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DNA breaks at fragile sites generate oncogenic RET/PTC rearrangements in human thyroid cells
Author(s) -
Dillon Laura,
Gandhi Manoj,
Pramanik Sreemanta,
Pierce Levi,
Nikiforov Yuri,
Wang YuhHwa
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.874.1
Subject(s) - chromosomal fragile site , breakpoint , biology , aphidicolin , gene , dna , gene duplication , chromosomal translocation , genetics , microbiology and biotechnology , genome , gene rearrangement , dna damage , cancer research , chromosome , dna replication
Common fragile sites are regions of the genome that are prone to DNA breakage and frequently coincide with the location of genes involved in carcinogenic chromosomal translocations. In this study, we examined the direct involvement of fragile sites in the formation of RET/PTC rearrangements, which are commonly found in papillary thyroid carcinomas, and are all a result of a translocation event involving the RET gene. We demonstrated that fragile site‐inducing chemicals, including aphidicolin, can induce the formation of RET/PTC rearrangements in thyroid cells. We further studied fragile site‐induced DNA breakage within the genes ( RET , CCDC6 , and NCOA4 ) participating in the two major types of RET/PTC rearrangements, RET/PTC1 and RET/PTC3 , through cytogenetic, molecular biology, and sequence analysis methods. Using FISH, we found the rate of DNA breakage at these genes to be similar to known fragile site‐induction levels of the common fragile sites containing these genes, FRA10C and FRA10G. We mapped the location of induced breakpoints using LM‐PCR and found them to be located near breakpoints observed in patients. Factors contributing to the formation of DNA breaks have been investigated using sequence analysis. These results provide the first direct evidence for the role of chromosomal fragile sites in the generation of cancer‐specific rearrangements in human cells. (Supported by the NCI, CA113863).