Comparison of the Breakpoint Regions of ELE1 and RET Genes Involved in the Generation of RET/PTC3 Oncogene in Sporadic and in Radiation-Associated Papillary Thyroid Carcinomas

Bongarzone, Italia; Butti, Marta G.; Fugazzola, Laura; Pacini, Furio; Pinchera, Aldo; Vorontsova, Tatiana; Demidchik, Eugene P.; Pierotti, Marco A.

doi:10.1006/geno.1997.4685

Cited by 52 publications

(33 citation statements)

References 15 publications

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“…In addition, breakpoint sites in RET/PTC3 in two previously reported post-Chernobyl cases (Bongarzone et al, 1997) showed similar patterns of correspondence. Such predictable relative positioning of chromosomal breaks in two dierent genes can occur if the chromosome is folded in a way to space these distant loci next to each other but pointed in opposite directions at the time of chromosomal breaks.…”

Section: Discussionsupporting

confidence: 65%

“…The other seven pairs of breakpoints can be aligned by sliding one gene with respect to the other ( Figure 4B and C). Interestingly, in the two other previously reported cases of Chernobyl-related cancers where fusion occurred between the ELE1 intron 5 and RET intron 11 (CH10 and CH4) (Bongarzone et al, 1997), the breaks that were joined to form RET/PTC3 can also be aligned by this procedure (Figure 4). …”

Section: Resultsmentioning

confidence: 80%

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Chromosomal breakpoint positions suggest a direct role for radiation in inducing illegitimate recombination between the ELE1 and RET genes in radiation-induced thyroid carcinomas

et al. 1999

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The RET/PTC3 rearrangement is formed by fusion of the ELE1 and RET genes, and is highly prevalent in radiation-induced post-Chernobyl papillary thyroid carcinomas. We characterized the breakpoints in the ELE1 and RET genes in 12 post-Chernobyl pediatric papillary carcinomas with known RET/PTC3 rearrangement. We found that the breakpoints within each intron were distributed in a relatively random fashion, except for clustering in the Alu regions of ELE1. None of the breakpoints occurred at the same base or within a similar sequence. There was also no evidence of preferential cleavage in AT-rich regions or other target DNA sites implicated in illegitimate recombination in mammalian cells. Modi®cation of sequences at the cleavage sites was minimal, typically involving a 1 ± 3 nucleotide deletion and/or duplication. Surprisingly, the alignment of ELE1 and RET introns in opposite orientation revealed that in each tumor the position of the break in one gene corresponded to the position of the break in the other gene. This tendency suggests that the two genes may lie next to each other but point in opposite directions in the nucleus. Such a structure would facilitate formation of RET/PTC3 rearrangements because a single radiation track could produce concerted breaks in both genes, leading to inversion due to reciprocal exchange via endjoining.

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Section: Discussionsupporting

confidence: 65%

Section: Resultsmentioning

confidence: 80%

Chromosomal breakpoint positions suggest a direct role for radiation in inducing illegitimate recombination between the ELE1 and RET genes in radiation-induced thyroid carcinomas

et al. 1999

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“…Analyses of genomic DNA fusion sites of RET/ PTC3 rearrangements in sporadic and post-Cherbobyl PTC have revealed a unique distribution of breakpoints (Bongarzone et al, 1997;Smanik et al, 1995). Ionizing radiation causes breaks and gaps in DNA, and such damage are the precursors of rearrangements through the recombination processes.…”

Section: Discussionmentioning

confidence: 99%

Preferential induction of RET/PTC1 rearrangement by X-ray irradiation

et al. 2000

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Ionizing radiation is a well known risk factor of thyroid cancer development, but the mechanism of radiation induced carcinogenesis is not clear. The RET/PTC oncogene, an activated form of the RET proto-oncogene, is frequently observed in papillary thyroid carcinoma (PTC); RET/PTC1, -2 and -3 are known to be the three major forms. High frequencies of RET/PTC rearrangements have been observed in radiation-associated PTC, such as those appearing post-Chernobyl or post-radiotherapy, but the rearrangement types dier between these two populations. We investigated whether a speci®c type of RET/PTC rearrangement was induced by X-rays in vivo and in vitro. In human normal thyroid tissues transplanted in scid mice, the RET/PTC1 rearrangement was predominantly detected throughout the observation period (up to 60 days) after X-ray exposure of 50 Gy. On the other hand, RET/PTC3 was detected only 7 days after X-irradiation, and no transcript of RET/PTC2 was detected. These results are supported by the results of an in vitro study. The RET/PTC1 rearrangement was preferentially induced in a dose-dependent manner by X-rays within a high dose range (10, 50 and 100 Gy) in four cell lines. On the other hand, RET/PTC3 was induced at a much lower frequency, and no induction of RET/PTC2 was observed. These results suggest that the preferential induction of the RET/PTC1 rearrangement may play an important role in the early steps of thyroid carcinogenesis induced by acute X-irradiation. Oncogene (2000) 19, 438 ± 443.

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“…Along these lines, some information about the early stages of cancer may provide important clues about this difference. RET/ PTC oncogenes are a family of fusion proteins derived from chromosomal rearrangements involving the tyrosine kinase domain of the c-RET proto-oncogene and are frequent mutations found early in the development of a variety of differentiated thyroid carcinomas (Jhiang et al, 1992;Santoro et al, 1992;Fusco et al, 1995;Takahashi et al, 1995;Fugazzola et al, 1996;Sugg et al, 1996;Bongarzone et al, 1997). Whereas RET/PTC expression has been frequently observed in patients affected with PTCs showing concurrent thyroiditis, its expression was also reported in thyroid tissue of patients afflicted with HT with no detectable cancer suggesting a common etiology of these two diseases (Wirtschafter et al, 1997;Sheils et al, 2000;Mechler et al, 2001;Pasquale et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Interleukin 24 is induced by the RET/PTC3 oncoprotein and is an autocrine growth factor for epithelial cells

Shinohara

Rothstein

2004

Oncogene

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Thyroid cancers, like hematological malignancies, are commonly associated with chromosomal translocations leading to the formation of fusion proteins. Through altered signaling by fusion proteins, cell death and survival pathways are disrupted and the physiological balance of cell-cell communication may be lost. A consequence of this disruption is the release of factors by stressed cells that alert the host. One type of host response is leukocytic infiltration that may develop into chronic inflammation or autoimmune disease. Although inflammation can be associated with neoplastic tissue, the mechanism driving this process is largely unknown. Therefore, to address the mechanism of cancer inflammation we investigated the effects of an oncogene in a murine model system. A comprehensive genetic analysis revealed several soluble factors that were induced by RET/papillary thyroid carcinoma (PTC)3 gene expression including several proinflammatory cytokines, chemokines and immunologically relevant costimulatory molecules. Following a large genetic screen using RP3-expressing thyroid cells, we identified a highly abundant transcript and later identified it as interleukin 24 (Il24), a cytokine with diverse tumor suppressor and inflammatory activities. We show that RET/PTC3 induces Il24 expression in rat thyrocytes and that this expression is dependent on the signaling properties of its tyrosine kinase. Likewise, RET/PTC3 induces large amounts of Il24 following expression in murine thyrocytes, but its expression is dramatically reduced in poorly differentiated carcinomas, a finding that parallels the loss of RET/PTC3 expression. Consistent with its behavior as a tumor suppressor, the loss of Il24 coincided with the loss of RET/PTC3 in poorly differentiated mouse tumors. A functional role of Il24 in the autocrine growth/survival of RET/PTC3-expressing thyroid cells was identified helping to support its role in cellular transformation. These data suggest that the induction of Il24 by oncogenes may support tumor growth at the early stages of cancer.

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Comparison of the Breakpoint Regions of ELE1 and RET Genes Involved in the Generation of RET/PTC3 Oncogene in Sporadic and in Radiation-Associated Papillary Thyroid Carcinomas

Cited by 52 publications

References 15 publications

Chromosomal breakpoint positions suggest a direct role for radiation in inducing illegitimate recombination between the ELE1 and RET genes in radiation-induced thyroid carcinomas

Chromosomal breakpoint positions suggest a direct role for radiation in inducing illegitimate recombination between the ELE1 and RET genes in radiation-induced thyroid carcinomas

Preferential induction of RET/PTC1 rearrangement by X-ray irradiation

Interleukin 24 is induced by the RET/PTC3 oncoprotein and is an autocrine growth factor for epithelial cells

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