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P Soares

Publications and source records attributed to P Soares.

At least 19 recordsLinked to original sources
PubMed2006

H-RAS 81 polymorphism is significantly associated with aneuploidy in follicular tumors of the thyroid.

Follicular thyroid tumors are often aneuploid. It was advanced that chromosomal instability is closely associated to RAS mutations, but such association remains unproven. H-RAS can be alternatively spliced in two different proteins, p21 and p19, the former being the active protein. In order to investigate the relationship between RAS mutational status and ploidy in thyroid tumors, we analysed RAS genes in a series of 99 follicular lesions (14 nodular goiters, 70 follicular adenomas and 15 follicular carcinomas), eight thyroid carcinoma cell lines and a control group of 102 blood donors, correlating the presence of RAS mutations with the ploidy of the tumors and evaluating the two spliced forms of H-RAS. Overall, 20% of the follicular tumors harbored RAS mutations and 62% of the patients with follicular tumors (and 51% of blood donors) harbored the H-RAS 81T --> C polymorphism. The presence of RAS mutations was not associated with aneuploidy. The H-RAS polymorphism did not seem to confer a higher propensity for neoplastic transformation as it was also found in hyperplastic lesions, but was strongly associated with aneuploidy (P<0.0001). The presence of the H-RAS 81T --> C polymorphism was associated with significantly higher amounts of total H-RAS mRNA expression, higher amounts of p21 isoform and a higher fraction of neoplastic cells in S phase. Our results suggest that the H-RAS 81T --> C polymorphism may induce aneuploidy through overexpression of the active p21 isoform of H-RAS.

Adenocarcinoma, Follicular↗
PubMed2005

PAX8-PPARgamma rearrangement is frequently detected in the follicular variant of papillary thyroid carcinoma.

CONTEXT: The clinicopathological characteristics and the molecular features of the follicular variant of papillary thyroid carcinoma (FVPTC) remain controversial. OBJECTIVE/DESIGN/PATIENTS: In an attempt to clarify such controversies and to find whether or not FVPTC cases share the molecular features of follicular tumors, we searched for the presence of PAX8-PPARgamma rearrangements, RAS mutations, and RAP-1, RAF-1, and BRAF mutations in a series of 40 FVPTCs as well as in 27 follicular thyroid carcinomas (FTCs) and 12 follicular thyroid adenomas (FTAs). Fluorescence in situ hybridization and RT-PCR were used to detect the PAX8-PPARgamma rearrangement and PCR, single strand confirmational polymorphism, and sequencing for searching the mutations. RESULTS: The frequency of PAX8-PPARgamma rearrangement was similar in FVPTCs (37.5%), FTCs (45.5%), and FTAs (33.3%). The same holds true regarding the frequency and type of RAS mutations: FVPTC, 25.0%; FTC, 22.2%; and FTA, 33.3%. BRAF mutations were only detected in FVPTC (10%); the BRAF mutations in these cases (K601E and G474R) are different from the typical BRAF(V600E) mutation of conventional PTCs. No mutations were detected in RAP-1 and RAF-1. In FVPTCs, the PAX8-PPARgamma rearrangement was significantly associated with multifocality and vascular invasion, whereas the RAS mutations were significantly associated with the large tumor size. There were three cases of FVPTC, three FTCs and one FTA, harboring both PAX8-PPARgamma rearrangement and RAS mutations; patients with such tumors were usually very young. CONCLUSIONS: We conclude that a subset of FVPTC shares some of the molecular features of follicular tumors. Further studies are necessary to clarify the putative clinical significance (e.g. association to blood-born metastases) of PAX8-PPARgamma rearrangement, RAS mutations, and BRAF(K601E) in FVPTCs.

Adult↗
PubMed2005

Somatic and germline mutation in GRIM-19, a dual function gene involved in mitochondrial metabolism and cell death, is linked to mitochondrion-rich (Hurthle cell) tumours of the thyroid.

Oxyphil or Hurthle cell tumours of the thyroid are characterised by their consistent excessive number of mitochondria. A recently discovered gene, GRIM-19 has been found to fulfil two roles within the cell: as a member of the interferon-beta and retinoic acid-induced pathway of cell death, and as part of the mitochondrial Complex I assembly. In addition, a gene predisposing to thyroid tumours with cell oxyphilia (TCO) has been mapped to chromosome 19p13.2 in one family. A cluster of genes involved in mitochondrial metabolism occurs in this region; one of these is GRIM-19. We have searched for GRIM-19 mutations in a series of 52 thyroid tumours. Somatic missense mutations in GRIM-19 were detected in three of 20 sporadic Hurthle cell carcinomas. A germline mutation was detected in a Hurthle cell papillary carcinoma arising in a thyroid with multiple Hurthle cell nodules. No mutations were detected in any of the 20 non-Hurthle cell carcinomas tested, nor in any of 96 blood donor samples. In one of the sporadic Hurthle cell papillary carcinomas positive for GRIM-19 mutation, we have also detected a ret/PTC-1 rearrangement. No GRIM-19 mutations were detected in any of the six cases of known familial Hurthle cell tumour tested, so that our results do not support the identification of GRIM-19 as the TCO gene. The GRIM-19 mutations we have detected are the first nuclear gene mutations specific to Hurthle cell tumours to be reported to date; we propose that such mutations can be involved in the genesis of sporadic or familial Hurthle cell tumours through the dual function of GRIM-19 in mitochondrial metabolism and cell death.

Adenoma, Oxyphilic↗
PubMed2003

E-cadherin loss rather than beta-catenin alterations is a common feature of poorly differentiated thyroid carcinomas.

AIMS: To investigate the immunohistochemical and molecular genetic features of the cadherins/catenins complex in thyroid carcinoma based on the hypothesis that poorly differentiated carcinoma of the thyroid represents an intermediate step between well-differentiated and undifferentiated carcinomas. METHODS AND RESULTS: Immunohistochemistry for E-, P- and N-cadherins and alpha-, beta- and gamma-catenins was performed in a series of 17 cases of poorly differentiated carcinoma of the thyroid. All cases showed absence of membranous expression of E-cadherin with no aberrant expression of P- or N-cadherins; regarding catenins there was heterogeneous loss of expression with membranous immunolocalization of the three catenins in most cases. Molecular analysis of the E-cadherin gene and exon 3 of the beta-catenin gene was also performed by polymerase chain reaction/single-strand conformation polymorphism and sequencing. No mutations in either gene were detected in any case. CONCLUSIONS: In contrast to previous reports, our results suggest that loss of E-cadherin rather than beta-catenin mutation is the crucial event in determining the differentiation 'level' of thyroid carcinomas.

Adult↗
PubMed2002

Specific haplotypes of the RET proto-oncogene are over-represented in patients with sporadic papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC), which may be sporadic (95%) or familial (5%), has a prevalence adjusted for age in the general population of 1:100 000. Somatic rearrangements of the RET proto-oncogene are present in up to 66% of sporadic tumours, while they are rarely found in familial cases. PURPOSE: In order to determine if some variants of this gene, or a combination of them, might predispose to PTC, we looked for an association of RET haplotype(s) in PTC cases and in controls from four countries matched for sex, age, and population. METHODS: Four single nucleotide polymorphisms (SNPs) across the RET coding sequence were typed and haplotype frequencies were estimated. Genotype and haplotype distributions were compared among these cases and controls. RESULTS: Ten haplotypes were observed, the seven most frequent of which have been previously described in sporadic Hirschsprung patients and controls. The single locus analyses suggested association of exon 2 and exon 13 SNPs with sporadic PTC. The haplotype analysis showed over-representation of one haplotype in French and Italian sporadic PTC, whereas a different haplotype was significantly under-represented in French familial PTC. CONCLUSIONS: Our data suggest that some variants of RET and some specific haplotypes may act as low penetrance alleles in the predisposition to PTC.

Age Factors↗
PubMed2001

E-cadherin gene (CDH1) promoter methylation as the second hit in sporadic diffuse gastric carcinoma.

In diffuse gastric carcinoma, despite common E-cadherin gene (CDH1) mutations, tumors show absence of CDH1 loss of heterozigosity (LOH) in most cases. This observation challenges the classical two-hit model of tumor suppressor gene inactivation. In order to investigate whether or not CDH1 promoter methylation may function as the second hit we analysed a series of 23 sporadic gastric carcinomas for the presence of CDH1 mutations, CDH1 promoter methylation, LOH and E-cadherin expression. CDH1 mutations were detected in nine of the 16 (56.3%) diffuse gastric carcinomas and in none of the seven intestinal gastric carcinomas. In diffuse gastric carcinomas harboring CDH1 mutations, LOH was observed in a single case. Loss of plasma membrane E-cadherin expression was consistently found in all nine cases with CDH1 mutation, suggesting that tumors inactivated the remaining CDH1 allele via a different mechanism. CDH1 promoter methylation was observed in nine of the 16 (56.3%) diffuse-type gastric carcinoma cases, including six of the nine cases (66.7%) harboring CDH1 mutations. CDH1 promoter methylation was also seen in two (28.6%) intestinal-type cases. Our results show that CDH1 promoter methylation is the second hit in more than half of the sporadic diffuse gastric carcinoma cases harboring CDH1 mutations.

Adenocarcinoma↗
PubMed2001

Microsatellite instability, mitochondrial DNA large deletions, and mitochondrial DNA mutations in gastric carcinoma.

Mitochondrial DNA (mtDNA) large deletions and mtDNA mutations have been demonstrated in various types of human cancer. The relationship between the occurrence of such alterations and the nuclear microsatellite instability (MSI) status of the neoplastic cells remains controversial. In an attempt to clarify the situation in gastric carcinoma, we studied, by PCR/SSCP and sequencing, five mitochondrial genes and two D-loop regions in 32 gastric carcinomas that had been previously screened for MSI and mitochondrial common deletion. MtDNA alterations were detected in 26 carcinomas (81%). All the mtDNA mutations, which occurred mainly in the D-loop and ND1 and ND5 genes, were transitions. D-loop alterations (insertions and/or deletions) were not significantly associated with mutations in the coding regions. There was a trend towards an inverse relationship between the occurrence of mitochondrial common deletion and mtDNA mutations. No significant relationship was observed between MSI status and mtDNA mutations, whereas the mitochondrial common deletion appeared to be almost exclusively restricted to MSI-negative tumors. The latter finding--almost no gastric carcinoma with MSI-positive phenotype has large deletions of mtDNA--needs to be confirmed in a larger series and in tumors from other organs.

Carcinoma↗
PubMed2001

Abnormalities of the E-cadherin/catenin adhesion complex in classical papillary thyroid carcinoma and in its diffuse sclerosing variant.

The cadherin/catenin complex regulates cellular adhesion and motility and is believed to function as an invasion suppressor system. Several studies have identified alterations in the expression profiles of those molecules in different histotypes of thyroid carcinoma. The diffuse sclerosing variant (DSV) of papillary thyroid carcinoma (PTC) is a rare, highly invasive variant of PTC in which an impairment of cell-cell adhesion may play a major role. In an attempt to progress in the understanding of the clinicopathological features of DSV, this study examined eight cases of DSV, 18 cases of classical PTC and a control group of normal thyroid by immunohistochemistry (E-, P- and N-cadherins and beta-, gamma- and alpha-catenins). The E-cadherin gene was also studied by polymerase chain reaction/single strand conformation polymorphism (PCR/SSCP) and methylation-specific PCR (MSP). In contrast to classical PTC, which showed heterogeneous loss of E-cadherin expression, in almost every case of DSV a pronounced reduction was observed in its membranous expression, accompanied by a relocation to the cytoplasm. Inactivation of the E-cadherin/catenin complex appears to occur in DSV via two different pathways: E-cadherin alteration either through mutation (one out of the eight cases) or through methylation of the E-cadherin gene promoter (three out of five cases); and beta- and/or gamma-catenin alterations (three of the eight cases). Methylation of the E-cadherin gene promoter, abnormalities of E-cadherin expression and alterations of gamma-catenin were also detected in classical PTC. In DSV, as in classical PTC, there is neo-expression of P-cadherin in areas of squamous metaplasia and no N-cadherin expression. In conclusion, abnormalities of the E-cadherin/catenin complex appear to be more pronounced in DSV than in classical PTC. It remains to be shown whether or not such differences are associated with the more aggressive behaviour of DSV compared with classical PTC.

Cadherins↗
PubMed2001

Fetal adenomas and minimally invasive follicular carcinomas of the thyroid frequently display a triploid or near triploid DNA pattern.

The ploidy pattern and the percentage of S-phase cells were investigated by means of flow cytometry using fresh or frozen samples in a series of 143 tumors and tumor-like lesions of the thyroid in an attempt to find whether there is any relationship between the histological characteristics of the lesions and their DNA content. The percentages of aneuploidy cases per category were: nodular goiter, 18.5% (15/81); fetal adenoma (including cases with trabecular/solid growth pattern), 58.3% (14/24); follicular adenoma other than fetal adenoma, 0% (0/18); papillary carcinoma, 11.1% (1/9); and minimally invasive follicular carcinoma, 57.1% (4/7). Regardless of the histological category, aneuploid lesions had a significantly higher (P < 0.001) percentage of S-phase cells (7.3%) than diploid lesions (4.1%). All the six cases with a DNA content within the triploid range were fetal adenomas, but one was a follicular carcinoma displaying a fetal adenoma-like growth pattern. The other three follicular carcinomas with an aneuploid DNA pattern also displayed foci of fetal adenoma-like growth pattern. Image cytometry of the four aneuploid follicular carcinomas showed similar DNA indexes in the peripheral, invasive foci of the lesions and in the central fetal adenoma-like areas. These results demonstrate that aneuploidy in benign tumors is restricted to adenomas displaying a fetal or fetal/embryonal growth pattern and support the concept that chromosome instability is a major pathway of tumorigenesis in thyroid follicular neoplasms.

Adenocarcinoma, Follicular↗
PubMed2000

Extended structural variation of a pentanucleotide repeat in the GSTP1 gene: characterisation in a normal population and in thyroid and gastric tumours.

The promoter region of the human GSTP1 gene contains a polymorphic short tandem repeat (STR) locus consisting of pentanucleotide repeat units (ATAAA). In this work we report the existence of a total of 26 alleles in a Caucasian population. While differences in size (ranging from one to five base pairs) were responsible for the major variation, in five size-defined classes, two alternative sequences were found. Automatic fragment sizing and sequencing analysis revealed that this polymorphism is of a highly complex nature in contrast with previous reports. A genetic population study was carried out on a random sample from Portugal showing no deviation from Hardy-Weinberg equilibrium. Somatic instability studies were also performed on gastric and thyroid tumours using this STR: no instability was detected in thyroid tumour tissues when compared with their normal counterpart but in gastric tumour tissues microsatellite instability (MSI) was detected in 9.6% of the cases and loss of heterozygosity (LOH) also in 9.6% of the cases studied. The results obtained with GSTP1 in gastric cancer were compared with previously reported data on MSI using BAT-26 and several dinucleotide repeat markers.

Alleles↗
PubMed1999

E-cadherin gene mutations provide a genetic basis for the phenotypic divergence of mixed gastric carcinomas.

Inactivation of the E-cadherin gene has been described previously in gastric carcinomas. In the present study, we investigated the alterations of the E-cadherin gene in gastric carcinomas and analyzed the relationship between such alterations and the histotypes of the tumors. We performed PCR/single-strain conformation polymorphism mutation screening and loss of heterozygosity analysis of the E-cadherin gene in a series of 26 gastric carcinomas, including 10 "pure" intestinal, 10 "pure" diffuse, and 6 mixed gastric carcinomas, the latter with intestinal and diffuse components. Fifteen mutations of the E-cadherin gene were identified in 12 cases (46.2%). Mutations included 10 missense mutations, 7 of which occurred in sequences coding for calcium binding motifs, 3 splice site mutations, 1 nonsense mutation, and 1 frameshift deletion. We found mutations of the E-cadherin gene in 7 of 10 "pure" diffuse carcinomas (70.0%) and in 5 of 6 mixed carcinomas (83.3%). No mutations were found in "pure" intestinal carcinomas. In mixed carcinomas, inactivating E-cadherin mutations were exclusively observed in the diffuse component of the tumors. We conclude that E-cadherin inactivation is significantly related with the diffuse histotype in gastric carcinomas, not only in "pure" diffuse carcinomas but also in the diffuse component of mixed tumors. To the best of our knowledge, this is the first report advancing a genetic basis for the phenotypic divergence of mixed gastric carcinomas.

Cadherins↗
PubMed1998

Sporadic ret-rearranged papillary carcinoma of the thyroid: a subset of slow growing, less aggressive thyroid neoplasms?

Despite the large amount of information accumulated on the role played by ret activation in the oncogenesis of papillary thyroid carcinoma (PTC), the biological and clinical significance of such activation 'in vivo' remains controversial. The aim of this study was to address some of the existing controversies by comparing two groups of unselected PTCs, one with and the other without ret rearrangement, with regard to several clinicopathological and biological features. Thirty-three PTCs were selected at random. ret rearrangement was found in eight cases (24.2 per cent) using Southern blot analysis. The mean age of the patients with tumours displaying ret rearrangement (28 +/- 3.1 years) was significantly lower than that of the patients harbouring cases that did not present rearrangement (45 +/- 2.9 years). The large majority of the tumours with ret rearrangement displayed a papillary or mixed follicular-papillary pattern and very low proliferative activity. ret rearrangement correlated significantly with decreased cytoplasmic expression of E-cadherin. No significant differences were found regarding the gender of the patients, tumour size, multicentricity, extrathyroidal growth, vascular invasion, lymphocytic infiltration, lymph node involvement or the expression of E-cadherin (membrane), c-erb-B2, c-met, Bcl-2, and vimentin. It is proposed that sporadic PTCs harbouring a ret rearrangement occur frequently as slow growing, papillary, or predominantly papillary tumours that do not usually progress towards less differentiated neoplasms representing what might be described as a Bonsai phenotype.

Adolescent↗
PubMed1997

E-cadherin gene alterations are rare events in thyroid tumors.

Reduced expression of E-cadherin has been associated with loss of differentiation and/or increased invasiveness and metastatic ability in several types of neoplasms. Rare studies on thyroid tumors have shown minimal or absent expression in undifferentiated carcinomas and a variable degree of immunoreactivity/mRNA expression in follicular and papillary carcinomas. We studied immunohistochemically 2 follicular adenomas, 8 follicular carcinomas, 18 papillary carcinomas and 3 poorly differentiated carcinomas to evaluate E-cadherin expression. In 7 papillary carcinomas, lymph node metastases were also studied. The E-cadherin gene was analysed in 27 tumors by PCR/SSCP followed, whenever appropriate, by DNA sequencing. LOH at the E-cadherin locus was assessed in 16 tumors. Reduced and heterogeneous expression of E-cadherin was found in primary and metastatic papillary carcinomas, whereas follicular carcinomas showed moderate to strong homogeneous immunoreactivity, and poorly differentiated carcinomas showed no or very faint immunoreactivity. The only case harbouring a (missense type) mutation of the E-cadherin gene was a papillary carcinoma exhibiting immunoreactivity in the primary tumor as well as in metastasis. LOH was found in a follicular adenoma and in a poorly differentiated carcinoma without evidence of mutation in the remaining allele. Our results show that irreversible alterations (allele loss or mutation) of the E-cadherin gene are infrequent in thyroid tumors. The reduced and heterogeneous expression of E-cadherin in thyroid carcinomas, particularly of the papillary histotype, appears to reflect transcriptional regulation or post-transcriptional modulation rather than structural abnormalities.

Adenocarcinoma, Follicular↗
PubMed1997

[Prognostic factors in differentiated thyroid gland carcinoma].

This review aims at describing the influence of established and not yet sufficiently characterized parameters on the prognosis of thyroid follicle cell carcinomas. The analysis of literature data covers a broad spectrum of pathologic and biologic factors from classical prognostic features like age, gender and tumor stage to mutation, activation or, where applicable, inactivation of tumor suppressor genes, metastasis-related genes and adhesion molecules.

Adenocarcinoma, Follicular↗
PubMed1997

Benign and malignant thyroid lesions show instability at microsatellite loci.

Forty-six benign and malignant tumours and tumour-like lesions of the thyroid were analysed for microsatellite instability (MI) at eight loci, mapping to four different chromosomes, 7 lesions (15%) displayed MI at one or more loci, including 2/13 nodular goitres, 2/15 follicular adenomas, 2/12 papillary carcinomas and 1/4 follicular carcinomas. Two benign and one malignant lesion among the seven unstable cases exhibited this phenotype at three or more loci. We found no mutations in the mismatch repair gene, hMSH2, in the seven affected cases, after screening all the exons by CDGE mutation analysis. At variance with the data on record, these results indicate that, despite being relatively infrequent, MI does occur not only in thyroid carcinomas but also in benign lesions (goitres and follicular adenomas of the thyroid).

Adenocarcinoma, Follicular↗