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1.
J Med Genet ; 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31494577

RESUMO

INTRODUCTION: Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary cancer syndromes associated with mismatch repair (MMR) deficiency. Tumours show microsatellite instability (MSI), also reported at low levels in non-neoplastic tissues. Our aim was to evaluate the performance of high-sensitivity MSI (hs-MSI) assessment for the identification of LS and CMMRD in non-neoplastic tissues. MATERIALS AND METHODS: Blood DNA samples from 131 individuals were grouped into three cohorts: baseline (22 controls), training (11 CMMRD, 48 LS and 15 controls) and validation (18 CMMRD and 18 controls). Custom next generation sequencing panel and bioinformatics pipeline were used to detect insertions and deletions in microsatellite markers. An hs-MSI score was calculated representing the percentage of unstable markers. RESULTS: The hs-MSI score was significantly higher in CMMRD blood samples when compared with controls in the training cohort (p<0.001). This finding was confirmed in the validation set, reaching 100% specificity and sensitivity. Higher hs-MSI scores were detected in biallelic MSH2 carriers (n=5) compared with MSH6 carriers (n=15). The hs-MSI analysis did not detect a difference between LS and control blood samples (p=0.564). CONCLUSIONS: The hs-MSI approach is a valuable tool for CMMRD diagnosis, especially in suspected patients harbouring MMR variants of unknown significance or non-detected biallelic germline mutations.

2.
Mol Cancer ; 17(1): 23, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29448935

RESUMO

Germline mutations in BUB1 and BUB3 have been reported to increase the risk of developing colorectal cancer (CRC) at young age, in presence of variegated aneuploidy and reminiscent dysmorphic traits of mosaic variegated aneuploidy syndrome. We performed a mutational analysis of BUB1 and BUB3 in 456 uncharacterized mismatch repair-proficient hereditary non-polyposis CRC families and 88 polyposis cases. Four novel or rare germline variants, one splice-site and three missense, were identified in four families. Neither variegated aneuploidy nor dysmorphic traits were observed in carriers. Evident functional effects in the heterozygous form were observed for c.1965-1G>A, but not for c.2296G>A (p.E766K), in spite of the positive co-segregation in the family. BUB1 c.2473C>T (p.P825S) and BUB3 c.77C>T (p.T26I) remained as variants of uncertain significance. As of today, the rarity of functionally relevant mutations identified in familial and/or early onset series does not support the inclusion of BUB1 and BUB3 testing in routine genetic diagnostics of familial CRC.


Assuntos
Polipose Adenomatosa do Colo/genética , Proteínas de Ciclo Celular/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Mutação em Linhagem Germinativa , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas Serina-Treonina Quinases/genética , Fuso Acromático/genética , Proteínas de Ciclo Celular/química , Humanos , Modelos Moleculares , Linhagem , Proteínas de Ligação a Poli-ADP-Ribose/química , Conformação Proteica , Proteínas Serina-Treonina Quinases/química
3.
Gastroenterology ; 154(1): 181-194.e20, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28912018

RESUMO

BACKGROUND & AIMS: Although there is a genetic predisposition to colorectal cancer (CRC), few of the genes that affect risk have been identified. We performed whole-exome sequence analysis of individuals in a high-risk family without mutations in genes previously associated with CRC risk to identify variants associated with inherited CRC. METHODS: We collected blood samples from 3 relatives with CRC in Spain (65, 62, and 40 years old at diagnosis) and performed whole-exome sequence analyses. Rare missense, truncating or splice-site variants shared by the 3 relatives were selected. We used targeted pooled DNA amplification followed by next generation sequencing to screen for mutations in candidate genes in 547 additional hereditary and/or early-onset CRC cases (502 additional families). We carried out protein-dependent yeast growth assays and transfection studies in the HT29 human CRC cell line to test the effects of the identified variants. RESULTS: A total of 42 unique or rare (population minor allele frequency below 1%) nonsynonymous genetic variants in 38 genes were shared by all 3 relatives. We selected the BRF1 gene, which encodes an RNA polymerase III transcription initiation factor subunit for further analysis, based on the predicted effect of the identified variant and previous association of BRF1 with cancer. Previously unreported or rare germline variants in BRF1 were identified in 11 of 503 CRC families, a significantly greater proportion than in the control population (34 of 4300). Seven of the identified variants (1 detected in 2 families) affected BRF1 mRNA splicing, protein stability, or expression and/or function. CONCLUSIONS: In an analysis of families with a history of CRC, we associated germline mutations in BRF1 with predisposition to CRC. We associated deleterious BRF1 variants with 1.4% of familial CRC cases, in individuals without mutations in high-penetrance genes previously associated with CRC. Our findings add additional evidence to the link between defects in genes that regulate ribosome synthesis and risk of CRC.


Assuntos
Neoplasias Colorretais/genética , Mutação em Linhagem Germinativa/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Adulto , Idoso , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Espanha
4.
Int J Cancer ; 141(7): 1365-1380, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28577310

RESUMO

In a proportion of patients presenting mismatch repair (MMR)-deficient tumors, no germline MMR mutations are identified, the so-called Lynch-like syndrome (LLS). Recently, MMR-deficient tumors have been associated with germline mutations in POLE and MUTYH or double somatic MMR events. Our aim was to elucidate the molecular basis of MSH2-deficient LS-suspected cases using a comprehensive analysis of colorectal cancer (CRC)-associated genes at germline and somatic level. Fifty-eight probands harboring MSH2-deficient tumors were included. Germline mutational analysis of MSH2 (including EPCAM deletions) and MSH6 was performed. Pathogenicity of MSH2 variants was assessed by RNA analysis and multifactorial likelihood calculations. MSH2 cDNA and methylation of MSH2 and MSH6 promoters were studied. Matched blood and tumor DNA were analyzed using a customized next generation sequencing panel. Thirty-five individuals were carriers of pathogenic or probably pathogenic variants in MSH2 and EPCAM. Five patients harbored 4 different MSH2 variants of unknown significance (VUS) and one had 2 novel MSH6 promoter VUS. Pathogenicity assessment allowed the reclassification of the 4 MSH2 VUS and 6 probably pathogenic variants as pathogenic mutations, enabling a total of 40 LS diagnostics. Predicted pathogenic germline variants in BUB1, SETD2, FAN1 and MUTYH were identified in 5 cases. Three patients had double somatic hits in MSH2 or MSH6, and another 2 had somatic alterations in other MMR genes and/or proofreading polymerases. In conclusion, our comprehensive strategy combining germline and somatic mutational status of CRC-associated genes by means of a subexome panel allows the elucidation of up to 86% of MSH2-deficient suspected LS tumors.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Proteínas de Ligação a DNA/genética , Mutação em Linhagem Germinativa , Proteína 2 Homóloga a MutS/deficiência , Proteína 2 Homóloga a MutS/genética , DNA Glicosilases/genética , Metilação de DNA , Análise Mutacional de DNA , Proteínas de Ligação a DNA/deficiência , Molécula de Adesão da Célula Epitelial/genética , Exodesoxirribonucleases/genética , Sequenciamento de Nucleotídeos em Larga Escala , Histona-Lisina N-Metiltransferase/genética , Humanos , Perda de Heterozigosidade , Regiões Promotoras Genéticas/genética , Proteínas Serina-Treonina Quinases/genética
5.
Psicooncología (Pozuelo de Alarcón) ; 14(1): 41-52, ene.-jun. 2017. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-163638

RESUMO

A lo largo de la consulta de Asesoramiento Genético se hace un gran énfasis en la necesidad de comunicar la información del riesgo familiar y del estudio genético a los familiares. Además, los informes clínicos especifican los familiares en situación de riesgo. Sin embargo, desconocemos el patrón de comunicación intra-familiar de los resultados genéticos diagnósticos tras el asesoramiento. Objetivo: Realizar un estudio descriptivo sobre el patrón de comunicación de resultado del estudio genético diagnóstico en predisposición hereditaria al cáncer en la Unidad de Asesoramiento Genético del ICO. Método: Se ha realizado un estudio descriptivo mediante entrevista telefónica a una muestra de casos índice atendidos en la Unidad de Asesoramiento Genético que recibieron el resultado de un diagnóstico genético, explorando a qué familiares han comunicado estos resultados (patrón de comunicación familiar). Del mismo modo, se han recogido variables demográficas, personales y del propio resultado genético, para explorar si alguna de ellas pudiera modificar el patrón de comunicación. Resultados: La mayoría de los pacientes comunican los resultados de los estudios genéticos a sus familiares. Sin embargo, esta comunicación no es completa, por lo que es posible diseñar estrategias de intervención que mejoren el patrón de comunicación de los pacientes que reciben estudios genéticos diagnósticos en el contexto de la predisposición hereditaria al cáncer


Throughout the Genetic Counselling process a great emphasis is done on the need to communicate the familial risk information and the genetic study to the relatives. In addition, the clinical reports specify the relatives at risk situation. However, the familial communication pattern of genetic results after the counselling remains unknown. Objective: To conduct a descriptive study about the communication pattern of results of the diagnostic genetic test in hereditary predisposition to cancer at the ICO Genetic Counselling Unit. Methods: A descriptive study has been performed by telephone interview on a sample of index individuals attended at the Genetic Counselling Unit. Patients were asked whether if they had communicated their genetic study results and to whom. Similarly, demographic, personal and genetic result itself variables have been collected to explore whether any of them could modify the communication pattern. Results: Most patients report the results of the genetic studies to their relatives. However, this communication is not complete, so it is possible to design intervention strategies which may improve the communication pattern of the patients who receive diagnostic genetic tests in the context of the hereditary predisposition to cancer


Assuntos
Humanos , Aconselhamento Genético/psicologia , Comunicação , Revelação da Verdade , Neoplasias/psicologia , Doenças Genéticas Inatas/psicologia , Relações Familiares/psicologia , Predisposição Genética para Doença/psicologia , Epidemiologia Descritiva
6.
Fam Cancer ; 16(4): 501-507, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28365877

RESUMO

The clinical spectrum of germline mismatch repair (MMR) gene variants continues increasing, encompassing Lynch syndrome, Constitutional MMR Deficiency (CMMRD), and the recently reported MSH3-associated polyposis. Genetic diagnosis of these hereditary cancer syndromes is often hampered by the presence of variants of unknown significance (VUS) and overlapping phenotypes. Two PMS2 VUS, c.2149G>A (p.V717M) and c.2444C>T (p.S815L), were identified in trans in one individual diagnosed with early-onset colorectal cancer (CRC) who belonged to a family fulfilling clinical criteria for hereditary cancer. Clinico-pathological data, multifactorial likelihood calculations and functional analyses were used to refine their clinical significance. Likelihood analysis based on cosegregation and tumor data classified the c.2444C>T variant as pathogenic, which was supported by impaired MMR activity associated with diminished protein expression in functional assays. Conversely, the c.2149G>A variant displayed MMR proficiency and protein stability. These results, in addition to the conserved PMS2 expression in normal tissues and the absence of germline microsatellite instability (gMSI) in the biallelic carrier ruled out a CMMRD diagnosis. The use of comprehensive strategies, including functional and clinico-pathological information, is mandatory to improve the clinical interpretation of naturally occurring MMR variants. This is critical for appropriate clinical management of cancer syndromes associated to MMR gene mutations.


Assuntos
Neoplasias Colorretais/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Mutação de Sentido Incorreto , Idade de Início , Estudos de Casos e Controles , Reparo de Erro de Pareamento de DNA , Feminino , Frequência do Gene , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Humanos , Masculino , Instabilidade de Microssatélites , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Linhagem
7.
Curr Pharm Biotechnol ; 17(5): 439-48, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26956109

RESUMO

We present a brief survey of some of the recent work of Professor Luis E. Díaz, performed together with his students and collaborators at the University of Buenos Aires. Dr Luis E. Díaz has been involved in research on biochemical and pharmaceutical sciences solving scientific and industry problems for over 40 years until he passed away. Prof. Díaz scientific interests included various topics from NMR spectroscopy to biomedicine but fundamentally he focused in various aspects of chemistry (analytical, organic, inorganic and environmental). This is not a complete survey but a sampling of prominent projects related to sol-gel chemistry with a focus on some of his recent publications.


Assuntos
Materiais Biocompatíveis/química , Transição de Fase , Antibacterianos/química , Humanos , Nanoestruturas/química , Propriedades de Superfície
8.
Med. clín (Ed. impr.) ; 146(4): 148-154, feb. 2016. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-147837

RESUMO

Fundamento y objetivo: Tener una predisposición hereditaria al cáncer puede asociarse a un impacto psicológico. Uno de los objetivos del consejo genético es favorecer la adaptación psicológica a la nueva situación, siendo necesarios instrumentos validados en este contexto. Por ser el autoconcepto un buen indicador de adaptación a la enfermedad o al riesgo de tenerla, y una variable relevante en oncología, el objetivo es adaptar culturalmente al castellano y validar la BRCA Self-Concept Scale. Material y método: Ciento sesenta y cinco portadoras de mutación en los genes BRCA respondieron al cuestionario previamente sometido a un proceso de traducción-retrotraducción, y a la Escala de Preocupación por el Cáncer (EPC) como medida de validez convergente. Se valoró la estructura del cuestionario mediante una prueba de expertos y un análisis factorial confirmatorio (AFC), se calculó el α de Cronbach de las 3 subescalas (Estigma, Vulnerabilidad y Control), y se correlacionaron con la EPC. Resultados: La prueba de expertos y el AFC no confirman la estructura original del cuestionario. El modelo reespecificado (con los ítems 10 y 13 en Vulnerabilidad) muestra mejor ajuste: comparative fit index 0,973;Tucker-Lewis index 0,968; root mean square error of approximation 0,067. El α de Cronbach es de 0,83 para Estigma, de 0,84 para Vulnerabilidad, y de 0,61 para Control. Se encuentra evidencia de validez convergente con la EPC (rho de Spearman 0,631 para Estigma, 0,683 para Vulnerabilidad, y −0,363 para Control; p < 0,001). Conclusiones: Los resultados apoyan la validez de la escala modificada de autoconcepto BRCA, siendo una medida potencialmente útil para valorar la adaptación a tener una alta predisposición hereditaria al cáncer (AU)


Background and objective: Having an inherited predisposition to cancer may have a psychological impact, and one goal of genetic counseling is to promote psychological adjustment to the new situation. Thus, in the genetic context, validated measures of adjustment are required. Given that self-concept is a good indicator of adjustment to the disease or to the risk for it, and a relevant variable in oncology, the goal of the study is to culturally adapt and validate the BRCA Self-Concept Scale. Material and Method: One hundred and sixty-five BRCA carriers’ women answered to the questionnaire, previously adapted through a process of forward/back-translation, and to the Cancer Worry Scale (CWS) as a measure of convergent validity. Theoretical structure of BRCA Self-Concept Scale was assessed by expert judges, and submitted to a confirmatory factor analysis (CFA). Cronbach's α was calculated for each subscale (Stigma, Vulnerability and Control), and correlations with CWS were performed. Results: Expert judges’ structure and CFA do not support the original structure of the questionnaire. The respecificity model (with items 10 and 13 loading on Vulnerability factor) show a better fit: comparative fit index 0.973; Tucker-Lewis index 0.968; root mean square error of approximation 0.067. The Cronbach's α is 0.83 for Stigma, 0.84 for Vulnerability, and 0.61 for Control. Evidence of convergent validity with CWS has been obtained (Spearman's rho 0.631 for Stigma, 0.683 for Vulnerability, and −0.363 for Control; P < .001). Conclusions: Results support the validity of the modified Spanish BRCA Self-Concept Scale, which is a potentially useful measure for the study of psychological adjustment to high risk for hereditary breast and ovarian cáncer (AU)


Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Ajustamento Social , Autoimagem , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/psicologia , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/psicologia , Mutagênese/genética , Adaptação Psicológica/fisiologia , Imagem Corporal , Inquéritos e Questionários , Adaptação Psicológica/classificação , Psicometria/métodos , Psicometria/tendências
9.
Genet Med ; 18(4): 325-32, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26133394

RESUMO

PURPOSE: Germ-line mutations in the exonuclease domains of POLE and POLD1 have been recently associated with polyposis and colorectal cancer (CRC) predisposition. Here, we aimed to gain a better understanding of the phenotypic characteristics of this syndrome to establish specific criteria for POLE and POLD1 mutation screening and to help define the clinical management of mutation carriers. METHODS: The exonuclease domains of POLE and POLD1 were studied in 529 kindred, 441 with familial nonpolyposis CRC and 88 with polyposis, by using pooled DNA amplification and massively parallel sequencing. RESULTS: Seven novel or rare genetic variants were identified. In addition to the POLE p.L424V recurrent mutation in a patient with polyposis, CRC and oligodendroglioma, six novel or rare POLD1 variants (four of them, p.D316H, p.D316G, p.R409W, and p.L474P, with strong evidence for pathogenicity) were identified in nonpolyposis CRC families. Phenotypic data from these and previously reported POLE/POLD1 carriers point to an associated phenotype characterized by attenuated or oligo-adenomatous colorectal polyposis, CRC, and probably brain tumors. In addition, POLD1 mutations predispose to endometrial and breast tumors. CONCLUSION: Our results widen the phenotypic spectrum of the POLE/POLD1-associated syndrome and identify novel pathogenic variants. We propose guidelines for genetic testing and surveillance recommendations.Genet Med 18 4, 325-332.


Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , DNA Polimerase III/genética , DNA Polimerase II/genética , Mutação , Polipose Adenomatosa do Colo/diagnóstico , Alelos , Neoplasias Colorretais/diagnóstico , DNA Polimerase II/química , DNA Polimerase III/química , Feminino , Estudos de Associação Genética , Testes Genéticos , Genótipo , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Linhagem , Fenótipo , Proteínas de Ligação a Poli-ADP-Ribose , Domínios e Motivos de Interação entre Proteínas/genética
10.
Med Clin (Barc) ; 146(4): 148-54, 2016 Feb 19.
Artigo em Espanhol | MEDLINE | ID: mdl-26654557

RESUMO

BACKGROUND AND OBJECTIVE: Having an inherited predisposition to cancer may have a psychological impact, and one goal of genetic counseling is to promote psychological adjustment to the new situation. Thus, in the genetic context, validated measures of adjustment are required. Given that self-concept is a good indicator of adjustment to the disease or to the risk for it, and a relevant variable in oncology, the goal of the study is to culturally adapt and validate the BRCA Self-Concept Scale. MATERIAL AND METHOD: One hundred and sixty-five BRCA carriers' women answered to the questionnaire, previously adapted through a process of forward/back-translation, and to the Cancer Worry Scale (CWS) as a measure of convergent validity. Theoretical structure of BRCA Self-Concept Scale was assessed by expert judges, and submitted to a confirmatory factor analysis (CFA). Cronbach's α was calculated for each subscale (Stigma, Vulnerability and Control), and correlations with CWS were performed. RESULTS: Expert judges' structure and CFA do not support the original structure of the questionnaire. The respecificity model (with items 10 and 13 loading on Vulnerability factor) show a better fit: comparative fit index 0.973; Tucker-Lewis index 0.968; root mean square error of approximation 0.067. The Cronbach's α is 0.83 for Stigma, 0.84 for Vulnerability, and 0.61 for Control. Evidence of convergent validity with CWS has been obtained (Spearman's rho 0.631 for Stigma, 0.683 for Vulnerability, and -0.363 for Control; P<.001). CONCLUSIONS: Results support the validity of the modified Spanish BRCA Self-Concept Scale, which is a potentially useful measure for the study of psychological adjustment to high risk for hereditary breast and ovarian cancer.


Assuntos
Ajustamento Emocional , Síndrome Hereditária de Câncer de Mama e Ovário/psicologia , Testes Psicológicos , Autoimagem , Adulto , Assistência à Saúde Culturalmente Competente , Análise Fatorial , Feminino , Humanos , Pessoa de Meia-Idade , Psicometria , Reprodutibilidade dos Testes , Traduções
11.
Life Sci ; 141: 188-92, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26454227

RESUMO

AIMS: Longitudinal and experimental studies have shown that chronic stress contributes to the onset and progression of different diseases. Although it is not possible to eliminate stress completely, people can learn to manage it by participating in different kinds of stress management interventions. This study examined the effectiveness of stress management interventions on neuroendocrine responses in stressed students and health professionals, by measuring hair cortisol in comparison to salivary cortisol. MAIN METHODS: Salivary and hair cortisol measurements were performed in 37 subjects (31women, 6 men; mean age 34.0±10.6) who attended to a Coping Stress and Quality of Care Program at the University of Buenos Aires. Cortisol was measured at the beginning and at the end of the program. The State-Trait Anxiety Inventory STAI was used to evaluate state and trait anxiety. KEY FINDINGS: In subjects who completed the program, no differences were observed in salivary cortisol levels between the first and the last session. However, in these subjects, hair cortisol obtained in the last session was significantly lower than hair cortisol in the first session. SIGNIFICANCE: Hair cortisol appears to be a better biomarker than salivary cortisol for evaluation of the effectiveness of a stress reduction program and it seems to be a better indicator of stress system dysregulation as well.


Assuntos
Cabelo/química , Hidrocortisona/análise , Estresse Psicológico/metabolismo , Estresse Psicológico/prevenção & controle , Adaptação Psicológica , Adulto , Ansiedade/psicologia , Argentina , Biomarcadores/metabolismo , Doença Crônica , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Sistemas Neurossecretores/metabolismo , Qualidade de Vida , Saliva/química , Fatores Socioeconômicos , Resultado do Tratamento
12.
Gastroenterology ; 149(3): 563-6, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26052075

RESUMO

Identification of genes associated with hereditary cancers facilitates management of patients with family histories of cancer. We performed exome sequencing of DNA from 3 individuals from a family with colorectal cancer who met the Amsterdam criteria for risk of hereditary nonpolyposis colorectal cancer. These individuals had mismatch repair-proficient tumors and each carried nonsense variant in the FANCD2/FANCI-associated nuclease 1 gene (FAN1), which encodes a nuclease involved in DNA inter-strand cross-link repair. We sequenced FAN1 in 176 additional families with histories of colorectal cancer and performed in vitro functional analyses of the mutant forms of FAN1 identified. We detected FAN1 mutations in approximately 3% of families who met the Amsterdam criteria and had mismatch repair-proficient cancers with no previously associated mutations. These findings link colorectal cancer predisposition to the Fanconi anemia DNA repair pathway, supporting the connection between genome integrity and cancer risk.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo do DNA/genética , Exodesoxirribonucleases/genética , Mutação em Linhagem Germinativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Pré-Escolar , Neoplasias Colorretais Hereditárias sem Polipose/enzimologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Exodesoxirribonucleases/metabolismo , Feminino , Predisposição Genética para Doença , Células HEK293 , Hereditariedade , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Adulto Jovem
14.
Eur J Cancer ; 50(13): 2241-50, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24953332

RESUMO

BACKGROUND AND AIMS: Individuals with tumours showing mismatch repair (MMR) deficiency not linked to germline mutations or somatic methylation of MMR genes have been recently referred as having 'Lynch-like syndrome' (LLS). The genetic basis of these LLS cases is unknown. MUTYH-associated polyposis patients show some phenotypic similarities to Lynch syndrome patients. The aim of this study was to investigate the prevalence of germline MUTYH mutations in a large series of LLS patients. METHODS: Two hundred and twenty-five probands fulfilling LLS criteria were included in this study. Screening of MUTYH recurrent mutations, whole coding sequencing and a large rearrangement analysis were undertaken. Age, sex, clinical, pathological and molecular characteristics of tumours including KRAS mutations were assessed. RESULTS: We found a prevalence of 3.1% of MAP syndrome in the whole series of LLS (7/225) and 3.9% when only cases fulfilling clinical criteria were considered (7/178). Patients with MUTYH biallelic mutations had more adenomas than monoallelic (P=0.02) and wildtype patients (P<0.0001). Six out of nine analysed tumours from six biallelic MUTYH carriers harboured KRAS-p.G12C mutation. This mutation was found to be associated with biallelic MUTYH germline mutation when compared with reported series of unselected colorectal cancer cohorts (P<0.0001). CONCLUSIONS: A proportion of unexplained LLS cases is caused by biallelic MUTYH mutations. The obtained results further justify the inclusion of MUTYH in the diagnostic strategy for Lynch syndrome-suspected patients.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , DNA Glicosilases/genética , Mutação em Linhagem Germinativa , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/genética
15.
Hum Mol Genet ; 23(13): 3506-12, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24501277

RESUMO

Germline mutations in DNA polymerase ɛ (POLE) and δ (POLD1) have been recently identified in families with multiple colorectal adenomas and colorectal cancer (CRC). All reported cases carried POLE c.1270C>G (p.Leu424Val) or POLD1 c.1433G>A (p.Ser478Asn) mutations. Due to the scarcity of cases reported so far, an accurate clinical phenotype has not been defined. We aimed to assess the prevalence of these recurrent mutations in unexplained familial and early-onset CRC and polyposis, and to add additional information to define the clinical characteristics of mutated cases. A total of 858 familial/early onset CRC and polyposis patients were studied: 581 familial and early-onset CRC cases without mismatch repair (MMR) deficiency, 86 cases with MMR deficiency and 191 polyposis cases. Mutation screening was performed by KASPar genotyping assays and/or Sanger sequencing of the involved exons. POLE p.L424V was identified in a 28-year-old polyposis and CRC patient, as a de novo mutation. None of the 858 cases studied carried POLD1 p.S478N. A new mutation, POLD1 c.1421T>C (p.Leu474Pro), was identified in a mismatch repair proficient Amsterdam II family. Its pathogenicity was supported by cosegregation in the family, in silico predictions, and previously published yeast assays. POLE and POLD1 mutations explain a fraction of familial CRC and polyposis. Sequencing the proofreading domains of POLE and POLD1 should be considered in routine genetic diagnostics. Until additional evidence is gathered, POLE and POLD1 genetic testing should not be restricted to polyposis cases, and the presence of de novo mutations, considered.


Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , DNA Polimerase III/genética , DNA Polimerase II/genética , Mutação em Linhagem Germinativa/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a Poli-ADP-Ribose
16.
Med. clín (Ed. impr.) ; 141(2): 62-66, jul. 2013.
Artigo em Espanhol | IBECS | ID: ibc-114351

RESUMO

Fundamento y objetivo: El síndrome de poliposis hiperplásica (SPH) es un cuadro poco frecuente caracterizado por la presencia de pólipos hiperplásicos (PH) ocasionalmente asociados a adenomas serrados (AS) o pólipos mixtos (PM), y definido por criterios clínicos (OMS/Cleveland). El SPH es heterogéneo con respecto al número, tamaño de los pólipos, asociación a cáncer colorrectal (CCR) e historia familiar. Se desconoce su base genética. Describimos aquellos individuos que cumplen criterios de SPH dentro de la serie de familias valoradas en nuestra Unidad de Consejo Genético por una poliposis colónica. Nuestro objetivo es identificar las características clínicas de este síndrome. Pacientes y método: Estudio retrospectivo de 197 familias con poliposis colónica (1998-2011), en que se identificaron aquellos individuos con criterios de SPH. Para saber el número total de pólipos, se tuvo en cuenta las polipectomías y/o el estudio histológico de las piezas quirúrgicas. Los pólipos se clasificaron en adenomas, lesiones serradas (PH y AS) y PM. Los estudios genéticos realizados fueron: inestabilidad de microsatélites (IMS), variantes del gen MUTYH (p.Tyr165Cys, p.Gly382Asp y p.Glu396GlyfsX43) y el gen APC. Resultados: Un total de 18 individuos, con una edad media de 51,1 años, cumplían criterios de SPH (11 varones y 7 mujeres). El número de PH osciló entre 14 y 100,coexistiendo con adenomas clásicos, AS y PM en 14 individuos (77,8%). La localización de pólipos fue: colon derecho e izquierdo en 13 individuos (72,2%) y solo colon izquierdo en 5 (27,8%). Se detectó CCR en 10/18 (55,6%) pacientes, 3 de ellos (30%) presentaban un doble CCR, una historia familiar de CCR en 3 pacientes (16,7%) y de SPH en uno. No se detectó IMS en 8 CCR ni en los 3 adenomas estudiados; se detectaron 2/13 mutaciones en heterocigosis en el gen MUTYH (p.Gly382Asp) y una variante de significado biológico desconocido en el gen APC (p.Ser926Pro). Conclusiones: La variabilidad fenotípica del SPH dificulta su identificación, por lo que es importante seguir los criterios clínicos establecidos para su clasificación, así como establecer pautas de cribado de CCR dada la elevada incidencia del mismo (AU)


Background and objective: Hyperplastic polyposis syndrome (HPS) is an uncommon disorder characterized by hyperplastic polyps (HP) occasionally associated with serrated adenomas (SA) or mixed polyps (MP) and defined by clinical criteria (OMS/Cleveland). HPS is heterogeneous regarding the number and size of polyps, and it is associated with colorectal cáncer (CRC) and a family history. Its genetic basis is unknow. We describe individuals with HPS criteria from a series of families assessed in our Unit of Genetic Advice for colonic polyposis. Our objective is to identify the clinical characteristics of this syndrome. Patients and methods: Retrospective study of 197 families with colonic polyposis (1998-2011), identifying patients with HPS criteria. To know the number of polyps, we took into account polypectomies and/or the histologic study of surgical samples. Polyps were classified into adenomas, serrated lesiones (HP and SA) and MP. Genetic studies revealed: microsatellite instability (MSI), MUTYH gene variants (p.Tyr165Cys, p.Gly382Asp and p.Glu396GlyfsX43) and APC gene. Results: Eighteen individuals, with a median age of 51.1 years, had criteria of HPS (11 M/7 F). Number of HP varied between 14 and 100 coexisting with classical adenomas, SA and MP in 14 individuals (77.8%). Localization of polyps: ascending and descending colon in 13 individuals (72.2%) and only descending colon in 5 (27.8%). A CRC was detected in 10/18 (55.6%) patients, and 3 of them had a double CRC, a family history in 3 patients (16.7%) and a history of HPS in one. IMS was not detected in 8 CRC nor in 3 adenomas studied; we detected 2/13 heterozygous mutations in the MUTYH gene(p.Gly382Asp) and one variant with an unknown biological significance in the APC gene (p.Ser926Pro). Conclusions: The phenotypic variability of HPS difficults its identification, hence it is important to adhere to the clinical criteria established for its classification as well as to establish screening guidelines for CRC on the basis of its high incidence (AU)


Assuntos
Humanos , Pólipos Intestinais/complicações , Neoplasias Colorretais/complicações , Polipose Adenomatosa do Colo/complicações , Fatores de Risco , Estudos Retrospectivos
17.
Med Clin (Barc) ; 141(2): 62-6, 2013 Jul 21.
Artigo em Espanhol | MEDLINE | ID: mdl-22809968

RESUMO

BACKGROUND AND OBJETIVE: Hyperplastic polyposis syndrome (HPS) is an uncommon disorder characterized by hyperplastic polyps (HP) occasionally associated with serrated adenomas (SA) or mixed polyps (MP) and defined by clinical criteria (OMS/Cleveland). HPS is heterogeneous regarding the number and size of polyps, and it is associated with colorectal cáncer (CRC) and a family history. Its genetic basis is unknow. We describe individuals with HPS criteria from a series of families assessed in our Unit of Genetic Advice for colonic polyposis. Our objective is to identify the clinical characteristics of this syndrome. PATIENTS AND METHODS: Retrospective study of 197 families with colonic polyposis (1998-2011), identifying patients with HPS criteria. To know the number of polyps, we took into account polypectomies and/or the histologic study of surgical samples. Polyps were classified into adenomas, serrated lesiones (HP and SA) and MP. Genetic studies revealed: microsatellite instability (MSI), MUTYH gene variants (p.Tyr165Cys, p.Gly382Asp and p.Glu396GlyfsX43) and APC gene. RESULTS: Eighteen individuals, with a median age of 51.1 years, had criteria of HPS (11M/7F). Number of HP varied between 14 and 100 coexisting with classical adenomas, SA and MP in 14 individuals (77.8%). Localization of polyps: ascending and descending colon in 13 individuals (72.2%) and only descending colon in 5 (27.8%). A CRC was detected in 10/18 (55.6%) patients, and 3 of them had a double CRC, a family history in 3 patients (16.7%) and a history of HPS in one. IMS was not detected in 8 CRC nor in 3 adenomas studied; we detected 2/13 heterozygous mutations in the MUTYH gene (p.Gly382Asp) and one variant with an unknown biological significance in the APC gene (p.Ser926Pro). CONCLUSIONS: The phenotypic variability of HPS difficults its identification, hence it is important to adhere to the clinical criteria established for its classification as well as to establish screening guidelines for CRC on the basis of its high incidence.


Assuntos
Polipose Adenomatosa do Colo/epidemiologia , Neoplasias Colorretais/epidemiologia , Neoplasias Primárias Múltiplas/epidemiologia , Adenoma/epidemiologia , Adenoma/genética , Adenoma/patologia , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Adulto , Idoso , Colonoscopia , DNA Glicosilases/genética , Feminino , Genes APC , Predisposição Genética para Doença , Genótipo , Humanos , Hiperplasia , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia , Fenótipo , Estudos Retrospectivos , Espanha/epidemiologia , Adulto Jovem
18.
Eur J Hum Genet ; 20(12): 1256-64, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22763379

RESUMO

Recently, constitutional MLH1 epimutations have been identified in a subset of Lynch syndrome (LS) cases. The aim of this study was the identification of patients harboring constitutional MLH1 epimutations in a set of 34 patients with a clinical suspicion of LS, MLH1-methylated tumors and non-detected germline mutations in mismatch repair (MMR) genes. MLH1 promoter methylation was analyzed in lymphocyte DNA samples by MS-MLPA (Methylation-specific multiplex ligation-dependent probe amplification). Confirmation of MLH1 constitutional methylation was performed by MS-MCA (Methylation-specific melting curve analysis), bisulfite sequencing and pyrosequencing in different biological samples. Allelic expression was determined using heterozygous polymorphisms. Vertical transmission was evaluated by MS-MLPA and haplotype analyses. MS-MLPA analysis detected constitutional MLH1 methylation in 2 of the 34 individuals whose colorectal cancers showed MLH1 methylation (5.9%). These results were confirmed by bisulfite-based methods. Both epimutation carriers had developed metachronous early-onset LS tumors, with no family history of LS-associated cancers in their first-degree relatives. In one of the cases, the identified MLH1 constitutional methylation was monoallelic and results in MLH1 and EPM2AIP1 allele-specific transcriptional silencing. It was present in normal somatic tissues and absent in spermatozoa. The methylated MLH1 allele was maternally transmitted and methylation was reversed in a daughter who inherited the same allele. MLH1 methylation screening in lymphocyte DNA from patients with early-onset MLH1-methylated LS-associated tumors allows the identification of epimutation carriers. The present study adds further evidence to the emerging entity of soma-wide MLH1 epimutation and its heritability.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Metilação de DNA , Triagem de Portadores Genéticos , Heterozigoto , Proteínas Nucleares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Epigênese Genética , Feminino , Inativação Gênica , Mutação em Linhagem Germinativa , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Especificidade de Órgãos , Linhagem , Polimorfismo Genético , Análise de Sequência de DNA , Transcrição Genética
19.
Am J Health Promot ; 26(6): e149-58, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22747323

RESUMO

PURPOSE: To design, implement, and examine the psychoneuroendocrine responses of three different types of stress management programs. DESIGN: Randomly assigned. A pre/post experimental design comparing variables between three different programs and a control group. The first program included training in deep breathing, relaxation response, meditation, and guided imagery techniques (RRGI). The second program included training in cognitive behavioral techniques (CB). The third program included both RRGI and CB (RRGICB). SETTING: The study was conducted at Buenos Aires University. SUBJECTS: Participants (N  = 52) were undergraduate students. MEASURES: Anxiety, anger, hopelessness, neuroticism, respiration rate, and salivary cortisol levels were assessed. ANALYSIS: Wilcoxon signed rank test was used to investigate differences in pre and post variables. RESULTS: Subjects in the RRGI group showed significantly lower levels of anxiety (p < .011), anger (p < .012), neuroticism (p < .01), respiratory rate (p < .002), hopelessness (p < .01), and salivary cortisol (p < .002) after the treatment. Subjects in the CB group showed significantly lower levels of anxiety (p < .018), anger (p < .037), and neuroticism (p < .03) after the treatment. Subjects in the RRGICB group showed significantly lower levels of anxiety (p < .001), anger (p < .001), neuroticism (p < .008), hopelessness (p < .01), respiratory rate (p < .001), and salivary cortisol (p < .002) after the treatment. Subjects in the control group showed only one variable modification, a significant increase in cortisol levels (p < .004). CONCLUSIONS: The combination of deep breathing, relaxation response, meditation, and guided imagery techniques with CB seems to be effective at helping people to deal with stress.


Assuntos
Adaptação Psicológica , Estresse Psicológico/prevenção & controle , Estudantes/psicologia , Adolescente , Ira , Ansiedade , Argentina , Feminino , Humanos , Hidrocortisona/análise , Masculino , Transtornos Neuróticos/psicologia , Psicometria , Estatísticas não Paramétricas , Estresse Psicológico/psicologia , Adulto Jovem
20.
J Clin Anesth ; 17(4): 304-13, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15950859

RESUMO

We undertook this case series to determine if preexisting neurological disease is exacerbated by either spinal or epidural anesthesia. In the website of the Arachnoiditis Foundation, we posted an offer to advise anesthesiologists in cases of neurological problems after either of these techniques was used. Contacts were made first by way of the Internet, confirmed by telephone, and maintained by fax, e-mail, or by special mail. Patients here described were cared for and observed by one of the authors, in a hospital, in Argentina or in Mexico. A total of 7 adult, ASA physical status I and II patients, including 3 men and 4 women, with subtle symptoms of neurological disease before anesthesia, are described. Two patients had continuous lumbar epidural anesthesia, 3 had spinals; in 2 more, attempted epidural blocks led to accidental dural puncture and were converted to subarachnoid anesthetics. All patients accepted neuraxial anesthesia without informing the anesthesiologists that they had mild neurological symptoms before surgery. Because anesthesiologists did not specifically inquire about subclinical neurological symptoms or prior neurological disease, anesthesiologists are advised to carefully inquire about prior neurological disease whether neuraxial anesthesia techniques are considered.


Assuntos
Anestesia Epidural/efeitos adversos , Raquianestesia/efeitos adversos , Doenças do Sistema Nervoso/complicações , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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