Potent Mitogenicity of the RET/PTC3 Oncogene Correlates with Its Prevalence in Tall-Cell Variant of Papillary Thyroid Carcinoma

Basolo, Fulvio; Giannini, Raffaello; Monaco, C; Melillo, Rosa Marina; Carlomagno, Francesca; Pancrazi, Martina; Salvatore, Giuliana; Chiappetta, Gennaro; Pacini, Furio; Elisei, Rossella; Miccoli, Paolo; Pinchera, Aldo; Fusco, Alfredo; Santoro, Massimo

doi:10.1016/s0002-9440(10)64368-4

Cited by 102 publications

(62 citation statements)

References 20 publications

(19 reference statements)

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“…It parallels the same findings in the rat RET/PTC3-transfected thyroid cell line (Basolo et al, 2002).…”

Section: Discussionsupporting

confidence: 89%

“…In the adult series of Basolo et al (2002), one-third is tall cell PTC, as in part of the Nakazawa et al (2005) PTC series. We cannot precisely determine whether or not our solid mouse tumour corresponds to a PTC with a spindle-cell metaplasia as described in human PTC (Vergilio et al, 2002) or to a progressive transformation in a less differentiated phenotype (Bronner and LiVolsi, 1991;Brandwein-Gensler et al, 2004).…”

Section: Discussionmentioning

confidence: 91%

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Human thyroid tumours, the puzzling lessons from E7 and RET/PTC3 transgenic mice

et al. 2008

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Human rearranged RET/PTC3 (papillary thyroid carcinoma) proto-oncogene and high-risk human papillomavirus (HPV) type 16 E7 oncogene induces in the mouse a neoplastic transformation of thyroid follicular cells. We present a detailed immuno-histological study (170 mouse thyroids: RET/PTC3, E7, wild type, 2-to 10-month-old) with cell cycle proliferation and signalling pathway indicators. The characteristics of both models are different. There is an 'oncogene dependent' cellular signature, maintained at all studied ages in the E7 model, less in the RET/PTC3 model. During tumour development a large heterogeneity occurred in the Tg-RET/PTC3 model within a same tumour or within a same thyroid lobe. The Tg-E7 model was less heterogeneous, with a dominant goitrous pattern. The solid tumour already described in the RET/PTC3 models associated with cribriform patterns, suggested 'PTC spindle cell changes' as in humans PTC rather than the equivalent of the solid human PTC. Proliferation and apoptosis in the two thyroid models are related to the causal oncogene rather than reflect a general tumorigenic process. The thyroids of RET/PTC3 mice appeared as a partial and transient model of human PTCs, whereas the Tg-E7 mice do not belong to the usual PTC type.

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“…It parallels the same findings in the rat RET/PTC3-transfected thyroid cell line (Basolo et al, 2002).…”

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 91%

Human thyroid tumours, the puzzling lessons from E7 and RET/PTC3 transgenic mice

et al. 2008

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“…12 The higher mitogenic effects of RET/PTC3 compared with RET/PTC1 have indeed been postulated as the molecular basis for the aggressive biologic behavior of tall cell papillary carcinoma. 46 However, none of our cases had morphologic findings to justify such a diagnosis and none expressed high RET/PTC3 levels. In fact, tumors with both RET/PTC3 and RET/PTC1 rearrangements did not exhibit any particular clinicopathologic feature.…”

Section: Discussionmentioning

confidence: 58%

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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“…In addition, cases that occurred early in this Chernobyl-related thyroid cancer endemic showed a higher proportion of RET-PTC 3-positive tumours; this proportion fell and the proportion of RET-PTC 1-positive cases rose with an increasing latent period (Rabes et al, 2000). RET-PTC 3 transgenic mice give rise to thyroid tumours with a more solid phenotype than those seen in RET PTC1 transgenic mice, and in vitro RET-PTC3-transfected cells show a higher growth rate than RET-PTC 1-transfected cells (Santoro et al, 1996;Powell et al, 1998;Basolo et al, 2002). …”

Section: Discussionmentioning

confidence: 99%

Thyroid carcinoma after Chernobyl latent period, morphology and aggressiveness

et al. 2004

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The large numbers of papillary thyroid carcinomas that have occurred in those exposed to high levels of short-lived isotopes in fallout after Chernobyl provide a unique opportunity to correlate latency and tumour biology. We show that short latency is associated with tumours with a phenotype that is significantly less structurally differentiated, shows significantly less peritumour fibrosis, and significantly more invasive spread when compared to tumours with a longer latent period. In contrast, the type of differentiation (papillary or follicular architecture) is associated with age at exposure. These findings suggest that the initial mutation at the time of exposure played a major role in tumour latency and aggressiveness. We and others have shown that RET-PTC3 rearrangements are associated with the solid morphology seen in these short latency tumours, while classical papillary carcinomas more often show RET-PTC1 rearrangements. Studies in transgenic mice show similar findings, and in vitro studies show that RET-PTC3 induces more rapid growth than RET-PTC1. We therefore suggest that the solid morphology, high frequency of RET-PTC3 rearrangements and aggressive behaviour noted in early investigations of post-Chernobyl tumours were characteristic of short latency rather than the nature of the mutagen, and that successive overlapping waves of papillary carcinoma with differing latency, differing patterns of mutations and differing clinical behaviour are occurring in those exposed to Chernobyl fallout.

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Potent Mitogenicity of the RET/PTC3 Oncogene Correlates with Its Prevalence in Tall-Cell Variant of Papillary Thyroid Carcinoma

Cited by 102 publications

References 20 publications

Human thyroid tumours, the puzzling lessons from E7 and RET/PTC3 transgenic mice

Human thyroid tumours, the puzzling lessons from E7 and RET/PTC3 transgenic mice

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

Thyroid carcinoma after Chernobyl latent period, morphology and aggressiveness

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