Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 95
Filtrar
1.
Cancer Genet ; 237: 55-62, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31447066

RESUMEN

BACKGROUND: A subsets of ovarian carcinomas (OCs) are related to inherited conditions including Hereditary Breast and Ovarian Cancers (HBOC) and Lynch Syndrome (LS). The identification of inherited conditions using genetic testing might be a strategic model for cancer prevention that include benefits for the ovarian cancer patients and for their family members. METHODS: We describe a retrospective Italian experience for the identification of inherited conditions in 232 patients affected by OCs using both somatic and germline analyses. RESULTS: Immunohistochemical and microsatellite analyses performed on OCs identified 20 out of 101 MMR defective cancers and 15 of these were from patients carriers of the MMR germline pathogenetic variants. BRCA1 and BRCA2 testing offered to 198 OC patients revealed 67 (34%) pathogenetic variant carriers of BRCA1/2 genes. Interestingly LS patients revealed a mean age of OC onset of 45.4 years, which was significantly lower than the mean age of OCs onset of HBOC patients. CONCLUSIONS: Somatic and germline analyses offered to OC patients has proved to be an efficient strategy for the identification of inherited conditions involving OC also in absence of suggestive family histories. The identification of LS and HBOC syndromes through OC patients is an effective tool for OC prevention.


Asunto(s)
Síndromes Neoplásicos Hereditarios/genética , Neoplasias Ováricas/genética , Femenino , Genes BRCA1 , Genes BRCA2 , Pruebas Genéticas , Humanos , Italia , Masculino , Persona de Mediana Edad , Linaje
2.
Rev Neurol ; 67(11): 463-464, 2018 12 01.
Artículo en Español | MEDLINE | ID: mdl-30484280

RESUMEN

TITLE: Sindrome de Guillain-Barre en tiempos de arbovirosis.


Asunto(s)
Síndrome de Guillain-Barré , Hospitales Generales , Humanos
4.
Lett Appl Microbiol ; 65(5): 381-387, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28862747

RESUMEN

In this work the fermentation performances of seven vineyard strains, together with the industrial strain EC1118, have been investigated at three differing yeast assimilable nitrogen (YAN) concentrations (300 mg N l-1 , 150 mg N l-1 and 70 mg N l-1 ) in synthetic musts. The results indicated that the response to different nitrogen levels is strain dependent. Most of the strains showed a dramatic decrease of the fermentation at 70 mg N l-1 but no significant differences in CO2 production were found when fermentations at 300 mg N l-1 and 150 mg N l-1 were compared. Only one among the vineyard strains showed a decrease of the fermentation when 150 mg N l-1 were present in the must. These results contribute to shed light on strain nitrogen requirements and offer new perspectives to manage the fermentation process during winemaking. SIGNIFICANCE AND IMPACT OF THE STUDY: Selected vineyard Saccharomyces cerevisiae strains can improve the quality and the complexity of local wines. Wine quality is also influenced by nitrogen availability that modulates yeast fermentation activity. In this work, yeast nitrogen assimilation was evaluated to clarify the nitrogen requirements of vineyard strains. Most of the strains needed high nitrogen levels to express the best fermentation performances. The results obtained indicate the critical nitrogen levels. When the nitrogen concentration was above the critical level, the fermentation process increased, but if the level of nitrogen was further increased no effect on the fermentation was found.


Asunto(s)
Nitrógeno/metabolismo , Saccharomyces cerevisiae/metabolismo , Vino/microbiología , Granjas , Fermentación , Nitrógeno/análisis , Vino/análisis
5.
Breast ; 22(6): 1130-5, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24011770

RESUMEN

PURPOSE: To evaluate in current practice the performance of BOADICEA and BRCAPRO risk models and empirical criteria based on cancer family history for the selection of individuals for BRCA genetic testing. PATIENTS AND METHODS: The probability of BRCA mutation according to the three tools was retrospectively estimated in 918 index cases consecutively undergone BRCA testing at 15 Italian cancer genetics clinics between 2006 and 2008. RESULTS: 179 of 918 cases (19.5%) carried BRCA mutations. With the strict use of the criteria based on cancer family history 173 BRCA (21.9%) mutations would have been detected in 789 individuals. At the commonly used 10% threshold of BRCA mutation carrier probability, the genetic models showed a similar performance [PPV (38% and 37%), sensitivity (76% and 77%) and specificity (70% and 69%)]. Their strict use would have avoided around 60% of the tests but would have missed approximately 1 every 4 carriers. CONCLUSION: Our data highlight the complexity of BRCA testing referral in routine practice and question the strict use of genetic models for BRCA risk assessment.


Asunto(s)
Neoplasias de la Mama/genética , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad , Modelos Genéticos , Femenino , Pruebas Genéticas , Heterocigoto , Humanos , Italia , Masculino , Mutación , Selección de Paciente , Valor Predictivo de las Pruebas , Probabilidad , Medición de Riesgo
7.
Breast Cancer Res Treat ; 138(3): 861-8, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23468243

RESUMEN

It is well-known that male breast cancer (MBC) susceptibility is mainly due to high-penetrance BRCA1/2 mutations. Here, we investigated whether common low-penetrance breast cancer (BC) susceptibility alleles may influence MBC risk in Italian population and whether variant alleles may be associated with specific clinicopathological features of MBCs. In the frame of the Italian Multicenter Study on MBC, we genotyped 413 MBCs and 745 age-matched male controls at 9 SNPs annotating known BC susceptibility loci. By multivariate logistic regression models, we found a significant increased MBC risk for 3 SNPs, in particular, with codominant models, for rs2046210/ESR1 (OR = 1.71; 95 % CI: 1.43-2.05; p = 0.0001), rs3803662/TOX3 (OR = 1.59; 95 % CI: 1.32-1.92; p = 0.0001), and rs2981582/FGFR2 (OR = 1.26; 95 % CI: 1.05-1.50; p = 0.013). Furthermore, we showed that the prevalence of the risk genotypes of ESR1 tended to be higher in ER- tumors (p = 0.062). In a case-case multivariate analysis, a statistically significant association between ESR1 and ER- tumors was found (OR = 1.88; 95 % CI: 1.03-3.49; p = 0.039). Overall, our data, based on a large and well-characterized MBC series, support the hypothesis that common low-penetrance BC susceptibility alleles play a role in MBC susceptibility and, interestingly, indicate that ESR1 is associated with a distinct tumor subtype defined by ER-negative status.


Asunto(s)
Neoplasias de la Mama Masculina/genética , Predisposición Genética a la Enfermedad , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Proteínas Reguladoras de la Apoptosis , Neoplasias de la Mama Masculina/epidemiología , Neoplasias de la Mama Masculina/etiología , Estudios de Casos y Controles , Receptor alfa de Estrógeno/genética , Proteínas del Grupo de Alta Movilidad , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Polimorfismo de Nucleótido Simple , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/genética , Transactivadores
8.
Tech Coloproctol ; 17(1): 79-87, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22976915

RESUMEN

BACKGROUND: Attenuated familial adenomatous polyposis (AFAP) is characterized by the presence of 10-99 colorectal adenomas. The disease may be associated with mutations in either APC or MUTYH genes. We purposed to evaluate the contribution of adenomatous polyposis coli (APC) and MutY homologue (MUTYH) germline alterations to the AFAP phenotype and to identify genotype/phenotype correlations. METHODS: During counselling for familial adenomatous polyposis (FAP), 91 probands (and 107 affected individuals) who met the criteria of AFAP were identified. Eighty-two families were screened for constitutional mutations of the APC and MUTYH genes. RESULTS: MUTYH mutations were detected in 21 families (25.6 % of the 82 tested), and APC mutations in 7 (8.5 %). Overall, constitutional alterations were found in 34.1 % of the probands. Patients with APC mutations were younger at cancer onset and had a higher mean number of polyps (48.5 ± 33.0 in APC+ individuals vs. 35.7 ± 24.9 in MUTYH+ individuals, and 33.2 ± 18.4 in the "no mutation" group). Clinical features rendered the "no mutation" group closer to MUTYH+ than to the APC+ group. Colorectal cancer at diagnosis was detected in 40 % of AFAP individuals. CONCLUSIONS: AFAP is a new clinical entity with its frequency in the general population still undefined. The number of adenomas varies greatly, with an average of 30-40 lesions. The molecular basis of AFAP can be established in approximately 1/3 of the patients. Both MUTYH and APC genes are implicated in AFAP, though the role of MUTYH is of considerably greater relevance.


Asunto(s)
ADN Glicosilasas/genética , Síndrome de Gardner/genética , Síndrome de Gardner/patología , Genes APC , Adolescente , Adulto , Factores de Edad , Anciano , Femenino , Genotipo , Humanos , Italia , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Estadísticas no Paramétricas , Carga Tumoral/genética , Adulto Joven
9.
Oncogene ; 32(38): 4500-8, 2013 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-23108399

RESUMEN

The DNA glycosylase MUTYH (mutY homolog (Escherichia coli)) counteracts the mutagenic effects of 8-oxo-7,8-dihydroguanine (8-oxodG) by removing adenine (A) misincorporated opposite the oxidized purine. Biallelic germline mutations in MUTYH cause the autosomal recessive MUTYH-associated adenomatous polyposis (MAP). Here we designed new tools to investigate the biochemical defects and biological consequences associated with different MUTYH mutations in human cells. To identify phenotype(s) associated with MUTYH mutations, lymphoblastoid cell lines (LCLs) were derived from seven MAP patients harboring missense as well as truncating mutations in MUTYH. These included homozygous p.Arg245His, p.Gly264TrpfsX7 or compound heterozygous variants (p.Gly396Asp/Arg245Cys, p.Gly396Asp/Tyr179Cys, p.Gly396Asp/Glu410GlyfsX43, p.Gly264TrpfsX7/Ala385ProfsX23 and p.Gly264TrpfsX7/Glu480del). DNA glycosylase assays of MAP LCL extracts confirmed that all these variants were defective in removing A from an 8-oxoG:A DNA substrate, but retained wild-type OGG1 activity. As a consequence of this defect, MAP LCLs accumulated DNA 8-oxodG in their genome and exhibited a fourfold increase in spontaneous mutagenesis at the PIG-A gene compared with LCLs from healthy donors. They were also hypermutable by KBrO3--a source of DNA 8-oxodG--indicating that the relatively modest spontaneous mutator phenotype associated with MUTYH loss can be significantly enhanced by conditions of oxidative stress. These observations identify accumulation of DNA 8-oxodG and a mutator phenotype as likely contributors to the pathogenesis of MUTYH variants.


Asunto(s)
Daño del ADN , ADN Glicosilasas/genética , ADN Glicosilasas/metabolismo , Inestabilidad Genómica , Estrés Oxidativo , 8-Hidroxi-2'-Desoxicoguanosina , Poliposis Adenomatosa del Colon/genética , Poliposis Adenomatosa del Colon/metabolismo , Adulto , Línea Celular , Reparación del ADN , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Activación Enzimática , Femenino , Expresión Génica , Heterocigoto , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Mutación , Tasa de Mutación , Fenotipo
10.
Mol Biol Rep ; 39(10): 9307-10, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22782591

RESUMEN

Hereditary non-polyposis colorectal cancer (HNPCC) is a genetic disorder caused by mutation in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) which predisposes to colorectal cancer and other malignances, that not yet include sarcomas. For sustaining that soft tissue sarcomas could be HNPCC related malignances, we report on a HNPCC patient with leiomyosarcoma and review the English literature. Overall, we report on eleven cases of soft tissue malignant tumors involving HNPCC patients, with a mean age of 34 years at diagnosis of sarcomas. In the majority of these tumors loss of MSH2 expression can be found at immunohistochemistry (IHC) and in 10 patients a germline mutation in one of the MMR genes was found (7 cases were MSH2 defective and 3 cases MLH1 defective). Data for supporting our hypothesis are also experimental, epidemiologic, histopathological: excess of sarcomas in PMS2 defective mice; sporadic soft tissue sarcomas are rare, with mean age at onset of 56 years and normal IHC for MMR proteins. In conclusion, the data collected support the hypothesis that soft tissue sarcomas could be included in the spectrum of tumors that, even if rarely, depend on MMR genes deficiency.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Músculo Deltoides/patología , Neoplasias Renales/diagnóstico , Leiomiosarcoma/diagnóstico , Neoplasias de los Músculos/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Análisis Mutacional de ADN , Estudios de Asociación Genética , Humanos , Neoplasias Renales/genética , Leiomiosarcoma/genética , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Neoplasias de los Músculos/genética , Proteína 2 Homóloga a MutS/genética , Eliminación de Secuencia
11.
Tumour Biol ; 33(3): 857-64, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22278153

RESUMEN

The reported incidence of hereditary colorectal cancers (CRCs) is widely variable. The principal aim of the study was to prospectively evaluate the incidence of familial CRCs in a region of northern Italy using a standardized method. Consecutive CRC patients were prospectively enrolled from October 2002 to December 2003. Patients underwent a structured family history, the microsatellite instability (MSI) test and a screen for MUTYH mutations. Following family history patients were classified as belonging to high, moderate and mild risk families. Immunohistochemistry for MLH1, MSH2, MSH6 and PMS2 proteins and investigation for MLH1/MSH2 mutations, for MLH1 promoter methylation and for the V600E hotspot BRAF mutation were performed in high MSI (MSI-H) cases. Of the 430 patients enrolled, 17 (4%) were high risk [4 hereditary non-polyposis colorectal cancer (HNPCC), 12 suspected HNPCC and 1 MUTYH-associated adenomatous polyposis coli (MAP)], 53 moderate risk and 360 mild risk cases. The MSI test was performed on 393 tumours, and 46 (12%) of them showed MSI-H. In these patients, one MLH1 pathogenetic mutations and two MSH2 pathogenetic mutations were found. Thirty-two (70%) MSI-H cases demonstrated MLH1 methylation and/or BRAF mutation: None of them showed MLH1/MSH2 mutation. Two biallelic germline MUTYH mutations were found, one with clinical features of MAP. A strong family history of CRC was present in 4% of the enrolled cases; incidence of MLH1/MSH2 or MUTHY mutations was 1.3% and of MSI-H phenotype was 12%. MLH1 methylation and BRAF mutation can exclude 70% of MSI-H cases from gene sequencing.


Asunto(s)
Poliposis Adenomatosa del Colon/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , ADN Glicosilasas/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Poliposis Adenomatosa del Colon/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Metilación de ADN , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Femenino , Genes APC , Mutación de Línea Germinal , Humanos , Incidencia , Italia/epidemiología , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Regiones Promotoras Genéticas , Estudios Prospectivos , Proteínas Proto-Oncogénicas B-raf/genética , Estudios Retrospectivos , Población Blanca/genética
12.
J Fr Ophtalmol ; 34(4): 256.e1-6, 2011 Apr.
Artículo en Francés | MEDLINE | ID: mdl-21444125

RESUMEN

PURPOSE: The role of streptococcal infections in the development of uveitis remains uncertain. Here we describe a series of patients with suspected poststreptococcal uveitis. OBSERVATION: Four retrospective cases were collected (two males and two females). All patients had a sore throat or an episode of pyrexia 2 to 10 weeks before the onset of uveitis and elevated antistreptolysin-O titer (ASOT); no other cause of uveitis was found. Uveitis was bilateral in all the cases and recurrent in only one. In two patients, inflammation was limited to the anterior segment. One patient had intermediate uveitis. One patient had posterior uveitis with multiple white-dot lesions as well as macular and optic disc swelling. The two cases with anterior uveitis were treated only topically and the two others received a short course of systemic steroids. No systemic antibiotics were given. CONCLUSIONS: These cases suggest that uveitis could be a manifestation of poststreptococcal syndrome and have a good prognosis.


Asunto(s)
Faringitis/diagnóstico , Infecciones Estreptocócicas/diagnóstico , Uveítis Anterior/diagnóstico , Uveítis Intermedia/diagnóstico , Uveítis Posterior/diagnóstico , Administración Oral , Adulto , Anciano , Antiinflamatorios/administración & dosificación , Antiestreptolisina/sangre , Femenino , Angiografía con Fluoresceína , Humanos , Masculino , Metilprednisolona/administración & dosificación , Soluciones Oftálmicas , Oftalmoscopía , Prednisolona/administración & dosificación , Prednisolona/análogos & derivados , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Uveítis Anterior/tratamiento farmacológico , Uveítis Intermedia/tratamiento farmacológico , Uveítis Posterior/tratamiento farmacológico , Adulto Joven
13.
Fam Cancer ; 10(1): 27-35, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20717847

RESUMEN

Single base substitutions can lead to missense mutations, silent mutations or intronic mutations, whose significance is uncertain. Aberrant splicing can occur due to mutations that disrupt or create canonical splice sites or splicing regulatory sequences. The assessment of their pathogenic role may be difficult, and is further complicated by the phenomenon of alternative splicing. We describe an HNPCC patient, with early-onset colorectal cancer and a strong family history of colorectal and breast tumors, who harbours a germ line MLH1 intronic variant (IVS9 c.790 +4A>T). The proband, together with 2 relatives affected by colorectal-cancer and 1 by breast cancer, have been investigated for microsatellite instability, immunohistochemical MMR protein staining, direct sequencing and Multiplex Ligation-dependent Probe Amplification. The effect of the intronic variant was analyzed both by splicing prediction software and by hybrid minigene splicing assay. In this family, we found a novel MLH1 germline intronic variant (IVS9 c.790 +4A>T) in intron 9, consisting of an A to T transversion, in position +4 of the splice donor site of MLH1. The mutation is associated with the lack of expression of the MLH1 protein and MSI in tumour tissues. Furthermore, our results suggest that this substitution leads to a complete skip of both exon 9 and 10 of the mutant allele. Our findings suggest that this intronic variant plays a pathogenic role.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Adenocarcinoma Mucinoso/genética , Neoplasias de la Mama/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Intrones/genética , Mutación/genética , Proteínas Nucleares/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patología , Adulto , Anciano , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/metabolismo , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Análisis Mutacional de ADN , Cartilla de ADN/química , ADN de Neoplasias/genética , Femenino , Genotipo , Humanos , Técnicas para Inmunoenzimas , Pérdida de Heterocigocidad , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Proteínas Nucleares/metabolismo , Linaje , Reacción en Cadena de la Polimerasa , Pronóstico , Adulto Joven
14.
Br J Cancer ; 101(12): 2048-54, 2009 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-19920816

RESUMEN

BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.


Asunto(s)
Proteínas de Unión al ADN/genética , Genes BRCA1 , Genes BRCA2 , Heterocigoto , Mutación , Polimorfismo de Nucleótido Simple , Estudios de Cohortes , Femenino , Humanos , Estudios Retrospectivos
15.
Int J Colorectal Dis ; 23(8): 801-6, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18446350

RESUMEN

PURPOSE: The Bethesda guidelines suggest to perform microsatellite instability (MSI) test in early onset rectal cancer and not in patients>50 years with proximal colon cancer. The aim of the study was to evaluate whether the risk of high MSI (MSI-H) is greater in proximal colon cancer of patients 51-60 years old than in early-onset rectal cancer. METHODS: Consecutive colorectal cancer (CRC) patients were evaluated. Tumor location, cancer family history, MSI status and histology were recorded. Mutations in MLH1/MSH2 were investigated in MSI-H tumors. Patients were subdivided into groups: group A, proximal colon cancer patients 51-60 years old and groups B, C and D, patients

Asunto(s)
Neoplasias del Colon/genética , Inestabilidad de Microsatélites , Neoplasias del Recto/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Adenocarcinoma/genética , Adulto , Anciano , Anciano de 80 o más Años , ADN de Neoplasias/genética , Femenino , Pruebas Genéticas , Humanos , Masculino , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS/genética , Mutación , Proteínas Nucleares/genética , Guías de Práctica Clínica como Asunto
16.
Exp Cell Res ; 313(12): 2521-30, 2007 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-17574238

RESUMEN

Alternative spliced variants of the human discs large (hDlg) tumour suppressor are characterized by combinations of insertions. Here, using insertions I2- and I3-specific antibodies, we show that I2 and I3 variants have distinct distributions in epidermal and cervical epithelia. In skin and cervix, I3 variants are found in the cytoplasm. Cytoplasmic localization of I3 variants decreases as cervical keratinocytes differentiate, concomitant with relocalization to the cell periphery. I2 variants are found at the cell periphery of differentiated epidermal and cervical keratinocytes. Nuclear localization of I2 variants was evident in both tissues, with concentration of nuclear I2 variants in basal and parabasal cervical keratinocytes. A prominent nuclear localization of hDlg in cells of hyperproliferative layers of psoriatic lesions, but not in mature differentiated keratinocytes, together with I2 redistribution in differentiating keratinocytes, suggests that nuclear hDlg functions may be pertinent to growth of undifferentiated cells. Supporting our findings in squamous tissues, a decrease of nuclear hDlg and an increase of membrane-bound and cytoplasmic hDlg upon calcium-induced keratinocyte differentiation were not concomitant processes. Furthermore, we confirm that the exit of I2 variants from the nucleus is linked to stimulation of epithelial differentiation. The dynamic redistribution of hDlg also correlated with a marked increase in the expression of I3 variants while the level of I2 variants showed only a moderate decrease. Because changes in the intracellular distribution of hDlg splice variants, and in their expression levels, correlate with changes in differentiation state we hypothesize that the different hDlg isoforms play distinct roles at various stages of epithelial differentiation.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Empalme Alternativo/genética , Diferenciación Celular , Queratinocitos/citología , Queratinocitos/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Empalme Alternativo/efectos de los fármacos , Anticuerpos/inmunología , Calcio/farmacología , Diferenciación Celular/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Células Cultivadas , Cuello del Útero/citología , Cuello del Útero/efectos de los fármacos , Cuello del Útero/metabolismo , Homólogo 1 de la Proteína Discs Large , Epidermis/efectos de los fármacos , Epidermis/patología , Femenino , Humanos , Queratinocitos/efectos de los fármacos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transporte de Proteínas/efectos de los fármacos , Factores de Tiempo
17.
Dis Markers ; 23(3): 179-87, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17473388

RESUMEN

Hereditary NonPolyposis Colorectal Cancer (Lynch syndrome) is an autosomal dominant disease caused by germline mutations in a class of genes deputed to maintain genomic integrity during cell replication, mutations result in a generalized genomic instability, particularly evident at microsatellite loci (Microsatellite Instability, MSI). MSI is present in 85-90% of colorectal cancers that occur in Lynch Syndrome. To standardize the molecular diagnosis of MSI, a panel of 5 microsatellite markers was proposed (known as the "Bethesda panel"). Aim of our study is to evaluate if MSI testing with two mononucleotide markers, such as BAT25 and BAT26, was sufficient to identify patients with hMLH1/hMSH2 germline mutations. We tested 105 tumours for MSI using both the Bethesda markers and the two mononucleotide markers BAT25 and BAT26. Moreover, immunohistochemical evaluation of MLH1 and MSH2 proteins was executed on the tumours with at least one unstable microsatellite, whereas germline hMLH1/hMSH2 mutations were searched for all cases showing two or more unstable microsatellites. The Bethesda panel detected more MSI(+) tumors than the mononucleotide panel (49.5% and 28.6%, respectively). However, the mononucleotide panel was more efficient to detect MSI(+) tumours with lack of expression of Mismatch Repair proteins (93% vs 54%). Germline mutations were detected in almost all patients whose tumours showed MSI and no expression of MLH1/MSH2 proteins. No germline mutations were found in patients with MSI(+) tumour defined only through dinucleotide markers. In conclusion, the proposed mononucleotide markers panel seems to have a higher predictive value to identify hMLH1 and hMSH2 mutation-positive patients with Lynch syndrome. Moreover, this panel showed increased specificity, thus improving the cost/effectiveness ratio of the biomolecular analyses.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Mutación de Línea Germinal/genética , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Nucleótidos/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/enzimología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Enzimas Reparadoras del ADN/genética , Marcadores Genéticos , Humanos , Inestabilidad de Microsatélites , Homólogo 1 de la Proteína MutL
18.
Clin Genet ; 71(2): 130-9, 2007 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17250661

RESUMEN

Hereditary non-polyposis colorectal cancer (HNPCC) is caused by inactivating mutations of DNA mismatch repair genes. Large genomic rearrangements in these genes have been increasingly recognized as important causes of HNPCC. Using multiplex ligation-dependent probe amplification, we identified three MSH2 deletions in Italian patients with HNPCC (proband A: exons 1-3, proband M: exon 8, and proband C: exons 1-6). Deletion breakpoint sequencing allowed us to develop rapid polymerase chain reaction-based mutation screening, which confirmed the presence of the deletions in affected and asymptomatic individuals of families A, C, and M. While the exon 8 and exon 1-3 deletions appear to be novel, the MSH2 1-6 deletion found in family C is identical to the one recently documented in two branches of another unrelated Italian family (family V+Va). Haplotype analysis showed that the kindreds C and V+Va (both from northeastern Italy, both displaying clinical features of the Muir-Torre syndrome) shared a seven-locus haplotype, indicating that the MSH2 1-6 deletion is probably a founder mutation. Families A, C, M, and V+Va all showed progressively earlier cancer-onset ages in successive generations. Analysis of 23 affected parent-child pairs in the four kindreds showed median anticipation of 12 years in offsprings' onset of cancer (p = 0.0001). No birth cohort effect was found. This is the first significant evidence of anticipation effects in HNPCC families carrying MSH2 deletions.


Asunto(s)
Anticipación Genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Mutación de Línea Germinal , Proteína 2 Homóloga a MutS/genética , Eliminación de Secuencia , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Cromosomas Humanos Par 2/genética , Exones , Femenino , Efecto Fundador , Humanos , Italia , Masculino , Persona de Mediana Edad , Linaje , Reacción en Cadena de la Polimerasa
19.
Breast Cancer Res Treat ; 103(1): 29-36, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17151928

RESUMEN

BRCA1 and 2 are major cancer susceptibility genes but their penetrance is highly variable. The folate metabolism plays an important role in DNA methylation and its alterated metabolism is associated with cancer risk. The role of allele variants 677T and 1298C (MTHFR gene) and 2756G (MS gene) has been investigated as potentially modifying factors of BRCA gene penetrance, evaluated as age at first diagnosis of cancer, in 484 BRCA1/BRCA2 carriers and in 108 sporadic breast cancer cases as a control group. The genotype analysis has been performed by means of PCR/RFLP's. The analysis of association between a particular genotype and disease risk was performed using Cox Regression with time to breast or ovarian cancer onset as the end-point. The presence of 677T allele confers an increased risk of breast cancer in BRCA1 carriers (P = 0.007) and the presence of 1298C allele confers an increased risk of breast cancer in sporadic cases (P = 0.015).


Asunto(s)
5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/genética , Neoplasias de la Mama/genética , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Adulto , Neoplasias de la Mama/epidemiología , Estudios de Casos y Controles , Metilación de ADN , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/epidemiología , Heterocigoto , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Múltiples/epidemiología , Neoplasias Primarias Múltiples/genética , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/genética , Penetrancia , Polimorfismo de Longitud del Fragmento de Restricción , Modelos de Riesgos Proporcionales , Riesgo
20.
Clin Genet ; 69(3): 254-62, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16542391

RESUMEN

Mutation-predicting models can be useful when deciding on the genetic testing of individuals at risk and in determining the cost effectiveness of screening strategies at the population level. The aim of this study was to evaluate the performance of a newly developed genetic model that incorporates tumor microsatellite instability (MSI) information, called the AIFEG model, and in predicting the presence of mutations in MSH2 and MLH1 in probands with suspected hereditary non-polyposis colorectal cancer. The AIFEG model is based on published estimates of mutation frequencies and cancer penetrances in carriers and non-carriers and employs the program MLINK of the FASTLINK package to calculate the proband's carrier probability. Model performance is evaluated in a series of 219 families screened for mutations in both MSH2 and MLH1, in which 68 disease-causing mutations were identified. Predictions are first obtained using family history only and then converted into posterior probabilities using information on MSI. This improves predictions substantially. Using a probability threshold of 10% for mutation analysis, the AIFEG model applied to our series has 100% sensitivity and 71% specificity.


Asunto(s)
Proteínas Portadoras/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Tamización de Portadores Genéticos/métodos , Modelos Genéticos , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Proteínas Adaptadoras Transductoras de Señales , Adulto , Anciano , Femenino , Pruebas Genéticas , Inestabilidad Genómica , Humanos , Italia , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Mutación , Programas Informáticos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA