin
Genetics
medicine
Humans
Thyroid Neoplasms
FRA10C/FRA10G
education
Molecular Biology
Gene
030304 developmental biology
RET/PTC Rearrangement
0303 health sciences
education.field_of_study
Base Sequence
Chromosome Fragile Sites
Chromosomal fragile site
DNA Breaks
Proto-Oncogene Proteins c-ret
Oncogenes
Chromosome Fragility
Carcinoma
Papillary
Introns
3. Good health
Chromosome Fragile Site
Dna breaks
030220 oncology & carcinogenesis
Cancer research
Human thyroid
Carcinogenesis
030217 neurology & neurosurgery
Biotechnology
Zdroj: Oncogene
ISSN: 1476-5594
0950-9232
DOI: 10.1038/onc.2009.502
Popis: Human chromosomal fragile sites are regions of the genome that are prone to DNA breakage, and are classified as common or rare, depending on their frequency in the population. Common fragile sites frequently coincide with the location of genes involved in carcinogenic chromosomal translocations, suggesting their role in cancer formation. However, there has been no direct evidence linking breakage at fragile sites to the formation of a cancer-specific translocation. Here, we studied the involvement of fragile sites in the formation of RET/PTC rearrangements, which are frequently found in papillary thyroid carcinoma (PTC). These rearrangements are commonly associated with radiation exposure; however most of the tumors found in adults are not linked to radiation. In this study, we provide structural and biochemical evidence that the RET, CCDC6, and NCOA4 genes participating in two major types of RET/PTC rearrangements, are located in common fragile sites FRA10C and FRA10G, and undergo DNA breakage after exposure to fragile site-inducing chemicals. Moreover, exposure of human thyroid cells to these chemicals results in the formation of cancer-specific RET/PTC rearrangements. These results provide the direct evidence for the involvement of chromosomal fragile sites in the generation of cancer-specific rearrangements in human cells.
Databáze: OpenAIRE
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