Low Frequency of Rearrangements of the <i>ret</i> and <i>trk</i> Proto‐oncogenes in Japanese Thyroid Papillary Carcinomas

Wajjwalku, Worawidh; Nakamura, Shigeo; Hasegawa, Yasuhisa; Miyazaki, Koichi; Satoh, Yasuyuki; Funahashi, Hiroomi; Matsuyama, Mutsushi; Takahashi, Masahide

doi:10.1111/j.1349-7006.1992.tb01963.x

Cited by 103 publications

(48 citation statements)

References 10 publications

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“…However, the chimeric transcript of RET/PTC oncogene, has also been found in one study in follicular adenomas . Contrasting with the high and very similar frequency (about 60%) of activation observed in the Chernobyl tumors Ito et al, 1994;Klugbauer et al, 1995), the frequency of ret activation in`spontaneous' thyroid tumors varies widely between di erent studies: from 2.5% to 34% Delvincourt et al, 1996;SaõÈ d et al, 1994;Santoro et al, 1992;Wajjwalku et al, 1992;Zou et al, 1994). It has been postulated that this variation could be the result of the di erent geographical origins of populations studied, the age at tumor occurrence, or the sensitivity of the experimental methods used to detect the rearrangement.…”

Section: Introductionmentioning

confidence: 90%

High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation

et al. 1997

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A high frequency (about 60%) of ret rearrangements in papillary thyroid carcinomas of children exposed to radioactive fallout in Belarus after the Chernobyl accident, has been reported by three recent studies Ito et al., 1994;Klugbauer et al., 1995). These studies suggested that the radiation exposure may be a direct inducer of activating rearrangements in the ret gene. In order to con®rm the postulated link between irradiation and the role of the ret protooncogene in thyroid tumorigenesis, we analysed for the presence of ret activating rearrangements using RT ± PCR, XL ± PCR, Southern blot and direct sequencing techniques, 39 human thyroid tumors (19 papillary carcinomas and 20 follicular adenomas), from patients who had received external radiation for benign or malignant conditions. As controls, we studied 39 spontaneous' tumors (20 papillary carcinomas and 19 follicular adenomas). Our data concerning the radiationassociated tumors, showed that: (1) the overall frequency of ret rearrangements was 84% in papillary carcinomas (16/19) and 45% (9/20) in follicular adenomas; (2) in contrast with the results obtained in the Chernobyl tumors, the most frequently observed chimeric gene was RET/PTC1 instead of the RET/PTC3 and (3) all the tumors were negative for RET/PTC2. In the`spontaneous' tumors, only the papillary carcinomas presented a ret rearrangement (15% : 3/20): 1 RET/PTC1, 1 RET/ PTC3 and 1 uncharacterized. In conclusion, our results con®rm the crucial role played by the ret proto-oncogene activating rearrangements in the development of radiation-associated thyroid tumors appearing after therapeutic or accidental ionizing irradiation, and show, for the ®rst time, the presence of RET/PTC genes in follicular adenomas appeared after external irradiation.

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Section: Introductionmentioning

confidence: 90%

High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation

et al. 1997

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“…These phenomena have seldom been detected in papillary thyroid carcinomas (less than 3%) in Japan, although until now Japanese investigators have examined this type of carcinoma only for the ret/PTC1 chimeric gene (Namba et al 1991;Wajjwalku et al 1992). The discrepancy in the reported frequency of ret/PTC oncogenes could be due to environmental, racial, or methodological factors.…”

Section: Introductionmentioning

confidence: 91%

“…The ret/ PTC1 oncogene is generally the most frequent form of RET rearrangement found in Caucasian populations, although the precise frequency varies with different studies (Jhiang et al 1992;Santoro et al 1992;Williams et al 1996;Bounacer et al 1997). In Japan, Namba et al (1991) examined ten papillary thyroid carcinomas only for ret/PTC1 rearrangements and found no rearrangement; Ishizaka et al (1991) found one ret/PTC1 rearrangement among 11 carcinomas, and Wajjwalku et al (1992) found only one such alteration among 38 carcinomas. On the basis of those observations, RET gene rearrangements in papillary thyroid carcinomas were thought to be rare in the Japanese population.…”

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confidence: 99%

Ret/PTC3 is the most frequent form of gene rearrangement in papillary thyroid carcinomas in Japan

et al. 1999

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Rearrangements of the RET and TRK protooncogenes, which generate fusion oncogenes, are frequent in papillary thyroid carcinomas in Caucasian populations. To determine the spectrum of gene rearrangements in Japanese patients, we systematically examined 40 papillary thyroid carcinomas for all possible types of gene fusion events involving RET or TRK genes. RET rearrangements were found in ten tumors (25%): ret/PTC1 had occurred in two tumors, ret/PTC2 in one, ret/PTC3 in six, and a novel RET rearrangement in the remaining patient. In this last patient, the 5Ј novel sequence was fused in-frame to the RET amino acid sequence; thus, the fusion gene may encode a protein with a RET kinase domain at the carboxy terminus. The RET gene was fused to 5Ј donor sequences at the beginning of exon 12 in all ten tumors. No rearrangements involving the TRK gene were found in this panel of carcinomas. Our results indicated that constitutive activation of the RET by gene rearrangement is a frequent mechanism of papillary thyroid carcinogenesis in Japanese adults.

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“…The most common techniques include Southern blotting, direct gel visualization of the RT-PCR amplicons and hybridization of blotted RT-PCR products. Meta-analysis of the data published worldwide over a greater than 10-year period (Table 3) demonstrates an average prevalence of 18% for Southern blotting (67/370 cases tested, range 0-33%), [26][27][28][29][30][31] 15% for direct visualization of the RT-PCR amplicons (47/309 cases tested, range 4-45%) 7,32-35 and 48% for hybridization of blotted RT-PCR products (153/314 cases tested, range 0-85%). 4,[21][22][23][36][37][38][39] Allowing for the fact that Southern blotting permits the identification of all RET/PTC variants while the cases analyzed by RT-PCR listed above only screened the tumors for RET/PTC1, -2 and -3, there is a good correspondence between the sensitivity of Southern blotting and of direct gel visualization of RT-PCR products, as also demonstrated by parallel analysis of the same samples with the two methods.…”

Section: Discussionmentioning

confidence: 99%

Real-time quantitative RT-PCR identifies distinct c-RET, RET/PTC1 and RET/PTC3 expression patterns in papillary thyroid carcinoma

Rhoden

Johnson

Brandao

et al. 2004

Laboratory Investigation

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RET/PTC1 and RET/PTC3 are the markers for papillary thyroid carcinoma. Their reported prevalence varies broadly. Nonrearranged c-RET has also been detected in a variable proportion of papillary carcinomas. The published data suggest that a wide range in expression levels may contribute to the different frequency of c-RET and, particularly, of RET/PTC detection. However, quantitative expression analysis has never been systematically carried out. We have analyzed by real-time RT-PCR 25 papillary carcinoma and 12 normal thyroid samples for RET/PTC1, RET/PTC3 and for RET exons 10-11 and 12-13, which are adjacent to the rearrangement site. The variability in mRNA levels was marked and four carcinoma groups were identified: one lacking RET/ PTC rearrangement with balanced RET exon levels similar to those of the normal samples (7/25 cases, 28%), the second (6/25 cases, 24%) with balanced RET expression and very low levels of RET/PTC1, the third with unbalanced RET exons 10-11 and 12-13 expression, high RET/PTC1 levels but no RET/PTC3 (7/25 cases, 28%), and the fourth with unbalanced RET expression, high RET/PTC1 levels and low levels of RET/PTC3 (5/25 cases, 20%). Papillary carcinomas with high RET/PTC1 expression showed an association trend for large tumor size (P ¼ 0.063). Our results indicate that the variability in c-RET and RET/PTC mRNA levels contributes to the apparent inconsistencies in their reported detection rates and should be taken into account not only for diagnostic purposes but also to better understand the role of c-RET activation in thyroid tumorigenesis. Oncogenic c-RET activation in thyroid tumors composed of follicular cells is the result of chromosomal rearrangements resulting in the fusion of the RET tyrosine-kinase (RET-TK) domain to the 5 0 -terminal region of heterologous genes. The rearrangements are a molecular marker for papillary thyroid carcinoma as their very name, RET/PTC for papillary thyroid carcinoma, implies, 1 and consist of balanced inversions or translocations that involve the 3.0 kb intron 11 of c-RET. To date, at least 16 chimeric mRNAs affecting 11 different genes have been reported (Saenko et al, 2 reviewed in Tallini and Asa 3 ), of which RET/PTC1 (consisting of the fusion of RET with H4) and RET/PTC3 (consisting of the fusion of RET with RFG/ELE1) are by far the most common. 3 Their prevalence varies broadly from zero to more than 60% in nonradiation-associated cases 3 and is close to 90% in some series of papillary carcinomas from the Chernobyl area diagnosed after the 1986 nuclear disaster. 4 While the high prevalence of RET/PTC in radiation-associated thyroid tumors is consistent with misrepair of radiationinduced double-strand DNA breaks, 5,6 the high variability in the prevalence of RET/PTC in sporadic tumors has no specific explanation. In addition to rearranged RET forms, c-RET expression has also been identified in a highly variable proportion of papillary carcinoma samples. Although its signifi-

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Low Frequency of Rearrangements of the ret and trk Proto‐oncogenes in Japanese Thyroid Papillary Carcinomas

Cited by 103 publications

References 10 publications

High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation

High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation

Ret/PTC3 is the most frequent form of gene rearrangement in papillary thyroid carcinomas in Japan

Real-time quantitative RT-PCR identifies distinct c-RET, RET/PTC1 and RET/PTC3 expression patterns in papillary thyroid carcinoma

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