1,721,025 research outputs found
GENETIC SCREENING OF RET CAN IDENTIFY NEW MUTATIONS EVEN AFTER 20 YEARS
No full textObjectives: In the last 20 years we performed RET genetic screening in more than 1000 hereditary or sporadic MTC patients.
Methods: RET analysis was performed in constitutive and/or somatic DNA by direct sequencing. TA cloning was performed to characterize new mutations and deletions. Site-directed mutagenesis, focus formation and soft agar assays were performed to test in vitro the activity of new mutations. The Align GVGD program was employed for the in silico analysis.
Results: we identified 3 new RET alterations. The first was a 7bp “somatic” in frame deletion in exon 11 encompassing codon 629-631. The second showed the simultaneous presence of a “somatic” E616Q mutation in exon 10 and a “somatic” C630G mutation in exon 11 on different alleles. Moreover, in the same patient, we found an alternative splicing causing the in frame skip of exon 10 in the allele carrying the C630G mutation. The third alteration was a new “germline” mutation (E632K, exon 11) and was found in an apparently sporadic MTC. According to the in vitro and in silico tests, both E616Q and E632K RET mutations were not transforming while the C630G RET mutation showed a high transforming activity.
Conclusions: 1) RET genetic screening should be performed by sequencing analysis in all MTC patients to detect also new RET mutations that would be missed when looking only at the “hot spot” mutations; 2) all new mutations must be evaluated by in silico and/or in vitro analysis to define their transforming ability since in some cases they may be inactive mutations
Systemic treatment of advanced, metastatic, medullary thyroid carcinoma
No full textMedullary thyroid carcinoma (MTC) is a rare endocrine tumor, which arises from thyroid parafollicular C cells. Through its ability to metastasize by blood and lymphatic vessels, it can show a more aggressive clinical behavior than differentiated thyroid cancers. Mutation of RET gene is the main molecular alteration involved in MTC origin. In the case of germline RET mutation, MTC can be inherited in an autosomal dominant way and show three different phenotypes: familial medullary thyroid carcinoma and multiple endocrine neoplasia types IIA and IIB. In addition, in sporadic cases, somatic RET mutation remains the key molecular alteration in most of cases. Total thyroidectomy with prophylactic or therapeutic central compartment lymph nodes dissection is the surgical treatment of choice. Further surgical treatments and local therapies should be used in the case of single or few local or distant metastasis. However, in cases with large metastatic spread of the disease, particularly in those with significant tumor progression, additional systemic treatments are needed. In this review, we discuss the key points of systemic treatment in advanced, metastatic MTC. We provide an update on the main aspects (from biological rationale to clinical experience) of each treatment, focusing our attention on the drugs used in clinical practice in the last years. Finally, we give insights about the emerging treatments from highly selective RET inhibitors to new radionuclide therapy
Predictive factors of short and long-term vandetanib response in locally advanced or metastatic medullary thyroid cancer: a single center experience
No full textObjectives: Vandetanib (V) is an important drug in the metastatic medullary thyroid cancer (MTC) treatment. The objective of this study was to evaluate the presence of predictors of V response, in short and long period, in locally advanced or metastatic MTC patients (pts).
Methods: Seventy-nine locally advanced or metastatic MTC pts with progressive or symptomatic disease, referred to our Center between 2007 and 2018 and already treated surgically and with other systemic therapies, were treated with V. During follow-up it was performed clinical examination, biochemical and morphological evaluation. Twenty-five pts were treated with V for less than 12 months (short responders, Group 1), 54 patients were treated with V for at least 12 months (long responders, Group 2).
Results: The genetic screening showed that in the Group 1, 4/25 (16%) pts were inherited forms and 21/25 (84%) pts were sporadic cases. In the Group 2, 8/54 (14.8%) pts were inherited forms and 46/54 (85.2%) pts were sporadic cases. The evaluation of somatic mutations showed that RET mutation was present in 82.3% and in 95.3% of pts in Group 1 and in Group 2, respectively. However, the presence of RET mutations, it wasn’t a predictor of response to treatment. The metastases site wasn’t correlated with the outcome. Otherwise, we observed that in long responders group, 47/54 (87%) pts showed at least one adverse events (AE) during V treatment with a correlation between AE and V response (P=0.02). In this group we also observed a statistically significant correlation between the younger age (<45 yrs) at screening and a greater response to V (P=0.01) and between the absence of progression disease at screening and response to V (P<0.0001). In the long term outcome, considering the last CT scan performed at the data cut-off during the treatment, 29/54 (53.7%) pts showed a persistent response to V after a median follow-up of 41 months. Moreover, we observed that the pts in the Group1 had a more aggressive disease and a more advanced age at screening than pts in Group 2. The estimated median Progression Free-Survival of all patients was 47 months.
Conclusions: In our study, it was observed that the appearance of AE during V treatment, the younger age and the absence of progression disease at screening were predictive factors of long-term response to V in MTC pts. Moreover, RET somatic mutations were very frequent in the metastatic MTC patients but it wasn’t a predictor of response to V
AFTER 20 YEARS, RET GENETIC SCREENING STILL INDENTIFIES NEW GERMILINE AND SOMATIC MUTATIONS
No full textObjectives: In the last 20 years we performed RET genetic screening in more than 1000 MTC patients either hereditary or sporadic.
Methods: RET genetic screening was performed in DNA extracted from blood and/or tissue by direct sequencing. TA cloning was performed to characterize new mutations and deletions. Site-directed mutagenesis, focus formation and soft agar assays were performed to test in vitro the activity of the new mutations. The Align GVGD program was employed for the in silico analysis.
Results: in the last year we identified 3 MTC patients with new RET alterations. The first case had a 7bp “somatic” in frame deletion in exon 11 encompassing codon 629-631. The second case showed the simultaneous presence of a “somatic” E616Q mutation in exon 10 and a “somatic” C630G mutation in exon 11 on different alleles. Moreover, in the same patient, we found an alternative splicing causing the in frame skip of exon 10 in the allele carrying the C630G mutation. The third case harboured a new “germline” mutation (E632K in exon 11) although the MTC was apparently sporadic. According to the in vitro and the in silico tests, both E616Q and E632K RET mutations were not transforming while the C630G RET mutation showed a high transforming activity.
Conclusions: 1) RET genetic screening should be performed by sequencing analysis in all MTC patients to detect also new RET mutations that would be missed when looking only at the “hot spot” mutations; 2) all new mutations must be evaluated by in silico and/or in vitro analysis to define their transforming ability since in some cases they may be inactive mutations
Prevalenza di mutazioni di BRAF e riarrangiamenti RET/PTC e TRK in una serie di carcinomi papillari della tiroide
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Ruolo putativo di H4 come gene oncosoppressore nella patogenesi del carcinoma papillare della tiroide
No full textInterventional bronchoscopy in the treatment of tracheal obstruction secondary to advanced thyroid cancer
No full textRET exon 11 (G691S) polymorphism is significantly more frequent in sporadic medullary thyroid carcinoma than in the general population
No full textThe RET protooncogene is constitutively activated by point mutations in hereditary medullary thyroid carcinomas (MTCs). RET somatic point mutations have also been reported in 40-50% of sporadic MTCs. Several single nucleotide polymorphisms of the RET gene have been described in the general population as well as in patients with MTC. These allelic variants do not seem to confer any transforming activity to the tyrosine kinase domain of the EET gene. Because the exon 11 RET polymorphism determines an important aminoacidic variation (6691S), we studied its frequency in 212 subjects, 108 sporadic MTC patients and 106 normal age-, sex-, race-, and geographic origin-matched controls. In 46 cases of sporadic MTCs, we also studied the cosegregation of somatic RET gene mutation and G691S polymorphism as well as the linkage of the polymorphism with RET germline mutation in 60 members of eight multiple endocrine neoplasia type 2 families. The influence of this polymorphism on the RET gene transcription has also been studied. In parallel we analyzed the frequencies of another three neutral polymorphisms (L769L, S836S, S904S). We found a statistically significant (P = 0.029) higher allelic frequency of G691S polymorphism in MTCs (27.83%) than that found in normal controls (18.86%), at variance with the three neutral polymorphisms whose frequencies were not different in patients and controls. With this study we excluded the influence of the G691S polymorphism on RET mRNA expression, the development of the somatic RET mutation, the linkage with the germline RET mutation, the younger onset of the MTCs, and the clinical outcome of the disease. A putative role of the G691S polymorphism as genetic modifier in the normal subjects remains to be established
The stage of differentiated thyroid cancer at diagnosis is significantly more advanced in children than in adolescent
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