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1.
Mod Pathol ; 24(3): 463-70, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21102419

RESUMEN

Epithelial ovarian cancer, the most lethal neoplasm of the female genital tract, is usually diagnosed at an advanced stage as obvious symptoms are absent at early stages. This disease is believed to originate from malignant transformation of the ovarian surface epithelium or fallopian tube. Histologically, several subtypes are being recognized, with serous histology accounting for the majority of cases. Serous tumors include serous borderline tumors and serous carcinomas. A better understanding of the tumor biology and molecular mechanisms involved in these tumors is needed, as both patient management and prognosis differ substantially. Previous microarray analysis identified SerpinA5, a uPA inhibitor, as key regulator for indolent borderline behavior. As carcinomas are characterized by loss of SerpinA5 mRNA expression, we hypothesized that SerpinA5 protein expression is reduced or lost in carcinomas when compared with borderline tumors. We performed SerpinA5 immunohistochemical staining on 32 serous borderline tumors, 187 primary serous carcinomas and 62 serous omental metastases. Reduced or absent SerpinA5 protein staining was observed in carcinomas when compared with borderline tumors (P<0.001). SerpinA5 protein expression was significantly lowered in the omental metastases (P<0.001) when compared with the matching primary carcinoma. Interestingly, SerpinA5 protein expression was reduced in advanced-stage borderline tumors, often characterized by micropapillary growth and/or microinvasion, when compared with early-stage borderline tumors (P=0.015). In conclusion, SerpinA5 expression is significantly reduced in advanced-stage serous borderline tumors and serous carcinomas when compared with the early-stage counterparts, and reduction of expression is linked to more aggressive features of borderline tumors.


Asunto(s)
Cistadenocarcinoma Seroso/secundario , Epiplón/patología , Neoplasias Ováricas/patología , Neoplasias Peritoneales/secundario , Lesiones Precancerosas/patología , Inhibidor de Proteína C/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Cistadenocarcinoma Seroso/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/metabolismo , Neoplasias Peritoneales/metabolismo , Lesiones Precancerosas/metabolismo , Adulto Joven
2.
Int J Gynecol Cancer ; 19(9): 1560-3, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19955937

RESUMEN

AIMS: To determine the incidence of activating v-raf murine sarcoma viral oncogene (BRAF) mutations in 30 serous borderline tumors (SBTs) of the ovary and the accompanying implants and to link BRAF mutation status to the clinical behavior of these tumors. METHODS AND RESULTS: Serous borderline tumors and noninvasive implants of 30 patients were analyzed for the presence of the BRAF V599E mutation, and mutation status was correlated to 70 months of clinical follow-up. Mutation status could be assessed in 27 SBTs. Eleven (41%) showed a BRAF mulation. Four (80%) of 5 patients with bilateral SBT showed a BRAF mutation in both ovaries. From the 8 implants that were analyzed for BRAF, 2 (25%) were mutated together with their primary tumor. v-Raf murine sarcoma viral oncogene mutation positive SBTs tend to present with a lower International Federation of Gynecology and Obstetrics stage and a higher tumor volume and are less frequently aneuploid. Seventy months' follow-up indicated no significant recurrence-free survival difference between these groups. CONCLUSIONS: v-Raf murine sarcoma viral oncogene mutations are common in ovarian SBT, are strongly associated with bilateral tumors, and are also found in implants. A larger number of tumors should be investigated to assess clinical importance of BRAF mutation status in SBTs.


Asunto(s)
Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/genética , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Adulto , Cistadenocarcinoma Seroso/patología , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Células HT29 , Humanos , Persona de Mediana Edad , Mutación/fisiología , Neoplasias Ováricas/patología , Pronóstico , Estudios Retrospectivos
3.
J Clin Oncol ; 23(29): 7257-64, 2005 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-16087957

RESUMEN

PURPOSE: Ovarian serous borderline tumors (SBT) are characterized by arborizing papillae lined by stratified epithelial cells, varying atypia, and absence of stromal invasion. Originally, these tumors have been classified as borderline because they behaved in a remarkably indolent manner, even with widespread tumor deposits called implants and the presence of lymph node involvement. The molecular biology of these lesions has just begun to be explored. High prevalence of B-RAF/K-RAS mutations in SBTs in contrast to serous carcinomas (SCAs) indicates that the mitogenic RAS-RAF-MEK-ERK-MAP kinase pathway is crucial for the pathogenesis of SBTs. The purpose of this study was to further unravel the genetic pathways through which SBTs develop, with a special focus on explaining the generally benign SBT behavior. MATERIALS AND METHODS: We generated RNA expression profiles of 38 ovarian serous neoplasms. Global Test pathway analysis and significance analysis of microarrays (SAM) of the expression profiles was performed. RESULTS: SAM and Global Testing showed that although the mitogenic pathway is activated in SBTs, activation of downstream genes involved in extracellular matrix (ECM) degradation is absent, suggesting an uncoupling of both events. In addition, we show that two genes involved in regulating this uncoupling, ERK-inhibitor Dusp 4 and uPA-inhibitor Serpina 5, are downregulated in SCAs in contrast to SBTs. In SCAs, this was associated with downstream MMP-9 activation at both mRNA and protein level. CONCLUSION: We propose that the putative tumor suppressor genes Dusp 4 and Serpina 5 provide a major clue to the indolent behavior of SBTs.


Asunto(s)
Neoplasias Quísticas, Mucinosas y Serosas/genética , Neoplasias Ováricas/genética , Inhibidor de Proteína C/genética , Proteínas Tirosina Fosfatasas/genética , Fosfatasas de Especificidad Dual , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Genes Supresores de Tumor , Genes ras/genética , Humanos , Metaloproteinasa 9 de la Matriz/genética , Fosfatasas de la Proteína Quinasa Activada por Mitógenos , Mutación , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Proto-Oncogénicas B-raf/genética
4.
Am J Pathol ; 162(4): 1095-101, 2003 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-12651602

RESUMEN

Patients with serous borderline tumors of the ovary often present with multiple tumors at different sites in the abdominal cavity. Whether different foci of ovarian serous borderline tumors are monoclonal in origin, arising as a consequence of spread from a single ovarian site, or whether such deposits are polyclonal and explained by independent molecular genetic alterations on the background of a field defect, is unknown. So far, only X-chromosome inactivation studies were performed to study this issue. We used a genome-wide allelotyping to assess clonality in 47 metachronous and/or synchronous multifocal tumors from 22 patients, using 59 microsatellite markers. Loss of heterozygosity (LOH) was observed in only 34 of 1969 informative markers in 9 of 22 serous borderline cases studied. Of these cases, 7 showed concordant LOH for at least one polymorphic marker in more than one tumor site. Flanking microsatellite markers enabled identification of identical chromosomal breakpoints in 6 of 7 cases. The LOH results strongly favor a common origin indicated by a likelihood ratio (possibility common origin/possibility independent origin) ranging from 39 to 14,163. Strong additional evidence for monoclonality is provided by the finding of identical microsatellite alterations in all three-tumor sites in one case.


Asunto(s)
Cromosomas Humanos X , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Mapeo Cromosómico , Femenino , Marcadores Genéticos , Humanos , Pérdida de Heterocigocidad , Repeticiones de Microsatélite , Reacción en Cadena de la Polimerasa , Probabilidad
5.
J Pathol ; 202(3): 336-40, 2004 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-14991899

RESUMEN

Genes of the RAF family, which mediate cellular responses to growth signals, encode kinases that are regulated by RAS and participate in the RAS/RAF/MEK/ERK/MAP-kinase pathway. Activating mutations in BRAF have recently been identified in melanomas, colorectal cancers, and thyroid and ovarian tumours. In the present study, an extensive characterization of BRAF and KRAS mutations has been performed in 264 epithelial and non-epithelial ovarian neoplasms. The epithelial tumours ranged from adenomas and borderline neoplasms to invasive carcinomas including serous, mucinous, clear cell, and endometrioid lesions. It is shown that BRAF mutations in ovarian tumours occur exclusively in low-grade serous neoplasms (33 of 91, 36%); these included serous borderline tumours (typical and micropapillary variants), an invasive micropapillary carcinoma and a psammocarcinoma. KRAS mutations were identified in 26 of 91 (29.5%) low-grade serous tumours, 7 of 49 (12%) high-grade serous carcinomas, 2 of 6 mucinous adenomas, 22 of 28 mucinous borderline tumours, and 10 of 18 mucinous carcinomas. Of note, two serous borderline tumours were found to harbour both BRAF and KRAS mutations. The finding that at least 60% of serous borderline tumours harbour mutations in two members of the ERK-MAP-kinase pathway (BRAF 36%, KRAS 30%) compared with 12% of high-grade serous carcinomas (BRAF 0%, KRAS 12%) indicates that the majority of serous borderline tumours do not progress to serous carcinomas. Furthermore, no BRAF mutations were detected in the other 173 ovarian tumours in this study.


Asunto(s)
Cistadenoma Seroso/genética , Mutación , Neoplasias Ováricas/genética , Proteínas Proto-Oncogénicas c-raf/genética , Cistoadenoma Mucinoso/genética , Cistoadenoma Mucinoso/patología , Cistoadenoma Papilar/genética , Cistoadenoma Papilar/patología , Cistadenoma Seroso/patología , Femenino , Humanos , Neoplasias Ováricas/patología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas B-raf , Proteínas Proto-Oncogénicas p21(ras) , Proteínas ras
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