RESUMEN
Activating mutations affecting the MET receptor tyrosine kinase are present in several types of human cancer, particularly in papillary renal cell carcinoma. Papillary thyroid carcinomas commonly express high levels of MET mRNA and protein, suggesting that increased MET signaling may be of importance in the molecular pathogenesis of differentiated thyroid carcinoma. To evaluate the role of MET mutations in thyroid carcinoma, we screened MET exons 2 to 21 for mutations in sporadic papillary, follicular, medullary, and anaplastic thyroid carcinomas using denaturing high-performance chromatography. A missense MET sequence alteration T1010I, located in exon 14 encoding for the juxtamembrane domain of MET, was found in 6 (6%) of the 104 thyroid carcinomas examined, whereas all 92 goiter samples had wild-type exon 14 (P = 0.031). Three (6%) of the 53 papillary, 2 (10%) of the 21 follicular, 1 (8%) of the 13 medullary, and none of the 17 anaplastic carcinomas studied had MET(T1010I). Four of the 6 T1010I sequence alterations were present also in the germline. MET protein expression showed no apparent association with the presence of MET(T1010I), and the clinical features of the patients with cancer with MET(T1010I) were similar to those of patients whose cancer did not harbor MET(T1010I). We conclude that MET(T1010I) sequence alteration is relatively frequent in differentiated thyroid carcinoma. The clinical and the molecular pathologic significance of this MET sequence alteration is not known.
Asunto(s)
Carcinoma/genética , Mutación de Línea Germinal , Proteínas Proto-Oncogénicas/genética , Receptores de Factores de Crecimiento/genética , Neoplasias de la Tiroides/genética , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/patología , Anciano , Biomarcadores de Tumor/metabolismo , Carcinoma/metabolismo , Carcinoma/patología , Carcinoma Medular/genética , Carcinoma Medular/patología , Carcinoma Papilar/genética , Carcinoma Papilar/patología , Cromatografía Líquida de Alta Presión , Análisis Mutacional de ADN , Cartilla de ADN/química , ADN de Neoplasias/análisis , Femenino , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Proteínas Proto-Oncogénicas c-met , Neoplasias de la Tiroides/metabolismoRESUMEN
PURPOSE: The clinical significance of intratumoral or peritumoral lymph vessel density is not known. LYVE-1, a lymphatic endothelium-specific hyaluronan receptor, is a novel lymphatic vessel marker that is expressed on lymph vessel endothelial cells of both normal and neoplastic tissues. EXPERIMENTAL DESIGN: We investigated expression of LYVE-1 by immunohistochemistry in 180 unilateral, invasive ductal breast carcinomas and assessed the presence and density of lymph vessels within the tumor and at the tumor periphery. RESULTS: A minority (12%) of breast carcinomas had intratumoral lymph vessels, whereas peritumoral lymph vessels were identified in almost all cases (94%). No substantial association was found between the number of LYVE-1-positive vessels and the number of CD31 or vascular endothelial growth factor receptor-3-positive vessels, or vascular endothelial growth factor-C expression. The number of metastatic axillary lymph nodes increased in parallel with increasing lymph vessel counts (P = 0.033). A higher than the median lymph vessel count at the tumor periphery was significantly associated with unfavorable distant disease-free survival and overall survival. Women with high peritumoral lymph vessel density had only 58% (95% confidence interval, 46-70%) 5-year distant disease-free survival as compared with 74% (66-83%) among those with a low peritumoral lymph vessel density (P = 0.0088). In contrast, the presence of intratumoral lymph vessels was associated with neither axillary nodal status nor survival. Lymph vessel density was not an independent prognostic factor in a multivariate survival analysis. CONCLUSIONS: A high peritumoral lymph vessel density is associated with a poor outcome in ductal breast cancer.
Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Endotelio/metabolismo , Glicoproteínas/farmacología , Vasos Linfáticos/patología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD34/biosíntesis , Neoplasias de la Mama/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Receptores de Hialuranos/metabolismo , Inmunohistoquímica , Persona de Mediana Edad , Análisis Multivariante , Metástasis de la Neoplasia , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/biosíntesis , Pronóstico , Factores de Tiempo , Resultado del Tratamiento , Factor C de Crecimiento Endotelial Vascular/biosíntesis , Receptor 3 de Factores de Crecimiento Endotelial Vascular/biosíntesis , Proteínas de Transporte VesicularRESUMEN
Germline mutations in the fumarate hydratase (FH) gene at 1q43 predispose to dominantly inherited cutaneous and uterine leiomyomas, uterine leiomyosarcoma, and papillary renal cell cancer (HLRCC syndrome). To evaluate the role of FH inactivation in sporadic tumorigenesis, we analyzed a series of 299 malignant tumors representing 10 different malignant tumor types for FH mutations. Additionally, 153 uterine leiomyomas from 46 unselected individuals were subjected to and informative in loss of heterozygosity analysis at the FH locus, and the five (3.3%) tumors displaying loss of heterozygosity were subjected to FH mutation analysis. Although mutation search in the 299 malignant tumors was negative, somatic FH mutations were found in two nonsyndromic leiomyomas; a splice site change IVS4 + 3A>G, leading to deletion of exon four, and a missense mutation Ala196Thr. The occurrence of somatic mutations strongly suggests that FH is a true target of the 1q43 deletions. Although uterine leiomyomas are the most common tumors of women, specific inactivating somatic mutations contributing to the formation of nonsyndromic leiomyomas have not been reported previously. Taking into account the apparent risk of uterine leiomyosarcoma associated with FH germline mutations, the finding raises the possibility that also some nonsyndromic leiomyomas may have a genetic profile that is more prone to malignant degeneration. Our data also indicate that somatic FH mutations appear to be limited to tumor types observed in hereditary leiomyomatosis and renal cell cancer.
Asunto(s)
Fumarato Hidratasa/genética , Leiomioma/genética , Neoplasias Uterinas/genética , Secuencia de Bases , Carcinoma de Células Renales/genética , Cromatografía Líquida de Alta Presión , Análisis Mutacional de ADN , Femenino , Humanos , Pérdida de Heterocigocidad , Masculino , Mutación , Reacción en Cadena de la PolimerasaRESUMEN
PURPOSE: To screen and validate the global gene expression in papillary thyroid carcinoma (PTC) using cDNA expression arrays and immunohistochemistry on tumor tissue microarrays in an attempt to find genes that may be of importance in the molecular pathogenesis and malignant progression of PTC. EXPERIMENTAL DESIGN: Eighteen PTC tissue specimens were compared with three morphologically normal thyroid specimens by applying Atlas Human Cancer 1.2 Array membranes printed with cDNAs of 1176 human genes involved in cancer. Results for selected genes were confirmed by reverse transcription-PCR. Protein expression of selected genes was further studied using a tissue microarray consisting of 107 PTCs and compared with histologically normal thyroid tissue samples. RESULTS: By cDNA arrays, two genes [c-MET and matrix metalloproteinase (MMP)-11] were expressed only in tumor tissue, where they were present in >50% of cases. Ten genes [macrophage inhibitory cytokine-1, CGD, fibronectin (FN), hypoxia-inducible factor 1, Fc-epsilon-receptor gamma-chain, lactate dehydrogenase A, HLA-DBP1, AH receptor, tissue inhibitor of metalloproteinase (TIMP-1), and glycyl-tRNA-synthetase] were found to be up-regulated >2-fold in 40-100% of cancers, whereas 9 genes (GADD153, polykystic kidney disease-1, CYR61, DPC4, HBA1, gravin, DLG3, protein tyrosine phosphatase sigma, and heterochromatin protein 1 homologue-alpha) were down-regulated to <50% of their normal levels in 40-94% of cases. Conventional reverse transcription-PCR gave consistent results with the cDNA array findings for all four genes selected to be studied (c-MET, FN, TIMP-1, and GADD153). Immunohistochemistry for three selected proteins, FN, MMP-11, and TIMP-1, showed positive staining in 81, 87, and 68% of the tumor samples, respectively. CONCLUSIONS: Several novel and previously undetected tumor promoting/inhibiting genes may be of importance in the molecular pathogenesis and malignant progression of PTC. Transcription of these genes may result in overexpression of proteins, such as c-MET, MMP-11, TIMP-1, and FN, which may contribute to the pathogenesis of PTC.
Asunto(s)
Carcinoma Papilar/metabolismo , Fibronectinas/biosíntesis , Metaloendopeptidasas/biosíntesis , Proteínas Proto-Oncogénicas c-met/biosíntesis , Neoplasias de la Tiroides/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/biosíntesis , Carcinoma Papilar/genética , ADN Complementario/metabolismo , Regulación hacia Abajo , Fibronectinas/genética , Humanos , Inmunohistoquímica , Hibridación in Situ , Metaloproteinasa 11 de la Matriz , Metaloendopeptidasas/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Proto-Oncogénicas c-met/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias de la Tiroides/genética , Inhibidor Tisular de Metaloproteinasa-1/genética , Regulación hacia ArribaRESUMEN
Deletion of chromosome 11q23 is a common alteration in parathyroid adenomas and hyperplasias. A new potential suppressor gene PPP2R1B encoding the beta isoform of the A subunit of the serine/threorine protein phosphatase 2A was recently identified and localized to chromosome 11q23. We performed polymerase chain reaction-based single-strand conformation polymorphism and direct sequencing on six parathyroid hyperplasias and 12 adenomas to evaluate the role of PPP2R1B in the pathogenesis of parathyroid lesions. A previously identified germline G-A transition (GGC-GAC) in codon 90, changing glycine (Gly) to aspartic acid (Asp), was detected in one adenoma. Both the common Gly allele and the variant Asp allele were detected by direct sequencing in the patient's somatic cells. We conclude mutations of PPP2R1B are not frequent in parathyroid lesions, and that other genes located at 11q23 may be more closely associated with pathogenesis of parathyroid hyperplasia and adenoma.