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Absence of G(s)alpha gene mutations in childhood thyroid tumors after Chernobyl in contrast to sporadic adult thyroid neoplasia.

https://arctichealth.org/en/permalink/ahliterature22036
Source
Cancer Res. 1997 Jun 15;57(12):2358-61
Publication Type
Article
Date
Jun-15-1997
Author
V. Waldmann
H M Rabes
Author Affiliation
Institute of Pathology, Ludwig Maximilians University of Munich, München, Germany.
Source
Cancer Res. 1997 Jun 15;57(12):2358-61
Date
Jun-15-1997
Language
English
Publication Type
Article
Keywords
Accidents, Radiation
Byelarus - epidemiology
Carcinoma, Papillary - epidemiology - genetics - pathology
Child
GTP-Binding Protein alpha Subunits, Gs - genetics
Humans
Mutation
Polymerase Chain Reaction
Research Support, Non-U.S. Gov't
Thyroid Neoplasms - epidemiology - genetics - pathology
Ukraine
Abstract
Heterotrimeric G proteins participate in the signal transduction cascade. Adult thyroid tumors have been shown to harbor specific point mutations in codons 201 and 227 of the G(s)alpha subunit of the adenylate cyclase stimulator. This protein affects the GDP/GTP turnover and finally results in an enhanced activation of G(s) and thus adenylate cyclase. We attempted to find out if G(s)alpha gene mutations were present in thyroid tumors of children from Belarus after the Chernobyl nuclear accident. Paraffin sections of 20 thyroid tumors were used for PCR amplification by oligonucleotide intron primers flanking exons 8 and 9, encompassing codon 201 and 227, respectively. By direct sequencing of the 274-bp amplification product, we did not detect any mutations of the G(s)alpha gene in codon 201 or 227. In contrast to thyroid neoplasia of adults, G(s)alpha gene mutations do not play a role in the development of childhood thyroid tumors after the Chernobyl reactor accident.
PubMed ID
9192808 View in PubMed
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Absence of RAS and p53 mutations in thyroid carcinomas of children after Chernobyl in contrast to adult thyroid tumours.

https://arctichealth.org/en/permalink/ahliterature21720
Source
Br J Cancer. 1998 Mar;77(6):952-5
Publication Type
Article
Date
Mar-1998
Author
B. Suchy
V. Waldmann
S. Klugbauer
H M Rabes
Author Affiliation
Institute of Pathology, University of Munich, Germany.
Source
Br J Cancer. 1998 Mar;77(6):952-5
Date
Mar-1998
Language
English
Publication Type
Article
Keywords
Accidents, Radiation
Adult
Age Factors
Base Sequence
Byelarus
Child
Exons
Gene Rearrangement
Genes, Regulator
Genes, p53
Genes, ras
Humans
Mutagenesis
Neoplasms, Radiation-Induced - etiology - genetics
Polymerase Chain Reaction
Polymorphism, Single-Stranded Conformational
Radioactive fallout
Research Support, Non-U.S. Gov't
Thyroid Neoplasms - etiology - genetics
Ukraine
Abstract
Thyroid carcinomas of an additional series of 34 children exposed to radioactive fall-out after the Chernobyl reactor accident were analysed for mutations in the H-, K- and N-RAS and the p53 gene. Allele-specific oligonucleotide hybridization, single-strand conformation polymorphism (SSCP) and direct sequencing did not disclose mutations in codons 12, 13 and 61 of RAS genes nor mutations in exons 5, 7 and 8 of p53. Considering the recently reported high prevalence of RET rearrangements of the PTC3 type in childhood tumours after Chernobyl (Klugbauer et al, 1995, Oncogene 11: 2459-2467), it follows that RET rearrangements are the most relevant molecular aberration in these radiation-induced tumours. RAS or p53 mutations do not play a role in childhood thyroid carcinogenesis after Chernobyl.
PubMed ID
9528840 View in PubMed
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High prevalence of RET rearrangement in thyroid tumors of children from Belarus after the Chernobyl reactor accident.

https://arctichealth.org/en/permalink/ahliterature22965
Source
Oncogene. 1995 Dec 21;11(12):2459-67
Publication Type
Article
Date
Dec-21-1995
Author
S. Klugbauer
E. Lengfelder
E P Demidchik
H M Rabes
Author Affiliation
Institute of Pathology, Ludwig Maximillyians University of Munich, Germany.
Source
Oncogene. 1995 Dec 21;11(12):2459-67
Date
Dec-21-1995
Language
English
Publication Type
Article
Keywords
Accidents, Radiation
Adult
Base Sequence
Carcinoma, Papillary - genetics
Child
Child, Preschool
Drosophila Proteins
Female
Gene Rearrangement
Humans
Infant
Male
Middle Aged
Molecular Sequence Data
Neoplasms, Radiation-Induced - genetics
Nuclear Reactors
Polymerase Chain Reaction
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins c-ret
Proto-Oncogenes
Receptor Protein-Tyrosine Kinases - genetics
Research Support, Non-U.S. Gov't
Thyroid Neoplasms - etiology - genetics
Ukraine
Abstract
RET rearrangement was studied in papillary thyroid carcinomas (PTC) of children exposed to radioactive fallout in Belarus after the Chernobyl accident. To detect RET rearrangement in small tissue samples from thyroidectomy specimen (12 PTC of children; 2 PTC and 1 follicular carcinoma of adults; non-tumorous thyroid tissue of 4 children and 4 adults as controls), a RT-multiplex PCR was developed using primers suited to amplify fragments in different quantities depending on the presence or absence of RET rearrangements in the tissues. The type of rearrangement was determined by RT-PCR and direct sequencing using primers for ret/PTC1, 2 and 3. Two-thirds of the papillary thyroid carcinomas of the children revealed a RET rearrangement, with ret/PTC3 being more frequent by a factor of 3 than ret/PTC1. ret/PTC2 was not detected. All RET rearrangement-positive tumors had lymph node metastasis while half of the tumors with wild-type cRET had not. More than half of the cases with ret/PTC3 expressed not only the ELE/RET transcript as expected, but also the RET/ELE transcript. Intrachromosomal rearrangement involving RET and the adjacent H4 or ELE gene on chromosome no. 10 is a very frequent event in thyroid cancer of children of the Chernobyl-contaminated zone of Belarus.
PubMed ID
8545102 View in PubMed
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A novel type of RET rearrangement (PTC8) in childhood papillary thyroid carcinomas and characterization of the involved gene (RFG8).

https://arctichealth.org/en/permalink/ahliterature20059
Source
Cancer Res. 2000 Dec 15;60(24):7028-32
Publication Type
Article
Date
Dec-15-2000
Author
S. Klugbauer
A. Jauch
E. Lengfelder
E. Demidchik
H M Rabes
Author Affiliation
Institute of Pathology, Ludwig Maximilians University of Munich, Germany.
Source
Cancer Res. 2000 Dec 15;60(24):7028-32
Date
Dec-15-2000
Language
English
Publication Type
Article
Keywords
Accidents, Radiation
Adolescent
Amino Acid Sequence
Base Sequence
Blotting, Northern
Carcinoma, Papillary - genetics
Chromosomes, Human, Pair 18
Cytoplasm - metabolism
DNA, Complementary - metabolism
Drosophila Proteins
Female
Gene Rearrangement
Humans
In Situ Hybridization, Fluorescence
Male
Molecular Sequence Data
Power Plants
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins c-ret
RNA, Messenger - metabolism
Receptor Protein-Tyrosine Kinases - genetics
Research Support, Non-U.S. Gov't
Reverse Transcriptase Polymerase Chain Reaction
Thyroid Neoplasms - genetics
Tissue Distribution
Translocation, Genetic
Ukraine
Abstract
As part of ongoing studies on the RET rearrangement frequency in children with papillary thyroid carcinoma (PTC) after their exposure to radioactive iodine after the Chernobyl reactor accident, new methods for the detection of novel types of RET rearrangements are being developed. In this study, an improved reverse transcription-PCR strategy is used successfully to identify a new type of RET rearrangement. This rearrangement is designated PTC8 and the involved RET-fused gene (RFG) as RFG8. The identification of two reciprocal transcripts coding for the RFG8/RET and RET/RFG8 fusions suggests that the PTC8 rearrangement results from a balanced chromosomal translocation. With a view to clarify its role in tumor induction, we compared the fusion products with those of previously described RET rearrangements. We therefore sequenced and characterized the RFG8 cDNA, which showed no significant similarity to any functional protein described as yet. RFG8 is located on chromosome 18q21-22 and is expressed ubiquitously. Bioinformatic analysis predicts with a high probability that the corresponding rfg8 protein is located in the cytoplasm and is involved putatively in intracellular transport processes. Furthermore, we identified coiled-coil structures upstream of the breakpoint with one of the coiled-coils showing dimerization capability. Thus the rfg8/ret fusion protein exhibits structures for oncogenic activation that are similar to those observed in previously described RET fusions.
PubMed ID
11156407 View in PubMed
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[Radiation-induced thyroid carcinomas in children: high prevalence of RET rearrangement]

https://arctichealth.org/en/permalink/ahliterature22268
Source
Verh Dtsch Ges Pathol. 1997;81:139-44
Publication Type
Article
Date
1997
Author
H M Rabes
S. Klugbauer
Author Affiliation
Pathologisches Institut, Ludwig-Maximilians-Universität München.
Source
Verh Dtsch Ges Pathol. 1997;81:139-44
Date
1997
Language
German
Publication Type
Article
Keywords
Accidents, Radiation
Adult
Carcinoma, Papillary - etiology - genetics
Child
Drosophila Proteins
English Abstract
Gene Rearrangement
Humans
Iodine Radioisotopes
Neoplasms, Radiation-Induced - etiology - genetics
Polymerase Chain Reaction
Proto-Oncogene Proteins - biosynthesis - genetics
Proto-Oncogene Proteins c-ret
Proto-Oncogenes
Radioactive fallout
Receptor Protein-Tyrosine Kinases - biosynthesis - genetics
Thyroid Neoplasms - etiology - genetics
Ukraine
Abstract
Papillary thyroid carcinomas were observed in children living in the Gomel region of Belarus at the time of the Chernobyl reactor accident in April 1986. Radioactive fallout, iodine-131 in particular, led to thyroid doses of > 10 Gy in some cases. Till now, more than 400 thyroid carcinomas developed. They provide a unique possibility to search for characteristic molecular aberrations. Small fresh frozen thyroid tumor samples from 59 children were available. cDNA after reverse transcription of mRNA was amplified by multiplex PCR and analyzed for the presence of RET rearrangement (PTC1, 2 or 3) by identification-PCR with specific primers and by direct sequencing. A significantly higher prevalence of RET rearrangement was found in the thyroid carcinomas of radiation-exposed children than formerly described for adult thyroid carcinomas. While the prevailing type of RET rearrangement in adult thyroid carcinomas is PTC1 involving RET and the H4 gene, the majority of tumors in radiation-exposed children shows PTC3. In this type of rearrangement the 3'-tyrosin kinase domain of RET becomes dependent on the 5'-regulatory part of the ELE gene. Different breakpoints were found in the ELE gene. Besides ELE/RET transcripts, reciprocal RET/ELE transcripts were expressed indicating a complete inversion of the two genes after double stand break and their functional activity in both rearranged forms. Paracentric inversion on chromosome 10 bringing the functional tyrosine kinase domain of c-RET under the regulatory control of the ubiquitously expressed ELE gene appears to be a typical molecular lesion in thyroid carcinomas of children after radiation. This rearrangement is thought to endow juvenile thyrocytes with a clonal growth advantage and may be a critical initiating event of thyroid carcinogenesis in radiation-exposed children.
PubMed ID
9474864 View in PubMed
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RET rearrangements in radiation-induced papillary thyroid carcinomas: high prevalence of topoisomerase I sites at breakpoints and microhomology-mediated end joining in ELE1 and RET chimeric genes.

https://arctichealth.org/en/permalink/ahliterature19858
Source
Genomics. 2001 Apr 15;73(2):149-60
Publication Type
Article
Date
Apr-15-2001
Author
S. Klugbauer
P. Pfeiffer
H. Gassenhuber
C. Beimfohr
H M Rabes
Author Affiliation
Institute of Pathology, Ludwig Maximilians University of Munich, Thalkirchner Strasse 36, D-80337 Munich, Germany.
Source
Genomics. 2001 Apr 15;73(2):149-60
Date
Apr-15-2001
Language
English
Publication Type
Article
Keywords
Accidents, Radiation
Base Sequence
Carcinoma, Papillary - genetics
Chromosomes, Human, Pair 10 - genetics
DNA Topoisomerases, Type I - metabolism
DNA, Neoplasm - genetics
Drosophila Proteins
Exons
Gene Rearrangement - radiation effects
Humans
Introns
Inversion, Chromosome
Molecular Sequence Data
Neoplasms, Radiation-Induced - genetics
Oncogene Proteins - genetics
Oncogenes - radiation effects
Polymerase Chain Reaction
Power Plants
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins c-ret
Receptor Protein-Tyrosine Kinases - genetics
Recombination, Genetic - radiation effects
Research Support, Non-U.S. Gov't
Sequence Deletion
Thyroid Neoplasms - genetics
Transcription Factors
Ukraine
Abstract
Children exposed to radioactive iodine after the Chernobyl reactor accident frequently developed papillary thyroid carcinomas (PTC). The predominant molecular lesions in these tumors are rearrangements of the RET receptor tyrosine kinase gene. Various types of RET rearrangements have been described. More than 90% of PTC with RET rearrangement exhibit a PTC1 or PTC3 type of rearrangement with an inversion of the H4 or ELE1 gene, respectively, on chromosome 10. To obtain closer insight into the mechanisms underlying PTC3 inversions, we analyzed the genomic breakpoints of 22 reciprocal and 4 nonreciprocal ELE1 and RET rearrangements in 26 post-Chernobyl tumor samples. In contrast to previous assumptions, an accumulation of breakpoints at the two Alu elements in the ELE1 sequence was not observed. Instead, breakpoints are distributed in the affected introns of both genes without significant clustering. When compared to the corresponding wildtype sequences, the majority of breakpoints (92%) do not contain larger deletions or insertions. Most remarkably, at least one topoisomerase I site was found exactly at or in close vicinity to all breakpoints, indicating a potential role for this enzyme in the formation of DNA strand breaks and/or ELE1 and RET inversions. The presence of short regions of sequence homology (microhomologies) and short direct and inverted repeats at the majority of breakpoints furthermore indicates a nonhomologous DNA end-joining mechanism in the formation of chimeric ELE1/Ret and Ret/ELE1 genes.
PubMed ID
11318605 View in PubMed
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The transcription coactivator HTIF1 and a related protein are fused to the RET receptor tyrosine kinase in childhood papillary thyroid carcinomas.

https://arctichealth.org/en/permalink/ahliterature20901
Source
Oncogene. 1999 Jul 29;18(30):4388-93
Publication Type
Article
Date
Jul-29-1999
Author
S. Klugbauer
H M Rabes
Author Affiliation
Institute of Pathology, Ludwig Maximilians University of Munich, Germany.
Source
Oncogene. 1999 Jul 29;18(30):4388-93
Date
Jul-29-1999
Language
English
Publication Type
Article
Keywords
Accidents, Radiation
Amino Acid Sequence
Blotting, Northern
Byelarus
Carcinoma, Papillary - genetics - metabolism
Child, Preschool
Drosophila Proteins
Female
Gene Rearrangement
Humans
Male
Molecular Sequence Data
Neoplasms, Radiation-Induced - genetics
Nuclear Proteins - chemistry - genetics
Power Plants
Proto-Oncogene Proteins - chemistry - genetics
Proto-Oncogene Proteins c-ret
RNA - analysis
Receptor Protein-Tyrosine Kinases - chemistry - genetics
Research Support, Non-U.S. Gov't
Reverse Transcriptase Polymerase Chain Reaction
Sequence Homology, Amino Acid
Thyroid Neoplasms - genetics - metabolism
Transcription Factors - chemistry - genetics
Ukraine
Abstract
Children exposed to radioactive iodine as a consequence of the Chernobyl reactor accident have an increased risk of papillary thyroid carcinomas (PTC). The predominant molecular lesions in these tumors are rearrangements of the RET receptor tyrosine kinase (tk). Here we report on two novel types of RET rearrangement, PTC6 and 7, and describe the fusion products and the ret fused gene (rfg) proteins. Like the other rfg proteins identified so far they are ubiquitously expressed, not membrane-bound and contain coiled coil domains required for constitutive activation of the ret tk domain. In the PTC6 rearrangement the ret tk domain is fused to the aminoterminal part of the human transcription intermediary factor htif 1. In the PTC7 rearrangement the ret tk domain is fused to a novel protein that is strongly related to htif1. Like htif1 it contains a RBCC motif (ring finger, B boxes, coiled coil domain) located in the aminoterminal part and a phd finger and a bromodomain in the carboxyterminal part. Htif1 and related proteins are transcription coactivators for nuclear receptors, thus participating in controlling cellular development, differentiation and homeostasis. This is the first report on their involvement in human thyroid carcinogenesis.
PubMed ID
10439047 View in PubMed
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7 records – page 1 of 1.