The Journal of Clinical Endocrinology & Metabolism, 2004
The BRAF gene has been shown to be a major target for mutations in papillary thyroid carcinoma (P... more The BRAF gene has been shown to be a major target for mutations in papillary thyroid carcinoma (PTC) (36 -69%), which forms almost all of the over 2000 cases of thyroid carcinoma that have occurred in Chernobyl. BRAF is activated by point mutation, and were it to occur at a high frequency in Chernobyl-related tumors, it would challenge the dominant role of double-strand breaks in radiation-induced PTC. In a previous study, we detected the BRAF V600E mutation in 46% (23 of 50) of sporadic adult PTC. Using the same methodology, we have analyzed 34 post-Chernobyl PTC and detected RET/PTC rearrangements in 14 (41%) and BRAF mutations (V600E) in four (12%). These two alterations did not coexist in any PTCs. The mean age at exposure of patients with PTC showing BRAF mutation was higher than that of patients with tumors without BRAF mutation irrespective of their RET status. We have also analyzed 17 sporadic cases of childhood PTC and found that only one (6%) harbored the BRAF V600E mutation. We conclude that the frequency of BRAF mutations is significantly lower (P ؍ 0.0008) in post-Chernobyl PTC than in adult sporadic PTC, whereas no significant difference was found between post-Chernobyl and sporadic childhood PTCs. (J Clin Endocrinol Metab 89: 4267-4271, 2004) Abbreviations: FA, Follicular adenoma; PTC, papillary thyroid carcinoma; SSCP, single strand conformation polymorphism. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.
Rearrangement of RET proto-oncogene is the major event in the etiopathogenesis of papillary thyro... more Rearrangement of RET proto-oncogene is the major event in the etiopathogenesis of papillary thyroid carcinoma (PTC). We report a high prevalence of BRAF V599E mutation in sporadic PTC and in PTC-derived cell lines. The BRAF V599E mutation was detected in 23 of 50 PTC (46%) and in three of four PTC-derived cell lines. The prevalence of the BRAF V599E mutation in PTC is the highest reported to date in human carcinomas, being only exceeded by melanoma. PTC with RET/PTC rearrangement as well as the TPC-1 cell line (the only one harboring RET/PTC rearrangement) did not show the BRAF V599E mutation. BRAF V599E mutation was not detected in any of 23 nodular goiters, 51 follicular adenomas and 18 follicular carcinomas. A distinct mutation in BRAF (codon K600E) was detected in a follicular adenoma. Activating mutations in RAS genes were detected in 15% of FA, 33% of FTC and 7% of PTC. BRAF V599E mutation did not coexist with alterations in any of the RAS genes in any of the tumors. These results suggest that BRAF V599E mutation is frequent in the etiopathogenesis of PTC. The BRAF V599E mutation appears to be an alternative event to RET/PTC rearrangement rather than to RAS mutations, which are rare in PTC. BRAF V599E may represent an alternative pathway to oncogenic MAPK activation in PTCs without RET/PTC activation.
Type and prevalence of BRAF mutations are closely associated with papillary thyroid carcinoma his... more Type and prevalence of BRAF mutations are closely associated with papillary thyroid carcinoma histotype and patients' age but not with tumour aggressiveness Abstract A high prevalence of the BRAF V600E somatic mutation was recently reported in several series of papillary thyroid carcinomas (PTC). This mutation appears to be particularly prevalent in PTC with a predominantly papillary architecture. Another BRAF mutation (K601E) was detected in a follicular adenoma and in some cases of the follicular variant of PTC. The few studies on record provided controversial data on the relationship between the occurrence of BRAF mutations and clinicopathologic parameters such as gender, age and tumour staging. In an attempt to clarify such controversies we decided to enlarge our previous series to 315 tumours or tumour-like lesions diagnosed in 280 patients, including a thorough analysis of several clinicopathologic features. The BRAF V600E mutation was exclusively detected in PTC with a papillary or mixed follicular/papillary architecture both of the conventional type (46%) and of other histotypes, such as microcarcinoma (43%), Warthin-like PTC (75%) and oncocytic variant of PTC (55%). The BRAF K601E mutation was detected in four of the 54 cases of the follicular variant of PTC (7%). The mean age of patients with conventional PTC harbouring BRAF V600E (46.7 years) was significantly higher (P<0.0001) than that of patients with conventional PTC without BRAF V600E (29.5 years). The BRAF (BRAF V600E ) mutated PTC did not exhibit signs of higher aggressiveness (size, vascular invasion, extra-thyroid extension and nodal metastasis) and were in fact less often multicentric than PTC without the mutation.
The hot-spot mutation BRAF V599E is frequently detected in PTC (36-69%), in contrast to its absen... more The hot-spot mutation BRAF V599E is frequently detected in PTC (36-69%), in contrast to its absence in other benign or malignant thyroid lesions. In order to unravel whether there is any association between the occurrence of the BRAF mutation and the histological pattern of PTC, in this study a previous series of 50 PTCs was extended to 134 cases, including ten cases of PTC-related entities -hyalinizing trabecular tumour (HTT) and mucoepidermoid carcinoma (MEC). Using PCR/SSCP and sequencing, the BRAF V599E mutation was detected in 45 of the 124 PTCs (36%). No mutations were detected in any case of HTT and MEC. BRAF V599E was present in 75% of Warthin-like PTCs and 53% of conventional PTCs, whereas no BRAF V599E mutations were detected in any of the 32 cases of the follicular variant of PTC. BRAF V599E was also detected in 6 of 11 cases of the oncocytic variant of PTC that displayed a papillary or mixed follicular-papillary growth pattern and in none of the four oncocytic PTCs with a follicular growth pattern. A distinct mutation in BRAF (codon K600E) was detected in three cases of the follicular variant of PTC. This study has confirmed the high prevalence of BRAF V599E in PTC and has shown that the mutation is almost exclusively seen in PTC with a papillary or mixed follicular-papillary growth pattern, regardless of the cytological features of the neoplastic cells. The results support the existence of an oncocytic variant of PTC that should be separated from the oncocytic variant of follicular carcinoma and suggest that the follicular variant of PTC may be genetically different from conventional PTC.
Arquivos Brasileiros de Endocrinologia & Metabologia, 2007
Papillary thyroid carcinoma (PTC) is the most prevalent type of endocrine cancer and, in recent e... more Papillary thyroid carcinoma (PTC) is the most prevalent type of endocrine cancer and, in recent epidemiological surveys, one of the types of human cancer whose incidence is growing. Despite the favourable outcome and long survival rates of most patients, some tumours display an aggressive behaviour and may progress to the highly aggressive and lethal, anaplastic thyroid carcinoma. In recent years, several progresses have been made on the molecular characterization of PTC, in general, and in the genetic alterations underlying the histotype diversity of this type of cancer, in particular. This holds true regarding alterations on nuclear DNA as well as mitochondrial DNA. In this review we have summarized the most recent findings in the genetic characterization of PTC, giving a particular emphasis to the genotype-phenotype associations, the prognosis implications, and the diagnostic and therapeutic value of the newly identified genetic markers. (Arq Bras Endocrinol Metab 2007;51/5:643-653) RESUMO Genética Molecular do Carcinoma Papilífero de Tireóide -Grandes Esperanças… O carcinoma papilífero de tireóide (CPT) é o tipo mais prevalente de câncer endócrino e, em pesquisas epidemiológicas recentes, um dos tipos de câncer humano cuja incidência vêm crescendo. A despeito do prognóstico favorável e da longa taxa de sobrevivência da maioria dos pacientes, alguns tumores mostram um comportamento agressivo e podem progredir para o altamente agressivo e letal carcinoma anaplásico de tireóide.
Objective: Our aim was to characterize the molecular and genotypic profile of eight thyroid carci... more Objective: Our aim was to characterize the molecular and genotypic profile of eight thyroid carcinoma-derived cell lines-TPC1, FB2, B-CPAP, K1, XTC-1, C643, 8505C, and Hth74-in order to use them as in vitro models of thyroid carcinogenesis. Design: We evaluated the expression of five thyroid-specific genes (Tg, TSHr, TPO, PAX8, and TTF-1) to establish the cell lineage and to assess the differentiation status of each of the cell lines. We screened for mutations in the most relevant oncogenes=tumor suppressor genes affected in thyroid carcinogenesis: RAS, BRAF, CTNNB1, and TP53 along with RET=PTC rearrangements. Considering the putative relevance in general carcinogenesis, we have also studied other molecules such as EGFR, PI3K, RAF-1, and THRB. To determine the genetic identity of the cell lines, we performed genotypic analysis. Main outcome: The panel of cell lines we have studied displayed activation of several oncogenes (BRAF, RAS, RET=PTC) and inactivation of tumor suppressor genes (TP53) known to be important for thyroid carcinogenesis. Two of the cell lines-TPC1 and FB2-shared the same genotypic profile, probably representing clones of an ancestor cell line (TPC1). Conclusion: Due to their different molecular alterations, these cell lines represent a valuable tool to study the molecular mechanisms underlying thyroid carcinogenesis. We suggest that genotypic analyses should be included as a routine procedure to guarantee the uniqueness of each cell line used in research.
Endocrinology and Metabolism Clinics of North America, 2008
The close genotype-phenotype relationship that characterizes thyroid oncology stimulated the auth... more The close genotype-phenotype relationship that characterizes thyroid oncology stimulated the authors to address this article by using a mixed, genetic and phenotypic approach. As such, this article addresses the following aspects of intragenic mutations in thyroid cancer: thyroid stimulating hormone receptor and guanine-nucleotide-binding proteins of the stimulatory family mutations in hyperfunctioning tumors; mutations in RAS and other genes and aneuploidy; PAX8-PPARgamma rearrangements; BRAF mutations; mutations in oxidative phosphorylation and Krebs cycle genes in Hürthle cell tumors; mutations in succinate dehydrogenase genes in medullary carcinoma and C-cell hyperplasia; and mutations in TP53 and other genes in poorly differentiated and anaplastic carcinomas.
Archiv Fur Pathologische Anatomie Und Physiologie Und Fur Klinische Medicin, Apr 17, 2004
Somatic mutations of the BRAF gene (BRAFV599E and BRAFK600E) were found to be closely associated ... more Somatic mutations of the BRAF gene (BRAFV599E and BRAFK600E) were found to be closely associated with different histotypes of papillary thyroid carcinoma (PTC). The V599E mutation is highly prevalent in PTC with a papillary or mixed papillary follicular growth pattern, and the K600E mutation is apparently restricted to the follicular variant of PTC. It is usually accepted that thyroid malignancies may follow a progression path from well-differentiated to poorly differentiated (PDC) and undifferentiated (UC) carcinomas. One would expect that at least some of the less differentiated carcinomas would harbour the genetic alterations of pre-existing well-differentiated tumours. In order to find the prevalence of BRAF mutations in PDC and UC, we screened a series of 19 PDCs and 17 UCs, as well as 3 UC-derived cell lines, for both mutation types. The group of PDCs was restricted to the so-called insular and insular-like PDCs, thus excluding PTCs with solid, insular or trabecular foci of growth and PDCs displaying typical PTC nuclei. No BRAF mutations were detected in any of the 19 cases of PDC, whereas 6 of the UCs (35%) and one UC-derived cell line presented the BRAFV599E mutation. The BRAFK600E mutation was not detected in any case. We conclude that UC may progress from BRAFV599E-mutated PTC. The absence of BRAF mutations in our series of PDC supports the assumption that pure insular and insular-like PDCs are more closely related to follicular carcinoma than to PTC.
The Journal of Clinical Endocrinology Metabolism, Jul 2, 2013
The BRAF gene has been shown to be a major target for mutations in papillary thyroid carcinoma (P... more The BRAF gene has been shown to be a major target for mutations in papillary thyroid carcinoma (PTC) (36 -69%), which forms almost all of the over 2000 cases of thyroid carcinoma that have occurred in Chernobyl. BRAF is activated by point mutation, and were it to occur at a high frequency in Cher-
BRAF gene mutations have been frequently detected in papillary thyroid carcinoma (PTC). Moreover,... more BRAF gene mutations have been frequently detected in papillary thyroid carcinoma (PTC). Moreover, there is a close association between the type of mutation and the PTC histotype: BRAF(V600E) is associated with conventional PTC and with histological variants of PTC displaying a prominent papillary growth pattern, whereas BRAF(K601E) is associated with the follicular variant of PTC. We report the detection of a novel BRAF triplet deletion in a case of PTC displaying a predominantly solid growth pattern. The deletion leads to the replacement of a valine and a lysine by a glutamate in the BRAF activation segment (BRAF(VK600-1E)), thus mimicking partially the 2 BRAF mutations previously described. Our study reinforces the existence of a close relationship between the occurrence of some types of BRAF mutation and some PTC histotypes. The genetic study of more cases of the solid variant of PTC is necessary to find whether there exists a significant association between the occurrence of BRA...
Somatic mutations of the BRAF gene (BRAFV599E and BRAFK600E) were found to be closely associated ... more Somatic mutations of the BRAF gene (BRAFV599E and BRAFK600E) were found to be closely associated with different histotypes of papillary thyroid carcinoma (PTC). The V599E mutation is highly prevalent in PTC with a papillary or mixed papillary follicular growth pattern, and the K600E mutation is apparently restricted to the follicular variant of PTC. It is usually accepted that thyroid malignancies may follow a progression path from well-differentiated to poorly differentiated (PDC) and undifferentiated (UC) carcinomas. One would expect that at least some of the less differentiated carcinomas would harbour the genetic alterations of pre-existing well-differentiated tumours. In order to find the prevalence of BRAF mutations in PDC and UC, we screened a series of 19 PDCs and 17 UCs, as well as 3 UC-derived cell lines, for both mutation types. The group of PDCs was restricted to the so-called insular and insular-like PDCs, thus excluding PTCs with solid, insular or trabecular foci of growth and PDCs displaying typical PTC nuclei. No BRAF mutations were detected in any of the 19 cases of PDC, whereas 6 of the UCs (35%) and one UC-derived cell line presented the BRAFV599E mutation. The BRAFK600E mutation was not detected in any case. We conclude that UC may progress from BRAFV599E-mutated PTC. The absence of BRAF mutations in our series of PDC supports the assumption that pure insular and insular-like PDCs are more closely related to follicular carcinoma than to PTC.
Objective: Our aim was to characterize the molecular and genotypic profile of eight thyroid carci... more Objective: Our aim was to characterize the molecular and genotypic profile of eight thyroid carcinoma-derived cell lines-TPC1, FB2, B-CPAP, K1, XTC-1, C643, 8505C, and Hth74-in order to use them as in vitro models of thyroid carcinogenesis. Design: We evaluated the expression of five thyroid-specific genes (Tg, TSHr, TPO, PAX8, and TTF-1) to establish the cell lineage and to assess the differentiation status of each of the cell lines. We screened for mutations in the most relevant oncogenes=tumor suppressor genes affected in thyroid carcinogenesis: RAS, BRAF, CTNNB1, and TP53 along with RET=PTC rearrangements. Considering the putative relevance in general carcinogenesis, we have also studied other molecules such as EGFR, PI3K, RAF-1, and THRB. To determine the genetic identity of the cell lines, we performed genotypic analysis. Main outcome: The panel of cell lines we have studied displayed activation of several oncogenes (BRAF, RAS, RET=PTC) and inactivation of tumor suppressor genes (TP53) known to be important for thyroid carcinogenesis. Two of the cell lines-TPC1 and FB2-shared the same genotypic profile, probably representing clones of an ancestor cell line (TPC1). Conclusion: Due to their different molecular alterations, these cell lines represent a valuable tool to study the molecular mechanisms underlying thyroid carcinogenesis. We suggest that genotypic analyses should be included as a routine procedure to guarantee the uniqueness of each cell line used in research.
The Journal of Clinical Endocrinology & Metabolism, 2004
The BRAF gene has been shown to be a major target for mutations in papillary thyroid carcinoma (P... more The BRAF gene has been shown to be a major target for mutations in papillary thyroid carcinoma (PTC) (36 -69%), which forms almost all of the over 2000 cases of thyroid carcinoma that have occurred in Chernobyl. BRAF is activated by point mutation, and were it to occur at a high frequency in Chernobyl-related tumors, it would challenge the dominant role of double-strand breaks in radiation-induced PTC. In a previous study, we detected the BRAF V600E mutation in 46% (23 of 50) of sporadic adult PTC. Using the same methodology, we have analyzed 34 post-Chernobyl PTC and detected RET/PTC rearrangements in 14 (41%) and BRAF mutations (V600E) in four (12%). These two alterations did not coexist in any PTCs. The mean age at exposure of patients with PTC showing BRAF mutation was higher than that of patients with tumors without BRAF mutation irrespective of their RET status. We have also analyzed 17 sporadic cases of childhood PTC and found that only one (6%) harbored the BRAF V600E mutation. We conclude that the frequency of BRAF mutations is significantly lower (P ؍ 0.0008) in post-Chernobyl PTC than in adult sporadic PTC, whereas no significant difference was found between post-Chernobyl and sporadic childhood PTCs. (J Clin Endocrinol Metab 89: 4267-4271, 2004) Abbreviations: FA, Follicular adenoma; PTC, papillary thyroid carcinoma; SSCP, single strand conformation polymorphism. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.
The Journal of Clinical Endocrinology & Metabolism, 2006
The clinicopathological characteristics and the molecular features of the follicular variant of p... more The clinicopathological characteristics and the molecular features of the follicular variant of papillary thyroid carcinoma (FVPTC) remain controversial.
The Journal of Clinical Endocrinology & Metabolism, 2004
The BRAF gene has been shown to be a major target for mutations in papillary thyroid carcinoma (P... more The BRAF gene has been shown to be a major target for mutations in papillary thyroid carcinoma (PTC) (36 -69%), which forms almost all of the over 2000 cases of thyroid carcinoma that have occurred in Chernobyl. BRAF is activated by point mutation, and were it to occur at a high frequency in Chernobyl-related tumors, it would challenge the dominant role of double-strand breaks in radiation-induced PTC. In a previous study, we detected the BRAF V600E mutation in 46% (23 of 50) of sporadic adult PTC. Using the same methodology, we have analyzed 34 post-Chernobyl PTC and detected RET/PTC rearrangements in 14 (41%) and BRAF mutations (V600E) in four (12%). These two alterations did not coexist in any PTCs. The mean age at exposure of patients with PTC showing BRAF mutation was higher than that of patients with tumors without BRAF mutation irrespective of their RET status. We have also analyzed 17 sporadic cases of childhood PTC and found that only one (6%) harbored the BRAF V600E mutation. We conclude that the frequency of BRAF mutations is significantly lower (P ؍ 0.0008) in post-Chernobyl PTC than in adult sporadic PTC, whereas no significant difference was found between post-Chernobyl and sporadic childhood PTCs. (J Clin Endocrinol Metab 89: 4267-4271, 2004) Abbreviations: FA, Follicular adenoma; PTC, papillary thyroid carcinoma; SSCP, single strand conformation polymorphism. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.
Rearrangement of RET proto-oncogene is the major event in the etiopathogenesis of papillary thyro... more Rearrangement of RET proto-oncogene is the major event in the etiopathogenesis of papillary thyroid carcinoma (PTC). We report a high prevalence of BRAF V599E mutation in sporadic PTC and in PTC-derived cell lines. The BRAF V599E mutation was detected in 23 of 50 PTC (46%) and in three of four PTC-derived cell lines. The prevalence of the BRAF V599E mutation in PTC is the highest reported to date in human carcinomas, being only exceeded by melanoma. PTC with RET/PTC rearrangement as well as the TPC-1 cell line (the only one harboring RET/PTC rearrangement) did not show the BRAF V599E mutation. BRAF V599E mutation was not detected in any of 23 nodular goiters, 51 follicular adenomas and 18 follicular carcinomas. A distinct mutation in BRAF (codon K600E) was detected in a follicular adenoma. Activating mutations in RAS genes were detected in 15% of FA, 33% of FTC and 7% of PTC. BRAF V599E mutation did not coexist with alterations in any of the RAS genes in any of the tumors. These results suggest that BRAF V599E mutation is frequent in the etiopathogenesis of PTC. The BRAF V599E mutation appears to be an alternative event to RET/PTC rearrangement rather than to RAS mutations, which are rare in PTC. BRAF V599E may represent an alternative pathway to oncogenic MAPK activation in PTCs without RET/PTC activation.
Type and prevalence of BRAF mutations are closely associated with papillary thyroid carcinoma his... more Type and prevalence of BRAF mutations are closely associated with papillary thyroid carcinoma histotype and patients' age but not with tumour aggressiveness Abstract A high prevalence of the BRAF V600E somatic mutation was recently reported in several series of papillary thyroid carcinomas (PTC). This mutation appears to be particularly prevalent in PTC with a predominantly papillary architecture. Another BRAF mutation (K601E) was detected in a follicular adenoma and in some cases of the follicular variant of PTC. The few studies on record provided controversial data on the relationship between the occurrence of BRAF mutations and clinicopathologic parameters such as gender, age and tumour staging. In an attempt to clarify such controversies we decided to enlarge our previous series to 315 tumours or tumour-like lesions diagnosed in 280 patients, including a thorough analysis of several clinicopathologic features. The BRAF V600E mutation was exclusively detected in PTC with a papillary or mixed follicular/papillary architecture both of the conventional type (46%) and of other histotypes, such as microcarcinoma (43%), Warthin-like PTC (75%) and oncocytic variant of PTC (55%). The BRAF K601E mutation was detected in four of the 54 cases of the follicular variant of PTC (7%). The mean age of patients with conventional PTC harbouring BRAF V600E (46.7 years) was significantly higher (P<0.0001) than that of patients with conventional PTC without BRAF V600E (29.5 years). The BRAF (BRAF V600E ) mutated PTC did not exhibit signs of higher aggressiveness (size, vascular invasion, extra-thyroid extension and nodal metastasis) and were in fact less often multicentric than PTC without the mutation.
The hot-spot mutation BRAF V599E is frequently detected in PTC (36-69%), in contrast to its absen... more The hot-spot mutation BRAF V599E is frequently detected in PTC (36-69%), in contrast to its absence in other benign or malignant thyroid lesions. In order to unravel whether there is any association between the occurrence of the BRAF mutation and the histological pattern of PTC, in this study a previous series of 50 PTCs was extended to 134 cases, including ten cases of PTC-related entities -hyalinizing trabecular tumour (HTT) and mucoepidermoid carcinoma (MEC). Using PCR/SSCP and sequencing, the BRAF V599E mutation was detected in 45 of the 124 PTCs (36%). No mutations were detected in any case of HTT and MEC. BRAF V599E was present in 75% of Warthin-like PTCs and 53% of conventional PTCs, whereas no BRAF V599E mutations were detected in any of the 32 cases of the follicular variant of PTC. BRAF V599E was also detected in 6 of 11 cases of the oncocytic variant of PTC that displayed a papillary or mixed follicular-papillary growth pattern and in none of the four oncocytic PTCs with a follicular growth pattern. A distinct mutation in BRAF (codon K600E) was detected in three cases of the follicular variant of PTC. This study has confirmed the high prevalence of BRAF V599E in PTC and has shown that the mutation is almost exclusively seen in PTC with a papillary or mixed follicular-papillary growth pattern, regardless of the cytological features of the neoplastic cells. The results support the existence of an oncocytic variant of PTC that should be separated from the oncocytic variant of follicular carcinoma and suggest that the follicular variant of PTC may be genetically different from conventional PTC.
Arquivos Brasileiros de Endocrinologia & Metabologia, 2007
Papillary thyroid carcinoma (PTC) is the most prevalent type of endocrine cancer and, in recent e... more Papillary thyroid carcinoma (PTC) is the most prevalent type of endocrine cancer and, in recent epidemiological surveys, one of the types of human cancer whose incidence is growing. Despite the favourable outcome and long survival rates of most patients, some tumours display an aggressive behaviour and may progress to the highly aggressive and lethal, anaplastic thyroid carcinoma. In recent years, several progresses have been made on the molecular characterization of PTC, in general, and in the genetic alterations underlying the histotype diversity of this type of cancer, in particular. This holds true regarding alterations on nuclear DNA as well as mitochondrial DNA. In this review we have summarized the most recent findings in the genetic characterization of PTC, giving a particular emphasis to the genotype-phenotype associations, the prognosis implications, and the diagnostic and therapeutic value of the newly identified genetic markers. (Arq Bras Endocrinol Metab 2007;51/5:643-653) RESUMO Genética Molecular do Carcinoma Papilífero de Tireóide -Grandes Esperanças… O carcinoma papilífero de tireóide (CPT) é o tipo mais prevalente de câncer endócrino e, em pesquisas epidemiológicas recentes, um dos tipos de câncer humano cuja incidência vêm crescendo. A despeito do prognóstico favorável e da longa taxa de sobrevivência da maioria dos pacientes, alguns tumores mostram um comportamento agressivo e podem progredir para o altamente agressivo e letal carcinoma anaplásico de tireóide.
Objective: Our aim was to characterize the molecular and genotypic profile of eight thyroid carci... more Objective: Our aim was to characterize the molecular and genotypic profile of eight thyroid carcinoma-derived cell lines-TPC1, FB2, B-CPAP, K1, XTC-1, C643, 8505C, and Hth74-in order to use them as in vitro models of thyroid carcinogenesis. Design: We evaluated the expression of five thyroid-specific genes (Tg, TSHr, TPO, PAX8, and TTF-1) to establish the cell lineage and to assess the differentiation status of each of the cell lines. We screened for mutations in the most relevant oncogenes=tumor suppressor genes affected in thyroid carcinogenesis: RAS, BRAF, CTNNB1, and TP53 along with RET=PTC rearrangements. Considering the putative relevance in general carcinogenesis, we have also studied other molecules such as EGFR, PI3K, RAF-1, and THRB. To determine the genetic identity of the cell lines, we performed genotypic analysis. Main outcome: The panel of cell lines we have studied displayed activation of several oncogenes (BRAF, RAS, RET=PTC) and inactivation of tumor suppressor genes (TP53) known to be important for thyroid carcinogenesis. Two of the cell lines-TPC1 and FB2-shared the same genotypic profile, probably representing clones of an ancestor cell line (TPC1). Conclusion: Due to their different molecular alterations, these cell lines represent a valuable tool to study the molecular mechanisms underlying thyroid carcinogenesis. We suggest that genotypic analyses should be included as a routine procedure to guarantee the uniqueness of each cell line used in research.
Endocrinology and Metabolism Clinics of North America, 2008
The close genotype-phenotype relationship that characterizes thyroid oncology stimulated the auth... more The close genotype-phenotype relationship that characterizes thyroid oncology stimulated the authors to address this article by using a mixed, genetic and phenotypic approach. As such, this article addresses the following aspects of intragenic mutations in thyroid cancer: thyroid stimulating hormone receptor and guanine-nucleotide-binding proteins of the stimulatory family mutations in hyperfunctioning tumors; mutations in RAS and other genes and aneuploidy; PAX8-PPARgamma rearrangements; BRAF mutations; mutations in oxidative phosphorylation and Krebs cycle genes in Hürthle cell tumors; mutations in succinate dehydrogenase genes in medullary carcinoma and C-cell hyperplasia; and mutations in TP53 and other genes in poorly differentiated and anaplastic carcinomas.
Archiv Fur Pathologische Anatomie Und Physiologie Und Fur Klinische Medicin, Apr 17, 2004
Somatic mutations of the BRAF gene (BRAFV599E and BRAFK600E) were found to be closely associated ... more Somatic mutations of the BRAF gene (BRAFV599E and BRAFK600E) were found to be closely associated with different histotypes of papillary thyroid carcinoma (PTC). The V599E mutation is highly prevalent in PTC with a papillary or mixed papillary follicular growth pattern, and the K600E mutation is apparently restricted to the follicular variant of PTC. It is usually accepted that thyroid malignancies may follow a progression path from well-differentiated to poorly differentiated (PDC) and undifferentiated (UC) carcinomas. One would expect that at least some of the less differentiated carcinomas would harbour the genetic alterations of pre-existing well-differentiated tumours. In order to find the prevalence of BRAF mutations in PDC and UC, we screened a series of 19 PDCs and 17 UCs, as well as 3 UC-derived cell lines, for both mutation types. The group of PDCs was restricted to the so-called insular and insular-like PDCs, thus excluding PTCs with solid, insular or trabecular foci of growth and PDCs displaying typical PTC nuclei. No BRAF mutations were detected in any of the 19 cases of PDC, whereas 6 of the UCs (35%) and one UC-derived cell line presented the BRAFV599E mutation. The BRAFK600E mutation was not detected in any case. We conclude that UC may progress from BRAFV599E-mutated PTC. The absence of BRAF mutations in our series of PDC supports the assumption that pure insular and insular-like PDCs are more closely related to follicular carcinoma than to PTC.
The Journal of Clinical Endocrinology Metabolism, Jul 2, 2013
The BRAF gene has been shown to be a major target for mutations in papillary thyroid carcinoma (P... more The BRAF gene has been shown to be a major target for mutations in papillary thyroid carcinoma (PTC) (36 -69%), which forms almost all of the over 2000 cases of thyroid carcinoma that have occurred in Chernobyl. BRAF is activated by point mutation, and were it to occur at a high frequency in Cher-
BRAF gene mutations have been frequently detected in papillary thyroid carcinoma (PTC). Moreover,... more BRAF gene mutations have been frequently detected in papillary thyroid carcinoma (PTC). Moreover, there is a close association between the type of mutation and the PTC histotype: BRAF(V600E) is associated with conventional PTC and with histological variants of PTC displaying a prominent papillary growth pattern, whereas BRAF(K601E) is associated with the follicular variant of PTC. We report the detection of a novel BRAF triplet deletion in a case of PTC displaying a predominantly solid growth pattern. The deletion leads to the replacement of a valine and a lysine by a glutamate in the BRAF activation segment (BRAF(VK600-1E)), thus mimicking partially the 2 BRAF mutations previously described. Our study reinforces the existence of a close relationship between the occurrence of some types of BRAF mutation and some PTC histotypes. The genetic study of more cases of the solid variant of PTC is necessary to find whether there exists a significant association between the occurrence of BRA...
Somatic mutations of the BRAF gene (BRAFV599E and BRAFK600E) were found to be closely associated ... more Somatic mutations of the BRAF gene (BRAFV599E and BRAFK600E) were found to be closely associated with different histotypes of papillary thyroid carcinoma (PTC). The V599E mutation is highly prevalent in PTC with a papillary or mixed papillary follicular growth pattern, and the K600E mutation is apparently restricted to the follicular variant of PTC. It is usually accepted that thyroid malignancies may follow a progression path from well-differentiated to poorly differentiated (PDC) and undifferentiated (UC) carcinomas. One would expect that at least some of the less differentiated carcinomas would harbour the genetic alterations of pre-existing well-differentiated tumours. In order to find the prevalence of BRAF mutations in PDC and UC, we screened a series of 19 PDCs and 17 UCs, as well as 3 UC-derived cell lines, for both mutation types. The group of PDCs was restricted to the so-called insular and insular-like PDCs, thus excluding PTCs with solid, insular or trabecular foci of growth and PDCs displaying typical PTC nuclei. No BRAF mutations were detected in any of the 19 cases of PDC, whereas 6 of the UCs (35%) and one UC-derived cell line presented the BRAFV599E mutation. The BRAFK600E mutation was not detected in any case. We conclude that UC may progress from BRAFV599E-mutated PTC. The absence of BRAF mutations in our series of PDC supports the assumption that pure insular and insular-like PDCs are more closely related to follicular carcinoma than to PTC.
Objective: Our aim was to characterize the molecular and genotypic profile of eight thyroid carci... more Objective: Our aim was to characterize the molecular and genotypic profile of eight thyroid carcinoma-derived cell lines-TPC1, FB2, B-CPAP, K1, XTC-1, C643, 8505C, and Hth74-in order to use them as in vitro models of thyroid carcinogenesis. Design: We evaluated the expression of five thyroid-specific genes (Tg, TSHr, TPO, PAX8, and TTF-1) to establish the cell lineage and to assess the differentiation status of each of the cell lines. We screened for mutations in the most relevant oncogenes=tumor suppressor genes affected in thyroid carcinogenesis: RAS, BRAF, CTNNB1, and TP53 along with RET=PTC rearrangements. Considering the putative relevance in general carcinogenesis, we have also studied other molecules such as EGFR, PI3K, RAF-1, and THRB. To determine the genetic identity of the cell lines, we performed genotypic analysis. Main outcome: The panel of cell lines we have studied displayed activation of several oncogenes (BRAF, RAS, RET=PTC) and inactivation of tumor suppressor genes (TP53) known to be important for thyroid carcinogenesis. Two of the cell lines-TPC1 and FB2-shared the same genotypic profile, probably representing clones of an ancestor cell line (TPC1). Conclusion: Due to their different molecular alterations, these cell lines represent a valuable tool to study the molecular mechanisms underlying thyroid carcinogenesis. We suggest that genotypic analyses should be included as a routine procedure to guarantee the uniqueness of each cell line used in research.
The Journal of Clinical Endocrinology & Metabolism, 2004
The BRAF gene has been shown to be a major target for mutations in papillary thyroid carcinoma (P... more The BRAF gene has been shown to be a major target for mutations in papillary thyroid carcinoma (PTC) (36 -69%), which forms almost all of the over 2000 cases of thyroid carcinoma that have occurred in Chernobyl. BRAF is activated by point mutation, and were it to occur at a high frequency in Chernobyl-related tumors, it would challenge the dominant role of double-strand breaks in radiation-induced PTC. In a previous study, we detected the BRAF V600E mutation in 46% (23 of 50) of sporadic adult PTC. Using the same methodology, we have analyzed 34 post-Chernobyl PTC and detected RET/PTC rearrangements in 14 (41%) and BRAF mutations (V600E) in four (12%). These two alterations did not coexist in any PTCs. The mean age at exposure of patients with PTC showing BRAF mutation was higher than that of patients with tumors without BRAF mutation irrespective of their RET status. We have also analyzed 17 sporadic cases of childhood PTC and found that only one (6%) harbored the BRAF V600E mutation. We conclude that the frequency of BRAF mutations is significantly lower (P ؍ 0.0008) in post-Chernobyl PTC than in adult sporadic PTC, whereas no significant difference was found between post-Chernobyl and sporadic childhood PTCs. (J Clin Endocrinol Metab 89: 4267-4271, 2004) Abbreviations: FA, Follicular adenoma; PTC, papillary thyroid carcinoma; SSCP, single strand conformation polymorphism. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.
The Journal of Clinical Endocrinology & Metabolism, 2006
The clinicopathological characteristics and the molecular features of the follicular variant of p... more The clinicopathological characteristics and the molecular features of the follicular variant of papillary thyroid carcinoma (FVPTC) remain controversial.
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Papers by Vitor Trovisco