Ret/PTC activation does not influence clinical and pathological features of adult papillary thyroid carcinomas

Puxeddu, Efisio; Moretti, Sonia; Giannico, Angela; Martinelli, Marco; Marino, Cecilia; Avenia, Nicola; Cristofani, Roberto; Farabi, Raffaele; Reboldi, Gianpaolo; Ribacchi, R; Pontecorvi, Alfredo; Santeusanio, Fausto

doi:10.1530/eje.0.1480505

Cited by 40 publications

(28 citation statements)

References 28 publications

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“…In our series, we found a total of ten out of 40 (25%) BRAF WT PTC samples with broken RET above the cut-off level, a prevalence slightly lower than that reported in other Italian studies of comparable size, ranging from 27.5 to 35% (16,30,62,73,74).…”

Section: Discussioncontrasting

confidence: 75%

Break–apart interphase fluorescence in situ hybridization assay in papillary thyroid carcinoma: on the road to optimizing the cut-off level for RET/PTC rearrangements

Colato

Vicentini

Cantara

et al. 2015

European Journal of Endocrinology

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Objective: Chromosomal rearrangements of the RET proto-oncogene is one of the most common molecular events in papillary thyroid carcinoma (PTC). However, their pathogenic role and clinical significance are still debated. This study aimed to investigate the prevalence of RET/PTC rearrangement in a cohort of BRAF WT PTCs by fluorescence in situ hybridization (FISH) and to search a reliable cut-off level in order to distinguish clonal or non-clonal RET changes. Design: Forty BRAF WT PTCs were analyzed by FISH for RET rearrangements. As controls, six BRAFV600E mutated PTCs, 13 follicular adenomas (FA), and ten normal thyroid parenchyma were also analyzed. Methods: We performed FISH analysis on formalin-fixed, paraffin-embedded tissue using a commercially available RET break-apart probe. A cut-off level equivalent to 10.2% of aberrant cells was accepted as significant. To validate FISH results, we analyzed the study cohort by qRT-PCR. Results: Split RET signals above the cut-off level were observed in 25% (10/40) of PTCs, harboring a percentage of positive cells ranging from 12 to 50%, and in one spontaneous FA (1/13, 7.7%). Overall, the data obtained by FISH matched well with qRT-PCR results. Challenging findings were observed in five cases showing a frequency of rearrangement very close to the cut-off. Conclusions: FISH approach represents a powerful tool to estimate the ratio between broken and non-broken RET tumor cells. Establishing a precise FISH cut-off may be useful in the interpretation of the presence of RET rearrangement, primarily when this strategy is used for cytological evaluation or for targeted therapy.

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Section: Discussioncontrasting

confidence: 75%

Break–apart interphase fluorescence in situ hybridization assay in papillary thyroid carcinoma: on the road to optimizing the cut-off level for RET/PTC rearrangements

Colato

Vicentini

Cantara

et al. 2015

European Journal of Endocrinology

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“…Regarding RET/PTC, only a limited number of studies have evaluated its prognostic value. Some studies were unable to find any significant association between the presence of RET rearrangements and several clinical pathological features of aggressiveness (21,40,41). Few studies suggested that RET/PTC3 correlates with more advanced stage of disease (42,43) and aggressive variants such as solid (33) or tall-cell (44).…”

Section: Discussionmentioning

confidence: 99%

BRAF V600E and decreased NIS and TPO expression are associated with aggressiveness of a subgroup of papillary thyroid microcarcinoma

Bastos

Oler

Nozima

et al. 2015

European Journal of Endocrinology

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Background: Thyroid cancer incidence has dramatically increased worldwide over the last two decades. The rise is mostly due to an increased detection of small papillary thyroid carcinomas (PTCs) (%20 mm), predominantly microPTC (%10 mm). Although small tumors generally have an excellent outcome, a considerable percentage may have a more aggressive disease and worse prognosis. The clinical challenge is to preoperatively identify those tumors that are more likely to recur. Aim: To improve risk stratification and patient management, we sought to determine the prognostic value of BRAF V600E, NRAS or RET/PTC mutations in patients with PTC measuring !20 mm, mainly microPTC. Methods: The prevalence of RET/PTC fusion genes was examined by quantitative RT-PCR. BRAF V600E and NRAS Q61 mutations were determined by PCR sequencing. To further elucidate why some small PTC are less responsive to radioactive iodine treatment therapy, we explored if these genetic alterations may modulate the expression of iodine metabolism genes (NIS,TPO,TG,TSHR and PDS) and correlated with clinico-pathological findings that are predictors of recurrence. Results: This study shows that tumors measuring %20 mm exhibited higher prevalence of BRAF V600E mutation, which correlated with aggressive histopathological parameters, higher risk of recurrence, and lower expression of NIS and TPO. Although this correlation was not found when microPTC were evaluated, we show that tumors measuring 7-10 mm, which were positive for BRAF mutation, presented more aggressive features and lower expression of NIS and TPO. Conclusion: We believe that our findings will help to decide the realistic usefulness of BRAF V600E mutation as a preoperative marker of poor prognosis in small PTC, primarily in microPTC.

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“…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. 44 When RT-PCR is followed by blotting of the amplicons and hybridization with RET-specific probes the sensitivity increases dramatically, by at least 100-fold according to some investigators.…”

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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Ret/PTC activation does not influence clinical and pathological features of adult papillary thyroid carcinomas

Cited by 40 publications

References 28 publications

Break–apart interphase fluorescence in situ hybridization assay in papillary thyroid carcinoma: on the road to optimizing the cut-off level for RET/PTC rearrangements

Break–apart interphase fluorescence in situ hybridization assay in papillary thyroid carcinoma: on the road to optimizing the cut-off level for RET/PTC rearrangements

BRAF V600E and decreased NIS and TPO expression are associated with aggressiveness of a subgroup of papillary thyroid microcarcinoma

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

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