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1.
Cancer Genet ; 237: 55-62, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31447066

RESUMO

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.


Assuntos
Síndromes Neoplásicas Hereditárias/genética , Neoplasias Ovarianas/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Testes Genéticos , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Linhagem
2.
Rev Neurol ; 67(11): 463-464, 2018 12 01.
Artigo em Espanhol | MEDLINE | ID: mdl-30484280

RESUMO

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


Assuntos
Síndrome de Guillain-Barré , Hospitais Gerais , Humanos
4.
Lett Appl Microbiol ; 65(5): 381-387, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28862747

RESUMO

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.


Assuntos
Nitrogênio/metabolismo , Saccharomyces cerevisiae/metabolismo , Vinho/microbiologia , Fazendas , Fermentação , Nitrogênio/análise , Vinho/análise
5.
Breast ; 22(6): 1130-5, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24011770

RESUMO

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.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Modelos Genéticos , Feminino , Testes Genéticos , Heterozigoto , Humanos , Itália , Masculino , Mutação , Seleção de Pacientes , Valor Preditivo dos Testes , Probabilidade , Medição de Risco
7.
Breast Cancer Res Treat ; 138(3): 861-8, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23468243

RESUMO

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.


Assuntos
Neoplasias da Mama Masculina/genética , Predisposição Genética para Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Proteínas Reguladoras de Apoptose , Neoplasias da Mama Masculina/epidemiologia , Neoplasias da Mama Masculina/etiologia , Estudos de Casos e Controles , Receptor alfa de Estrogênio/genética , Proteínas de Grupo de Alta Mobilidade , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/genética , Transativadores
8.
Tech Coloproctol ; 17(1): 79-87, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22976915

RESUMO

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.


Assuntos
DNA Glicosilases/genética , Síndrome de Gardner/genética , Síndrome de Gardner/patologia , Genes APC , Adolescente , Adulto , Fatores Etários , Idoso , Feminino , Genótipo , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Estatísticas não Paramétricas , Carga Tumoral/genética , Adulto Jovem
9.
Oncogene ; 32(38): 4500-8, 2013 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-23108399

RESUMO

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.


Assuntos
Dano ao DNA , DNA Glicosilases/genética , DNA Glicosilases/metabolismo , Instabilidade Genômica , Estresse Oxidativo , 8-Hidroxi-2'-Desoxiguanosina , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/metabolismo , Adulto , Linhagem Celular , Reparo do DNA , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Ativação Enzimática , Feminino , Expressão Gênica , Heterozigoto , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mutação , Taxa de Mutação , Fenótipo
10.
Mol Biol Rep ; 39(10): 9307-10, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22782591

RESUMO

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.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Músculo Deltoide/patologia , Neoplasias Renais/diagnóstico , Leiomiossarcoma/diagnóstico , Neoplasias Musculares/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Análise Mutacional de DNA , Estudos de Associação Genética , Humanos , Neoplasias Renais/genética , Leiomiossarcoma/genética , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Neoplasias Musculares/genética , Proteína 2 Homóloga a MutS/genética , Deleção de Sequência
11.
Tumour Biol ; 33(3): 857-64, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22278153

RESUMO

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.


Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , DNA Glicosilases/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Polipose Adenomatosa do Colo/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Metilação de DNA , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Feminino , Genes APC , Mutação em Linhagem Germinativa , Humanos , Incidência , Itália/epidemiologia , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Regiões Promotoras Genéticas , Estudos Prospectivos , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , População Branca/genética
12.
J Fr Ophtalmol ; 34(4): 256.e1-6, 2011 Apr.
Artigo em Francês | MEDLINE | ID: mdl-21444125

RESUMO

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.


Assuntos
Faringite/diagnóstico , Infecções Estreptocócicas/diagnóstico , Uveíte Anterior/diagnóstico , Uveíte Intermediária/diagnóstico , Uveíte Posterior/diagnóstico , Administração Oral , Adulto , Idoso , Anti-Inflamatórios/administração & dosagem , Antiestreptolisina/sangue , Feminino , Angiofluoresceinografia , Humanos , Masculino , Metilprednisolona/administração & dosagem , Soluções Oftálmicas , Oftalmoscopia , Prednisolona/administração & dosagem , Prednisolona/análogos & derivados , Estudos Retrospectivos , Tomografia de Coerência Óptica , Uveíte Anterior/tratamento farmacológico , Uveíte Intermediária/tratamento farmacológico , Uveíte Posterior/tratamento farmacológico , Adulto Jovem
13.
Fam Cancer ; 10(1): 27-35, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20717847

RESUMO

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.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Adenocarcinoma Mucinoso/genética , Neoplasias da Mama/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Íntrons/genética , Mutação/genética , Proteínas Nucleares/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Análise Mutacional de DNA , Primers do DNA/química , DNA de Neoplasias/genética , Feminino , Genótipo , Humanos , Técnicas Imunoenzimáticas , Perda de Heterozigosidade , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteínas Nucleares/metabolismo , Linhagem , Reação em Cadeia da Polimerase , Prognóstico , Adulto Jovem
14.
Br J Cancer ; 101(12): 2048-54, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-19920816

RESUMO

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.


Assuntos
Proteínas de Ligação a DNA/genética , Genes BRCA1 , Genes BRCA2 , Heterozigoto , Mutação , Polimorfismo de Nucleotídeo Único , Estudos de Coortes , Feminino , Humanos , Estudos Retrospectivos
15.
Int J Colorectal Dis ; 23(8): 801-6, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18446350

RESUMO

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

Assuntos
Neoplasias do Colo/genética , Instabilidade de Microssatélites , Neoplasias Retais/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenocarcinoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , DNA de Neoplasias/genética , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/genética , Mutação , Proteínas Nucleares/genética , Guias de Prática Clínica como Assunto
16.
Exp Cell Res ; 313(12): 2521-30, 2007 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-17574238

RESUMO

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.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Processamento Alternativo/genética , Diferenciação Celular , Queratinócitos/citologia , Queratinócitos/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Processamento Alternativo/efeitos dos fármacos , Anticorpos/imunologia , Cálcio/farmacologia , Diferenciação Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Células Cultivadas , Colo do Útero/citologia , Colo do Útero/efeitos dos fármacos , Colo do Útero/metabolismo , Proteína 1 Homóloga a Discs-Large , Epiderme/efeitos dos fármacos , Epiderme/patologia , Feminino , Humanos , Queratinócitos/efeitos dos fármacos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transporte Proteico/efeitos dos fármacos , Fatores de Tempo
17.
Dis Markers ; 23(3): 179-87, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17473388

RESUMO

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.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Mutação em Linhagem Germinativa/genética , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Nucleotídeos/genética , Neoplasias Colorretais Hereditárias sem Polipose/enzimologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Enzimas Reparadoras do DNA/genética , Marcadores Genéticos , Humanos , Instabilidade de Microssatélites , Proteína 1 Homóloga a MutL
18.
Clin Genet ; 71(2): 130-9, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17250661

RESUMO

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.


Assuntos
Antecipação Genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Mutação em Linhagem Germinativa , Proteína 2 Homóloga a MutS/genética , Deleção de Sequência , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 2/genética , Éxons , Feminino , Efeito Fundador , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Linhagem , Reação em Cadeia da Polimerase
19.
Breast Cancer Res Treat ; 103(1): 29-36, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17151928

RESUMO

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).


Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Adulto , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Metilação de DNA , Feminino , Frequência do Gene , Predisposição Genética para Doença/epidemiologia , Heterozigoto , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/epidemiologia , Neoplasias Primárias Múltiplas/genética , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Penetrância , Polimorfismo de Fragmento de Restrição , Modelos de Riscos Proporcionais , Risco
20.
Clin Genet ; 69(3): 254-62, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16542391

RESUMO

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.


Assuntos
Proteínas de Transporte/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Triagem de Portadores Genéticos/métodos , Modelos Genéticos , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Feminino , Testes Genéticos , Instabilidade Genômica , Humanos , Itália , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Mutação , Software
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