RESUMEN
Mutations in four genes encoding subunits or cofactors of succinate dehydrogenase (SDH) cause hereditary paraganglioma and pheochromocytoma syndromes. Mutations in SDHB and SDHD are generally the most common, whereas mutations in SDHC and SDHAF2 are far less frequently observed. A total of 1045 DNA samples from Dutch paraganglioma and pheochromocytoma patients and their relatives were analyzed for mutations of SDHB, SDHC, SDHD or SDHAF2. Mutations in these genes were identified in 690 cases, 239 of which were index cases. The vast majority of mutation carriers had a mutation in SDHD (87.1%). The second most commonly affected gene was SDHAF2 (6.7%). Mutations in SDHB were found in only 5.9% of samples, whereas SDHC mutations were found in 0.3% of samples. Remarkably, 69.1% of all carriers of a mutation in an SDH gene in the Netherlands can be attributed to a single founder mutation in SDHD, c.274G>T and p.Asp92Tyr. Moreover, 88.8% of all SDH mutation carriers carry one of just six Dutch founder mutations in SDHB, SDHD and SDHAF2. The dominance of SDHD mutations is unique to the Netherlands, contrasting with the higher prevalence of SDHB mutations found elsewhere. In addition, we found that most SDH mutation-related paragangliomas-pheochromocytomas in the Netherlands can be explained by only six founder mutations in SDHAF2, SDHB and SDHD. The findings underline the regional differences in the SDH mutation spectrum, differences that should be taken into account in the development of effective screening protocols. The results show the crucial role that demographic factors play in the frequency of gene mutations.
Asunto(s)
Efecto Fundador , Mutación , Succinato Deshidrogenasa/genética , Neoplasias de las Glándulas Suprarrenales/genética , Humanos , Países Bajos/epidemiología , Paraganglioma/genética , Feocromocitoma/genética , PrevalenciaRESUMEN
OBJECTIVE: Head and neck paragangliomas (HNPGL) are associated with mutations in genes encoding subunits of succinate dehydrogenase (SDH). The aim of this study was to evaluate SDH mutations, family history and phenotypes of patients with HNPGL in the Netherlands. DESIGN: We evaluated the clinical data and the mutation status of 236 patients referred between 1950 and 2009 to Leiden University Medical Center. RESULTS: The large majority of the patients carried mutations in SDHD (83%), and the p.Asp92Tyr Dutch founder mutation in SDHD alone accounted for 72% of all patients with HNPGL. A mutation in SDHAF2 was found in 4%, mutations in SDHB in 3% and a mutation in SDHC was identified in a single patient (0·4%). Over 80% of patients presented with positive family history, of whom 99·5% carried a mutation in an SDH gene. SDH mutations were also found in 56% of isolated patients, chiefly in SDHD (46%), but also in SDHB (8%) and SDHC (2%). The clinical parameters of these different subgroups are discussed: including the age at diagnosis, associated pheochromocytomas, tumour multifocality and malignancy rate. CONCLUSION: The majority of Dutch patients with HNPGL present with a positive family history, in contrast to other European countries. The clinical characteristics of patients with HNPGL are chiefly determined by founder mutations in SDHD, the major causative gene in both familial and isolated patients with HNPGL. The high frequency of founder mutations in SDHD suggests a higher absolute prevalence of paraganglioma syndrome in the Netherlands.
Asunto(s)
Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Paraganglioma/genética , Paraganglioma/patología , Succinato Deshidrogenasa/genética , Adulto , Femenino , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Mutación , Países BajosRESUMEN
Today, breast cancer is the most commonly occurring cancer among women. It accounts for 22% of all female cancers and the estimated annual incidence of breast cancer worldwide is about one million cases. Many risk factors have been identified but a positive family history remains among the most important ones established for breast cancer, with first-degree relatives of patients having an approximately two-fold elevated risk. It is currently estimated that approximately 20-25% of this risk is explained by known breast cancer susceptibility genes, mostly those conferring high risks, such as BRCA1 and BRCA2. However, these genes explain less than 5% of the total breast cancer incidence, even though several studies have suggested that the proportion of breast cancer that can be attributed to a genetic factor may be as high as 30%. It is thus likely that there are still breast cancer susceptibility genes to be found. It is presently not known how many such genes there still are, nor how many will fall into the class of rare high-risk (e.g. BRCAx) or of common low-risk susceptibility genes, nor if and how these factors interact with each other to cause susceptibility (a polygenic model). In this review we will address this question and discuss the different undertaken approaches used in identifying new breast cancer susceptibility genes, such as (genome-wide) linkage analysis, CGH, LOH, association studies and global gene expression analysis.
Asunto(s)
Neoplasias de la Mama/genética , Genes Relacionados con las Neoplasias , Predisposición Genética a la Enfermedad , Mapeo Cromosómico , Genes BRCA1 , Genes BRCA2 , HumanosRESUMEN
Already published data were further analyzed regarding the association between the CHEK2*1100delC germ line mutation and estrogen receptor (ER) status in patients with breast cancer. The CHEK2*1100delC mutation was more prevalent among the patients with a positive ER status (4.2% versus 1.0%). An ER-negative status was beside CHEK2*1100delC mutation and independently associated with an earlier of age onset of breast cancer. There was a trend that an ER-negative status, beside the presence of a CHEK2*1100delC mutation, was associated with a worse disease-free survival. There might be an association between ER status and a CHEK2*1100delC mutation. More studies with larger number of patients are needed to further investigate the relation between CHEK2*1100delC and ER status.
Asunto(s)
Neoplasias de la Mama/genética , Mutación de Línea Germinal/genética , Proteínas Serina-Treonina Quinasas/genética , Receptores de Estrógenos/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Quinasa de Punto de Control 2 , Femenino , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
REASONS FOR PERFORMING STUDY: In vitro, glucocorticoids potentiate vasoconstriction of equine digital vessels to catecholamines and this has been implicated as a mechanism of glucocorticoid-induced laminitis. This observation has never been confirmed in vivo. OBJECTIVES: To study the effects of glucocorticoid therapy on vasoconstrictor responsiveness in the horse in vivo. METHODS: In a blinded, randomised cross-over experiment, 9 horses were treated with either dexamethasone (0.1 mg/kg bwt i.v. q. 24 h) or saline i.v. for 6 days. The changes in local average skin temperature before (baseline) and after intradermal injections of the alpha1-adrenoceptor agonist phenylephrine (PHE; 10(-4), 10(-5), 10(-6), 10(-7) and 10(-8) mol/l), endothelin-1 (ET-1; 10(-5), 10(-6), 10(-7), 10(-8) and 10(-9) mol/l) or ET-1 plus a blocker (BQ-123 10(-6) mol/l; RES-701 10(-6) mol/l; and L-NAME 10(-4) mol/l) were investigated with a thermograph. RESULTS: Dexamethasone (DEX) decreased baseline skin temperatures, suggesting reduced blood flow as a consequence of an increase in vasomotor tone. This was accompanied by potentiation of the response to PHE as demonstrated by a left shift in the dose-response curve and a decrease in the EC50. Dexamethasone did not potentiate ET-1, but the interplay with the lower baseline temperature resulted in a significantly lower skin temperature for this vasoconstrictor after DEX. The different ET-1 blockers had no effect on ET-1 modulated skin temperatures. CONCLUSIONS: Dexamethasone decreases skin perfusion. This is accompanied by a potentiated alpha1-adrenoceptor agonist response and a greater response to ET-1. POTENTIAL RELEVANCE: Glucocorticoid therapy probably decreases perfusion of the equine hoof. During disease states that already are characterised by hypoperfusion and/or increased levels of circulating catecholamines, glucocorticoid therapy could, according to the vascular model of laminitis, tilt the balance in favour of laminitis.
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Temperatura Corporal/efectos de los fármacos , Endotelina-1/farmacología , Caballos/fisiología , Fenilefrina/farmacología , Piel/irrigación sanguínea , Termografía/veterinaria , Vasoconstrictores/farmacología , Animales , Antiinflamatorios/farmacología , Área Bajo la Curva , Estudios Cruzados , Dexametasona/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Termografía/métodosRESUMEN
Using genome-wide expression profiling of a panel of 27 human mammary cell lines with different mechanisms of E-cadherin inactivation, we evaluated the relationship between E-cadherin status and gene expression levels. Expression profiles of cell lines with E-cadherin (CDH1) promoter methylation were significantly different from those with CDH1 expression or, surprisingly, those with CDH1 truncating mutations. Furthermore, we found no significant differentially expressed genes between cell lines with wild-type and mutated CDH1. The expression profile complied with the fibroblastic morphology of the cell lines with promoter methylation, suggestive of epithelial-mesenchymal transition (EMT). All other lines, also the cases with CDH1 mutations, had epithelial features. Three non-tumorigenic mammary cell lines derived from normal breast epithelium also showed CDH1 promoter methylation, a fibroblastic phenotype and expression profile. We suggest that CDH1 promoter methylation, but not mutational inactivation, is part of an entire programme, resulting in EMT and increased invasiveness in breast cancer. The molecular events that are part of this programme can be inferred from the differentially expressed genes and include genes from the TGFbeta pathway, transcription factors involved in CDH1 regulation (i.e. ZFHX1B, SNAI2, but not SNAI1, TWIST), annexins, AP1/2 transcription factors and members of the actin and intermediate filament cytoskeleton organisation.
Asunto(s)
Neoplasias de la Mama/patología , Cadherinas/biosíntesis , Metilación de ADN , Perfilación de la Expresión Génica , Línea Celular Tumoral , Transformación Celular Neoplásica , Análisis Mutacional de ADN , Regulación hacia Abajo , Células Epiteliales , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Mesodermo/citología , Invasividad Neoplásica , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas , Transcripción Genética , Factor de Crecimiento Transformador beta/fisiologíaRESUMEN
REASON FOR PERFORMING STUDY: Limited information exists about the physiological changes and clinical problems that occur in elite horses competing in high-speed 160 km endurance races. OBJECTIVES: To provide initial data describing changes in physiological and laboratory measurements in horses competing in a high-speed, 160 km endurance race under temperate conditions and to compare data between horses that successfully completed the race and those that failed to finish. METHODS: Body mass (BM) was measured, blood samples were collected, and veterinary examinations performed on horses before, during, and at the finish of a CEI*** 160 km endurance race. RESULTS: Of 36 horses participating in the study, 22 (61%) completed the race. Twelve horses were eliminated for lameness and 2 for persistent heart rate elevation. Mean speed of finishers was 15.2 km/h. Mean +/- s.d. BM loss of finishers at the end of the race (5.7 +/- 2.6%) was not different (P = 0.58) from BM loss of nonfinishers at elimination (6.7 +/- 34%). Similarly, there were no significant differences in heart rate or veterinary assessment of hydration at the race end for finishers as compared to the elimination point for nonfinishers. PCV increased while sodium, chloride and potassium concentrations decreased with exercise but differences between finishers and nonfinishers were not detected. In contrast, both total and ionised calcium concentrations decreased in successful horses but remained unchanged in nonfinishers. CONCLUSIONS: Elite endurance horses are more likely to be eliminated from competition for lameness than metabolic problems; however, it remains unclear whether these conditions are entirely distinct. The magnitude of the decrease in sodium concentration in both finishers and nonfinishers was greater than in previous reports of 160 km rides. POTENTIAL RELEVANCE: These data should be of use for both organisers and participants in elite 160 km endurance races. The tendency toward hyponatraemia as well as the difference in calcium concentrations between finishers and nonfinishers warrant further study.
Asunto(s)
Calcio/sangre , Caballos/fisiología , Condicionamiento Físico Animal/fisiología , Resistencia Física/fisiología , Sodio/sangre , Animales , Peso Corporal/fisiología , Cloruros/sangre , Frecuencia Cardíaca/fisiología , Caballos/sangre , Potasio/sangre , Factores de Tiempo , Pérdida de Peso/fisiologíaRESUMEN
OBJECTIVE: The aim of this study was to identify the prevalence of catecholamine excess and phaeochromocytomas in a well-defined population of people with hereditary head and neck paragangliomas. METHODS: We studied in a prospective follow-up protocol all consecutive patients referred to the Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands with documented head and neck paragangliomas and either a positive family history for paragangliomas or a proven SDHD gene mutation. Initial analysis included medical history, physical examination and the measurement of excretion of catecholamines in two 24-h urine collections. In the case of documented catecholamine excess iodinated meta-iodobenzylguanidine (123I-MIBG) scintigraphy and magnetic resonance imaging were done. RESULTS: Between 1988 and 2003, 40 consecutive patients (20 male and 20 female) with documented head and neck paragangliomas were screened. Biochemical screening revealed urinary catecholamine excess in 15 patients (37.5%). In nine of these 15 patients a lesion was found by 123I-MIBG scintigraphy. Exact localization by magnetic resonance imaging revealed phaeochromocytomas in seven of the 15 patients. One of the nine patients had an extra-adrenal paraganglioma. Histopathological examination in a subset of tumors displayed loss of heterozygosity of the wild-type SDHD allele in all cases. CONCLUSIONS: The prevalence of catecholamine excess (37.5%) and phaeochromocytomas (20.0%) is high in patients with familial head and neck paragangliomas. Therefore, patients with hereditary head and neck paragangliomas require lifelong follow up by biochemical testing for catecholamine excess.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/orina , Catecolaminas/orina , Neoplasias de Cabeza y Cuello/orina , Proteínas de la Membrana/genética , Paraganglioma/orina , Feocromocitoma/orina , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/metabolismo , Adulto , Estudios de Cohortes , ADN de Neoplasias/genética , Femenino , Mutación de Línea Germinal , Neoplasias de Cabeza y Cuello/genética , Humanos , Imidazoles , Pérdida de Heterocigocidad/genética , Masculino , Persona de Mediana Edad , Paraganglioma/genética , Feocromocitoma/genética , Estudios Prospectivos , Succinato DeshidrogenasaRESUMEN
BACKGROUND: The germline CHEK2*1100delC variant has been associated with breast cancer in multiple case families where involvement of BRCA1 and BRCA2 has been excluded. METHODS: We have investigated the tumour characteristics and prognosis of carriers of this germline variant by means of a prospective cohort study in an unselected cohort of 1084 consecutive patients with primary breast cancer. Data were collected for 34 patients with a germline CHEK2*1100delC mutation and for 102 patients without this mutation, stratified by age and date of diagnosis of the first primary breast cancer (within 1 year). RESULTS: Carriers developed steroid receptor positive tumours (oestrogen receptor (ER): 91%; progesterone receptor (PR): 81%) more frequently than non-carriers (ER: 69%; PR: 53%; p = 0.04). Mutation carriers more frequently had a female first or second degree relative with breast cancer (p = 0.03), or had any first or second degree relative with breast or ovarian cancer (p = 0.04). Patients with the CHEK2 variant had a more unfavourable prognosis regarding the occurrence of contralateral breast cancer (relative risk (RR) = 5.74; 95% confidence interval (CI) 1.67 to 19.65), distant metastasis-free survival (RR = 2.81; 95% CI 1.20 to 6.58), and disease-free survival (RR = 3.86; 95% CI 1.91 to 7.78). As yet, no difference with respect to overall survival has been found at a median follow up of 3.8 years. CONCLUSION: We conclude that carrying the CHEK2*1100delC mutation is an adverse prognostic indicator for breast cancer. If independently confirmed by others, intensive surveillance, and possibly preventive measures, should be considered for newly diagnosed breast cancer cases carrying the CHEK2*1100delC variant.
Asunto(s)
Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Variación Genética/genética , Mutación de Línea Germinal/genética , Proteínas Serina-Treonina Quinasas/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Quinasa de Punto de Control 2 , Estudios de Cohortes , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Análisis de SupervivenciaRESUMEN
REASONS FOR PERFORMING STUDY: Although the efficacy of dexamethasone for the treatment of recurrent airway obstruction (RAO) has been documented, the speed of onset of effect and duration of action are unknown, as is the efficacy of orally administered dexamethasone with or without fasting. OBJECTIVES: To document the time of onset of effect and duration of action of a dexamethasone solution i.v. or orally with and without fasting. METHODS: Protocol 1 used 8 RAO-affected horses with airway obstruction in a crossover design experiment that compared the effect of i.v. saline and dexamethasone (0.1 mg/kg bwt) on pulmonary function over 4 h. Protocol 2 used 6 similar horses to compare, in a crossover design, the effects of dexamethasone i.v. (0.1 mg/kg bwt), dexamethasone per os (0.164 mg/kg bwt) with and without prior fasting, and dexamethasone per os (0.082 mg/kg) with fasting. RESULTS: Dexamethasone i.v. caused significant improvement in lung function within 2 h with a peak effect at 4-6 h. Dexamethasone per os was effective within 6 h with peak effect at 24 h at a dose of 0.164 mg/kg bwt prior to feeding. The duration of effect was, for all dexamethasone treatments, statistically significant for 30 h when compared to saline and tended to have a longer duration of effect when used orally. Dexamethasone per os at a dose of 0.164 mg/kg bwt to fed horses had mean effects comparable to dexamethasone at a dose of 0.082 mg/kg bwt per os given to fasted horses, indicating that feeding decreases bioavailability. CONCLUSIONS: Dexamethasone administered i.v. has a rapid onset of action in RAO-affected horses. Oral administration of a bioequivalent dose of the same solution to fasted horses is as effective as i.v. administration and tends to have longer duration of action. Fasting horses before oral administration of dexamethasone improves the efficacy of treatment. POTENTIAL RELEVANCE: Oral administration to fasted horses of a dexamethasone solution intended for i.v. use provides an effective treatment for RAO-affected animals.
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Obstrucción de las Vías Aéreas/veterinaria , Dexametasona/uso terapéutico , Enfermedades de los Caballos/tratamiento farmacológico , Administración Oral , Obstrucción de las Vías Aéreas/tratamiento farmacológico , Animales , Disponibilidad Biológica , Estudios Cruzados , Dexametasona/administración & dosificación , Dexametasona/farmacocinética , Relación Dosis-Respuesta a Droga , Ayuno/fisiología , Femenino , Caballos , Inyecciones Intravenosas/veterinaria , Masculino , Distribución Aleatoria , Recurrencia , Resultado del TratamientoAsunto(s)
Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Genes p16 , Predisposición Genética a la Enfermedad/genética , Mutación de Línea Germinal/genética , Neoplasias del Sistema Respiratorio/genética , Alelos , Neoplasias de la Mama/genética , Carcinoma de Células Escamosas/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/análisis , Neoplasias del Sistema Digestivo/genética , Femenino , Humanos , Inmunohistoquímica , Pérdida de Heterocigocidad/genética , Neoplasias Pulmonares/genética , Masculino , Melanoma/genética , Neoplasias de la Boca/genética , LinajeRESUMEN
Hereditary head and neck paragangliomas are tumours associated with the autonomic nervous system. Recently, mutations in genes coding for subunits of mitochondrial complex II, succinate-ubiquinone-oxidoreductase (SDHB, SDHC, and SDHD), have been identified in the majority of hereditary tumours and a number of isolated cases. In addition, a fourth locus, PGL2, has been mapped to chromosome 11q13 in an isolated family. In order to characterize phenotypic effects of these mutations, the present study investigated the immunohistochemical expression of the catalytic subunits of complex II (flavoprotein and iron protein), SDH enzyme activity, and mitochondrial morphology in a series of 22 head and neck paragangliomas. These included 11 SDHD-, one SDHB-, two PGL2-linked tumours, and eight sporadic tumours. In the majority of the tumours (approximately 90%), the enzyme-histochemical SDH reaction was negative and immunohistochemistry of catalytic subunits of complex II showed reduced expression of iron protein and enhanced expression of flavoprotein. Ultrastructural examination revealed elevated numbers of tightly packed mitochondria with abnormal morphology in SDHD-linked and sporadic tumours. Immuno-electron microscopy showed localization of the flavoprotein on the remnants of the mitochondrial inner membranes, whereas virtually no signal for the iron protein was detected. These results indicate that the function of mitochondrial complex II is compromised in the majority of head and neck paragangliomas.
Asunto(s)
Complejo II de Transporte de Electrones/genética , Neoplasias de Cabeza y Cuello/genética , Mitocondrias/patología , Paraganglioma/genética , Adulto , Anciano , Análisis Mutacional de ADN/métodos , ADN de Neoplasias/genética , Transporte de Electrón/genética , Flavoproteínas/análisis , Neoplasias de Cabeza y Cuello/enzimología , Neoplasias de Cabeza y Cuello/patología , Humanos , Inmunohistoquímica/métodos , Hierro/análisis , Proteínas Hierro-Azufre/genética , Proteínas de la Membrana/genética , Microscopía Electrónica/métodos , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Paraganglioma/enzimología , Paraganglioma/patología , Subunidades de Proteína , Succinato Deshidrogenasa/genéticaRESUMEN
Possible effects of consistently applying published guidelines on healthy women with breast cancer in their family history were analysed. We investigated 1060 unrelated breast cancer patients and calculated the numbers of first-degree relatives that would be referred to a familial cancer clinic if the guidelines were consistently applied. A first-degree relative was considered a candidate for referral if she was female, without breast cancer at the moment of the interview, alive and over the age of 24. The criteria for referral were based on one Dutch and two British guidelines. According to the Dutch guideline, for one affected woman with breast cancer, 0.25 (95% CI 0.22-0.28) healthy first-degree female relatives should be offered a consultation at a familial cancer clinic (FCC). Application of the British guidelines would lead to a similar number of referrals. Of all healthy first-degree female relatives, who should be referred to an FCC, 34-37% had an index case among their family who was already known at a genetic department. If current guidelines are consistently applied, a sharp increase in referrals to FCCs may be expected. These guidelines, however, are arbitrary and only limited data are available on the efficacy of this surveillance for high-risk healthy women.
Asunto(s)
Neoplasias de la Mama/genética , Adhesión a Directriz/tendencias , Derivación y Consulta , Anciano , Neoplasias de la Mama/diagnóstico , Estudios de Cohortes , Inglaterra , Femenino , Humanos , Tamizaje Masivo/tendencias , Persona de Mediana Edad , Países BajosRESUMEN
Using a BRCA1 cDNA probe in Southern analysis, we detected a sequence of 348 bp on 4q28 that is homologous to the 3' end of BRCA1. A 28-kb sequence contig has been assembled spanning the homologous region, which we designated BRCA1-h. An open reading frame was identified encoding a sequence of 82 amino acids; 22 of the last 23 amino acids are identical to the last 23 residues of BRCA1. BLAST-searches, RT-PCR and RACE-experiments have been unable to provide evidence that BRCA1-h is part of an expressed gene.
Asunto(s)
Cromosomas Humanos Par 4/genética , Genes BRCA1 , Sistemas de Lectura Abierta/genética , Homología de Secuencia de Ácido Nucleico , Secuencia de Aminoácidos , Animales , Southern Blotting , Mapeo Contig , Exones/genética , Etiquetas de Secuencia Expresada , Humanos , Hibridación Fluorescente in Situ , Datos de Secuencia MolecularRESUMEN
Thus far, studies investigating the differences in tumour characteristics between breast cancer in BRCA1-carriers and other patients, have focused on highly selected groups of patients, potentially limiting the conclusions that can be drawn. Previously, we had identified 10 patients with BRCA1 germline mutations in a hospital-based series of 642 breast cancer patients not selected for age or family history. The aim of this analysis is to investigate the clinical and pathological features of these BRCA1 associated carcinomas as compared to other breast cancers in this representative sample. Tumours from patients with BRCA1 germline mutations (n = 10) were compared to an age-matched sample of other patients (n = 50) from the same cohort. The following characteristics were considered: axillary nodal status and tumour size, histologic parameters (tumour type, histologic grade, mitotic rate, tubule formation, nuclear grade, CIS and lymphangio invasion) and expression of several proteins (oestrogen and progesterone receptors, cyclin D1, p53, HER2/neu, E-cadherin). In BRCA1 associated tumours receptors for oestrogen and progesterone were expressed less frequently (respectively, P = 0.001 and P = 0.002) than in controls, which is in line with findings from other studies. Other differences were also in accordance with findings from other studies, although not statistically significant. We conclude that the features of BRCA1 associated tumours detected in a hospital-based series of breast cancer patients not selected for family history of age at diagnosis are similar to tumours in cases selected for family history or age at diagnosis.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma/genética , Carcinoma/patología , Genes BRCA1 , Mutación de Línea Germinal , Adulto , Estudios de Cohortes , ADN de Neoplasias , Femenino , Regulación Neoplásica de la Expresión Génica , Hospitalización , Humanos , Metástasis Linfática , Invasividad Neoplásica , Reacción en Cadena de la Polimerasa , Receptores de Estrógenos/análisis , Receptores de Estrógenos/biosíntesis , Receptores de Progesterona/análisis , Receptores de Progesterona/biosíntesisRESUMEN
Many publications have documented loss of heterozygosity (LOH) on many different chromosomes in a wide variety of tumours, implicating the existence of multiple tumour suppressor genes (TSGs). Knudson's two-hit hypothesis predicts that these LOH events are the second step in the inactivation of both alleles of a TSG. However, to date the number of TSGs identified that are inactivated mainly at the somatic level in cancers and are not inherited has remained disappointingly small. Here we postulate that the accurate mapping of LOH events in a series of tumours to define a common LOH region is greatly confounded by deficient LOH detection, genetic instability and intertumour heterogeneity. Finding the TSGs in chromosomal regions of frequent LOH might require 'brute-force' genomic approaches.
Asunto(s)
Pérdida de Heterocigocidad , Modelos Genéticos , Neoplasias/genética , Alelos , Mapeo Cromosómico , Cocarcinogénesis , Genes Supresores de Tumor , Humanos , Neoplasias/etiologíaAsunto(s)
Absceso Encefálico/veterinaria , Infecciones por Escherichia coli/veterinaria , Enfermedades de los Caballos/terapia , Infecciones Estreptocócicas/veterinaria , Animales , Animales Recién Nacidos , Antiinfecciosos/uso terapéutico , Absceso Encefálico/tratamiento farmacológico , Absceso Encefálico/cirugía , Craneotomía/veterinaria , Diagnóstico Diferencial , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/cirugía , Femenino , Enfermedades de los Caballos/diagnóstico por imagen , Caballos/lesiones , Masculino , Hueso Parietal/lesiones , Fractura Craneal Deprimida/diagnóstico por imagen , Fractura Craneal Deprimida/cirugía , Fractura Craneal Deprimida/veterinaria , Infecciones Estreptocócicas/tratamiento farmacológico , Infecciones Estreptocócicas/cirugía , Tomografía Computarizada por Rayos X/veterinariaRESUMEN
Recently, we and others reported instability in the (C)8 repeat in exon 5 of MSH6 as a preferential target for somatic mutations in tumours from MSH6 germline mutation carriers. Here, we report that in 45% of tumours from MLH1, MSH2 and MSH6 germline mutation carriers no sequence change in the (C)8 repeat of MSH6 was found upon DNA sequencing analysis of PCR products with a shift in electrophoresis mobility. Using "standard" PCR primers a high frequency of instability (50-86%) of the (C)8 repeat was found, but using a modified PCR reverse primer, accomplishing modulation of non-templated addition of adenine during in vitro PCR amplification by the Taq polymerase, a markedly lower frequency of instability was found in tumours from MLH1, MSH2 and MSH6 mutation carriers (6, 13 and 40%, respectively). Furthermore, a significant difference of the frequency of instability of the (C)8 repeat in tumours from MSH6 mutation carriers was found compared to MLH1, MSH2 mutation carriers. These results might have important implications for the detection of instability of other short mononucleotide repeats, e.g. TGFbetaRII, BAX, IGFRII, PTEN, BRCA2.
Asunto(s)
Proteínas de Unión al ADN , Proteínas Fúngicas/genética , Proteínas de Saccharomyces cerevisiae , Expansión de Repetición de Trinucleótido , Proteínas Adaptadoras Transductoras de Señales , Sesgo , Proteínas Portadoras , Análisis Mutacional de ADN , Cartilla de ADN/metabolismo , Exones , Eliminación de Gen , Humanos , Repeticiones de Microsatélite , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS , Mutación , Proteínas de Neoplasias/genética , Proteínas Nucleares , Reacción en Cadena de la Polimerasa , Proteínas Proto-Oncogénicas/genética , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Males with a BRCA1/BRCA2 mutation are not at greatly increased risk for cancer, whereas their (grand)daughters, and other female relatives who carry the mutation, are. Males from BRCA1/BRCA2 families may opt for genetic testing to confirm whether or not they may have transmitted the mutation to their children and, if so, to inform them at an appropriate age about the genetic risk and its implications. The psychological implications of genetic testing for men at risk of being a BRCA1/BRCA2 mutation carrier have received little attention. We report on 28 men requesting BRCA1 or BRCA2 testing, and their partners. Men were at 25% (n =4) or 50% risk (n =24) of being a mutation carrier, the majority with daughters and half of them with daughters aged over 20 years. Levels of psychological distress were assessed several weeks before and after disclosure of the test result. In addition, we investigated the level of intrusive thoughts and feelings about breast and ovarian cancer and the tendency to avoid these. By means of interviews and questionnaires, participants could report on (expected) emotional implications of genetic testing for themselves and their children, on experiences with cancer in the family and on personality trait optimism. Distress levels prior to the result in tested men and their partners were low. Many men and partners expected the test result to affect their children's, but not their own level of problems. Men without daughters and those with an optimistic personality had especially low distress prior to disclosure. Most men reported that they did not actively avoid the issue. Only four of the 28 men were identified as mutation carriers. High distress after disclosure of the result was reported by one mutation carrier and by three non-mutation carriers. Verbatim transcripts from interviews showed a large variation of psychological reactions in male mutation carriers (eg regarding guilt feelings). Low pre-test distress in males does not necessarily indicate avoidance of the issue. Future studies may indicate which psychological reactions occur in male mutation carriers when the problem becomes more acute, eg when a daughter is found to carry the mutation and/or is diagnosed with breast or ovarian cancer.
Asunto(s)
Neoplasias de la Mama/genética , Heterocigoto , Neoplasias Ováricas/genética , Adulto , Anciano , Ansiedad , Proteína BRCA1/genética , Proteína BRCA2 , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/psicología , Depresión , Salud de la Familia , Femenino , Pruebas Genéticas/métodos , Pruebas Genéticas/psicología , Humanos , Masculino , Persona de Mediana Edad , Mutación , Proteínas de Neoplasias/genética , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/psicología , Factores de Transcripción/genética , Revelación de la VerdadRESUMEN
Hereditary paragangliomas or glomus tumors are usually benign slow-growing tumors in the head and neck region. The inheritance pattern of hereditary paraganglioma is autosomal dominant with imprinting. Recently, we have identified the SDHD gene encoding subunit D of the mitochondrial respiratory chain complex II as one of the genes involved in hereditary paragangliomas. Here, we demonstrate that two founder mutations, Asp92Tyr and Leu139Pro, are responsible for paragangliomas in 24 and 6 of the 32 independently ascertained Dutch paraganglioma families, respectively. These two mutations were also detected among 20 of 55 isolated patients. Ten of the isolated patients had multiple paragangliomas, and in eight of these SDHD germline mutations were found, indicating that multicentricity is a strong predictive factor for the hereditary nature of the disorder in isolated patients. In addition, we demonstrate that the maternally derived wild-type SDHD allele is lost in tumors from mutation-carrying patients, indicating that SDHD functions as a tumor suppressor gene.