Expression of the <i>RET</i> proto-oncogene in papillary thyroid carcinoma and its correlation with clinical outcome

Kjellman, Petra; Learoyd, Diana; Messina, Marinella; Weber, Günther; Höög, Anders; Wallin, Göran; Larsson, Catharina; Robinson, Bruce G.; Zedenius, Jan

doi:10.1046/j.1365-2168.2001.01734.x

Cited by 38 publications

(34 citation statements)

References 22 publications

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“…RET immunoreactivity was found to correlate with the expression of the TK domain of RET by RT-PCR (39 -41). This expression may be due to the presence of activating RET/PTC rearrangements or may correspond to the activity of wild-type RET (34,42,43). Alternatively spliced RET transcripts were also found in PC (44).…”

Section: Discussionmentioning

confidence: 99%

Thyroid follicular adenomas may display features of follicular carcinoma and follicular variant of papillary carcinoma

Vasko

Gaudart²,

Allasia³

et al. 2004

Eur J Endocrinol

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Thyroid follicular adenomas (FA) are encapsulated tumors lacking vascular, capsular or lymphatic invasion and the typical nuclear features of papillary carcinoma (PC). However, some FA demonstrate nuclear atypia reminiscent of either follicular carcinomas (FC) or follicular variant of papillary carcinomas (FVPC), suggesting they may represent precursors of malignant transformation. We hypothesized that an objective evaluation of nuclear chromatin patterns could be used to define atypical follicular tumors (AFT) that are likely to be premalignant. To test this hypothesis, we used a computer-aided image analysis system to define the chromatin pattern of nuclei from thyroid tumors. To validate the system, we analyzed 3000 nuclei from 10 FA, 10 FC, and 10 FVPC samples and accurately distinguished between these classes of tumors. Then, we analyzed nine AFT and, in parallel, we analyzed the tumors for activating mutations of N2-RAS and over-expression of RET. The predominant chromatin pattern of AFT was of FA type in two cases, FC type in two cases, and PC type in three cases. One case contained similar numbers of FC and PC nuclei and one was comprised of a mixture of the three nuclear types. Neither RAS mutation nor RET overexpression were detected in FA. N2-RAS mutations were found in 33% of AFT, 20% of FC and 20% of FVPC without correlation with chromatin pattern. Over-expression of RET was detected in 45% of AFT, 20% of FC and 50% of FVPC and was correlated with PC nuclei. These results show that AFT are a heterogenous group of tumors, containing genuine benign tumors and tumors that share morphological and molecular features with follicular and papillary carcinomas that might be precursors of both types of thyroid carcinomas. European Journal of Endocrinology 151 779-786

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Section: Discussionmentioning

confidence: 99%

Thyroid follicular adenomas may display features of follicular carcinoma and follicular variant of papillary carcinoma

Vasko

Gaudart²,

Allasia³

et al. 2004

Eur J Endocrinol

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“…The expression level is variable, particularly among tumor samples, explaining the apparent inconsistency of the reported detection rates. [8][9][10] The levels of c-RET expression are in any case B1000 times lower when compared to the control TT medullary carcinoma cell line. The expression level of RET exons 12-13 in individual cases is statistically higher relative to that of exons 10-11 only in those cases which express high levels of rearranged RET.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…[7][8][9][10][11] Wild-type RET may coexist with RET/ PTC 9,10 and it has been proposed as a marker for aggressive disease. 10 Similar to RET/PTC, c-RET mRNA has been reported in a variable proportion of papillary carcinomas with frequencies ranging from 21% 10 to 100%. 8,9 To address the issue of the expression level of RET and its rearranged forms in thyroid papillary carcinoma we have utilized real-time RT-PCR and quantitatively analyzed high-quality RNA extracted from frozen samples for the expression of RET/ PTC1, RET/PTC3 and RET exons 10-11 and 12-13, which are adjacent to the RET/PTC rearrangement site.…”

Section: Discussionmentioning

confidence: 99%

“…Although its signifi-cance is unclear, c-RET may also play a role in thyroid tumorigenesis. [7][8][9][10][11] Analysis of the data published in the literature suggests a wide range in the expression levels of RET/PTC and c-RET in tumor samples. This may contribute more than geographical factors to the differences in the reported frequencies of c-RET and, particularly, of RET/PTC detection.…”

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confidence: 99%

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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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CCDC6: the identity of a protein known to be partner in fusion

Cerrato

Merolla

Morra

et al. 2017

Intl Journal of Cancer

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Coiled Coil Domain Containing 6 gene, CCDC6, was initially isolated as part of a tumorigenic DNA originated by the fusion of CCDC6 with the tyrosine kinase of RET receptor, following a paracentric inversion of chromosome 10. For a long time, CCDC6 has been considered as an accidental partner of the RET protooncogene, providing the promoter and the first 101 aa necessary for the constitutive activation of the oncogenic Tyrosine Kinase (TK) RET in thyroid cells. With the advent of more refined diagnostic tools and bioinformatic algorithms, an exponential growth in fusion genes discoveries has allowed the identification of CCDC6 as partner of genes other than RET in different tumor types. CCDC6 gene product has a proper role in sustaining the DNA damage checkpoints in response to DNA damage. The inactivation of CCDC6 secondary to chromosomal rearrangements or gene mutations could enhance tumor progression by impairing the apoptotic response upon the DNA damage exposure, contributing to the generation of radio- and chemoresistance. Preclinical studies indicate that the attenuation of CCDC6 in cancer, while conferring a resistance to cisplatinum, sensitizes the cancer cells to the small molecule inhibitors of Poly (ADP-ribose) polymerase (PARP1/2) with a synthetic lethal effect. Several CCDC6 mutations and gene rearrangements have been described so far in different types of cancer and CCDC6 may represent a possible predictive biomarker of tumor resistance to the conventional anticancer treatments. Nevertheless, the detection of a CCDC6 impairment in cancer patients may help to select, in future clinical trials, those patients who could benefit of PARP-inhibitors treatment alone or in combination with other treatments.

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Expression of the RET proto-oncogene in papillary thyroid carcinoma and its correlation with clinical outcome

Cited by 38 publications

References 22 publications

Thyroid follicular adenomas may display features of follicular carcinoma and follicular variant of papillary carcinoma

Thyroid follicular adenomas may display features of follicular carcinoma and follicular variant of papillary carcinoma

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

CCDC6: the identity of a protein known to be partner in fusion

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