Biomedical subjects
Valdemar Máximo
Publications and source records attributed to Valdemar Máximo.
Reply to: Low prevalence of BRAF mutations in radiation-induced thyroid tumors in contrast to sporadic papillary carcinomas.
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Molecular pathology of well-differentiated thyroid carcinomas.
The newly discovered molecular features of well-differentiated thyroid carcinomas derived from follicular cells are reviewed, within the frame of the 2004 WHO classification of thyroid tumours, under the following headings: "Follicular carcinoma", "Papillary carcinoma", "Follicular variant of papillary carcinoma" and "Hürthle cell tumours". A particular emphasis is put on the meaning of PAX8-PPARgamma rearrangements, RAS and BRAF mutations, and deletions and mutations of mitochondrial genes and of nuclear genes encoding for mitochondrial enzymes, for thyroid tumorigenesis.
Type and prevalence of BRAF mutations are closely associated with papillary thyroid carcinoma histotype and patients' age but not with tumour aggressiveness.
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.
Mitochondrial D-Loop instability in thyroid tumours is not a marker of malignancy.
Despite the numerous studies describing a high frequency of mitochondrial DNA (mtDNA) somatic mutations in many types of human primary tumors the mechanisms that generate such mutations and the role of mtDNA mutations in tumor development remain unclear. We present the results obtained in the study of mtDNA displacement-loop (D-Loop) region in a series of 66 thyroid tumors, and respective adjacent parenchyma, including benign (adenomas, n=30) and malignant tumors (follicular carcinomas, n=17 and papillary carcinomas, n=19). Three repetitive regions were analyzed [two mononucleotide repetitive (D310 and D568) and one dinucleotide repetitive (D514)]. Thirty-two (48.5%) of the 66 tumors [15/30 (50.0%) adenomas, 8/17 (47.1%) follicular carcinomas and 9/19 (47.4%) papillary carcinomas] harbored somatic insertions in D-Loop repetitive regions. Twenty (30.3%) of the 66 tumors [12/30 (40%) adenomas, 3/17 (17.6%) follicular carcinomas and 5/19 (26.3%) papillary carcinomas] harbored somatic insertions at the D310 mononucleotide repeat. Three (4.6%) of the 66 tumors [1/30 (3.3%) adenomas and 2/17 (11.8%) follicular carcinomas] harbored somatic insertions at the D568 mononucleotide repeat. Fifteen (22.7%) of the 66 tumors [3/30 (10.0%) adenomas, 5/17 (29.4%) follicular carcinomas and 7/19 (36.8%) papillary carcinomas] harbored somatic insertions at the D514 dinucleotide repeat. Five (7.6%) of the 66 tumors [1/30 (3.3%) adenomas, 1/17 (5.9%) follicular carcinomas and 2/19 (10.5%) papillary carcinomas] harbored somatic insertions in more than one region, and in one of them (a carcinoma) alterations were detected in the three regions. We conclude that mutations in the mtDNA D-Loop region are frequent in benign and malignant thyroid tumors and cannot be considered a marker of malignancy. Our study shows, furthermore, two repetitive regions (D310 and D514) that appear to be susceptible to mutation in thyroid tumors.
Hürthle (oncocytic) cell tumors of thyroid: etiopathogenesis, diagnosis and clinical significance.
The etiopathogenesis and the classification of oncocytic (Hürthle cell) tumors of the thyroid is reviewed with an emphasis on the role played by mitochondrial and nuclear genetic abnormalities that interfere with mitochondrial function. Oxyphilia is classified into primary or secondary and the so-called Hürthle cell carcinoma is divided into oncocytic (Hürthle cell) variants of papillary and follicular carcinoma.
Core I gene is overexpressed in Hürthle and non-Hürthle cell microfollicular adenomas and follicular carcinomas of the thyroid.
BACKGROUND: Most of the steps involved in the initiation and progression of Hürthle (oncocytic, oxyphilic) cell carcinomas of the thyroid remain unknown. METHODS: Using differential display and semiquantitative RT-PCR we found, among other alterations, overexpression of the gene encoding the Core I subunit of the complex III of the mitochondrial respiratory chain in a follicular carcinoma composed of Hürthle cells. RESULTS: Similar high levels of Core I gene expression were detected in nine follicular carcinomas (seven with Hürthle cell features), in seven microfollicular adenomas (one with Hürthle cell features) and in one micro/macrofollicular adenoma, in contrast to a lower/normal expression in nine papillary carcinomas (three with Hürthle cell features) and five macrofollicular adenomas (one of which displaying Hürthle cell features). No significative correlation was found between Core I overexpression and the proliferative activity of the lesions. CONCLUSIONS: We conclude that Core I overexpression in thyroid tumours is not associated with malignancy, Hürthle cells or proliferative activity. The pathogenetic mechanism linking Core I overexpression to the microfollicular pattern of growth of thyroid tumours remains to be clarified.
BRAF mutations are associated with some histological types of papillary thyroid carcinoma.
Mutations in the BRAF gene have recently been detected in a wide range of neoplastic lesions with a particularly high prevalence in melanoma and papillary thyroid carcinoma (PTC). 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.
BRAF mutations are not a major event in post-Chernobyl childhood thyroid carcinomas.
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.
BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC.
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.
Re: Lohrer,H.D., Hieber,L. and Zitzelsberger,H. (2002) Differential mutation frequency in mitochondrial DNA from thyroid tumours. Carcinogenesis, 23, 1577-1582.
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Alterations of the SDHD gene locus in midgut carcinoids.
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Germline succinate dehydrogenase subunit D mutation segregating with familial non-RET C cell hyperplasia.
C cell hyperplasia is associated with medullary carcinoma of the thyroid in the inherited MEN2 syndromes, in which the great majority of cases have been shown to be due to a mutation in the RET oncogene. We report a study of a family with C cell hyperplasia and hypercalcitoninemia in which no cases of medullary carcinoma have yet occurred and which lacked an identifiable causative RET mutation. Four of the family members showed hypercalcitoninemia, and marked C cell hyperplasia was present in each of the three in whom thyroidectomy has been performed. We investigated the possible involvement of the SDHD gene, because somatic and germline mutations in this gene have been found in a variety of tumors of neural crest-derived tissue. A germline mutation in exon 2 of the SDHD gene (c149 A-G, His 50 Arg) was found in six members of the family; all the four available members with hypercalcitoninemia possessed the mutation. One of the five available members without hypercalcitoninemia, an 18-yr-old female, also showed the mutation. We conclude that we have identified a new syndrome, characterized by familial non-RET C cell hyperplasia. Our studies suggest that a mutation in SDHD may be causative. These observations have implications for apparently incidental cases of hypercalcitoninemia or C cell hyperplasia.
Mucoepidermoid carcinoma of the thyroid: a tumour histotype characterised by P-cadherin neoexpression and marked abnormalities of E-cadherin/catenins complex.
The cadherin/catenins complex regulates cell-cell adhesion and motility and is believed to have an invasion suppressor role. Primary mucoepidermoid carcinoma of the thyroid (MECT) is a rare tumour characterised by a distinct morphological appearance and a questionable histogenesis. The coexistence of papillary thyroid carcinoma (PTC) foci in many patients with MECT suggests an association between the two tumour histotypes. In an attempt to clarify the putative relationship between MECT and PTC, we analysed tissue from 11 patients with MECT by immunohistochemistry (E-, P- and N-cadherins and alpha-, beta- and gamma-catenins). The E-cadherin gene was also analysed by polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP). The results were compared with a control group of normal thyroid, classical PTC and the diffuse sclerosing variant of PTC. Compared with normal thyroid and PTC, MECT displays marked abnormalities of the cadherin/catenin complex. Such abnormalities include the consistent neoexpression of P-cadherin and major alterations in the expression of E-cadherin and the three catenins. Our results point to the close relationship between the de novo expression of P-cadherin and the disruption of the cadherin/catenins complex with the squamoid phenotype of MECT.
Mitochondrial DNA somatic mutations (point mutations and large deletions) and mitochondrial DNA variants in human thyroid pathology: a study with emphasis on Hürthle cell tumors.
In an attempt to progress in the understanding of the relationship of mitochondrial DNA (mtDNA) alterations and thyroid tumorigenesis, we studied the mtDNA in 79 benign and malignant tumors (43 Hürthle and 36 non-Hürthle cell neoplasms) and respective normal parenchyma. The mtDNA common deletion (CD) was evaluated by semiquantitative polymerase chain reaction. Somatic point mutations and sequence variants of mtDNA were searched for in 66 tumors (59 patients) and adjacent parenchyma by direct sequencing of 70% of the mitochondrial genome (including all of the 13 OXPHOS system genes). We detected 57 somatic mutations, mostly transitions, in 34 tumors and 253 sequence variants in 59 patients. Follicular and papillary carcinomas carried a significantly higher prevalence of non-silent point mutations of complex I genes than adenomas. We also detected a significantly higher prevalence of complex I and complex IV sequence variants in the normal parenchyma adjacent to the malignant tumors. Every Hürthle cell tumor displayed a relatively high percentage (up to 16%) of mtDNA CD independently of the lesion's histotype. The percentage of deleted mtDNA molecules was significantly higher in tumors with D-loop mutations than in mtDNA stable tumors. Sequence variants of the ATPase 6 gene, one of the complex V genes thought to play a role in mtDNA maintenance and integrity in yeast, were significantly more prevalent in patients with Hürthle cell tumors than in patients with non-Hürthle cell neoplasms. We conclude that mtDNA variants and mtDNA somatic mutations of complex I and complex IV genes seem to be involved in thyroid tumorigenesis. Germline polymorphisms of the ATPase 6 gene are associated with the occurrence of mtDNA CD, the hallmark of Hürthle cell tumors.
Molecular pathology of papillary, follicular and Hürthle cell carcinomas of the thyroid.
In the review some of the molecular alterations that can relate to the neoplastic development of well differentiated thyroid carcinomas (follicular and papillary carcinoma) and of the so-called Hürthle cell carcinomas are described. Diagnostic and/or prognostic significance of the most recent findings is discussed.