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2.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31519528

RESUMO

Gestational diabetes mellitus (GDM) increases the risk of adverse events in pregnancy and jeopardizes long-term health of the mother and offspring. There is currently no consensus as to what screening strategies improve the efficiency of GDM diagnosis. Which criteria should be used? Is the one-step or two-step procedure better? There is no agreement as to what the best dietary approach in the treatment of GDM is. In addition, different nutritional interventions have been studied in the prevention of GDM. The Mediterranean diet seems to be effective in preventing GDM and other maternofoetal outcomes. We review herein our experience using the one-step criteria for GDM screening; the treatment and prevention strategies used; and the overall impact of nutrition on maternofoetal health.

3.
J Clin Med ; 8(9)2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31546914

RESUMO

An early antenatal dietary intervention could play an important role in the prevention of metabolic diseases postpartum. The aim of this study is to evaluate whether an early, specific dietary intervention reduces women's cardiovascular risk in the "fourth trimester". This prospective cohort study compares 1675 women from the standard-care group (ScG/n = 676), who received standard-care dietary guidelines, with the intervention group (IG/n = 999), who received Mediterranean diet (MedDiet)-based dietary guidelines, supplemented with extra-virgin olive oil and nuts. Cardiovascular risk was determined by the presence of metabolic syndrome (MetS) and insulin resistance syndrome (IrS) (HOMA-IR 3.5) at 12-14 weeks postpartum. MetS was less frequent in the IG (11.3 vs. 19.3%, p < 0.05). The intervention was associated with a reduction in the relative risk of having MetS: 0.74 (95% CI, 0.60-0.90), but not in the risk of IrS. When analyzing the presence of having one or more components of the MetS, the IG had significantly higher rates of having 0 components and lower rates of having ≥1 (p-trend = 0.029). An early MedDiet-based nutritional intervention in pregnancy is associated with reductions in postpartum rates of MetS.

4.
Sci Rep ; 9(1): 9020, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227763

RESUMO

The cancer-predisposing syndrome caused by biallelic mutations in NTHL1 may not be a solely colorectal cancer (CRC) and polyposis syndrome but rather a multi-tumor recessive disease. The presence of ≤10 adenomas in several mutation carriers suggests a possible causal role of NTHL1 in hereditary or early-onset nonpolyposis CRC. The involvement of NTHL1 in serrated/hyperplastic polyposis remains unexplored. The aim of our study is to elucidate the role of NTHL1 in the predisposition to personal or familial history of multiple tumor types, familial/early-onset nonpolyposis CRC, and serrated polyposis. NTHL1 mutational screening was performed in 312 cancer patients with personal or family history of multiple tumor types, 488 with hereditary nonpolyposis CRC, and 96 with serrated/hyperplastic polyposis. While no biallelic mutation carriers were identified in patients with personal and/or family history of multiple tumor types or with serrated polyposis, one was identified among the 488 nonpolyposis CRC patients. The carrier of c.268C>T (p.Q90*) and 550-1G>A was diagnosed with CRC and meningioma at ages 37 and 45 respectively, being reclassified as attenuated adenomatous polyposis after the cumulative detection of 26 adenomas. Our findings suggest that biallelic mutations in NTHL1 rarely cause CRC, a personal/familial multi-tumor history, or serrated polyposis, in absence of adenomas.

5.
Hum Mutat ; 40(11): 1910-1923, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31243857

RESUMO

Technological advances have allowed the identification of new adenomatous and serrated polyposis genes, and of several candidate genes that require additional supporting evidence of causality. Through an exhaustive literature review and mutational screening of 177 unrelated polyposis patients, we assessed the involvement of MCM9, FOCAD, POLQ, and RNF43 in the predisposition to (nonserrated) colonic polyposis, as well as the prevalence of NTHL1 and MSH3 mutations among genetically unexplained polyposis patients. Our results, together with previously reported data and mutation frequency in controls, indicate that: MCM9 and POLQ mutations are not associated with polyposis; germline RNF43 mutations, with a prevalence of 1.5-2.5% among serrated polyposis patients, do not cause nonserrated polyposis; MSH3 biallelic mutations are highly infrequent among European polyposis patients, and the prevalence of NTHL1 biallelic mutations among unexplained polyposes is ~2%. Although nonsignificant, FOCAD predicted deleterious variants are overrepresented in polyposis patients compared to controls, warranting larger studies to provide definite evidence in favor or against their causal association with polyposis predisposition.

6.
Nutrients ; 11(6)2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31141972

RESUMO

We reported that a Mediterranean Diet (MedDiet), supplemented with extra-virgin olive oil (EVOO) and pistachios, reduces GDM incidence and several other adverse outcomes. In order to assess its translational effects in the real world we evaluated the effect of MedDiet from 1st gestational visit in GDM rate compared with control (CG) and intervention (IG) groups from the previously referred trial. As secondary objective we also compared adverse perinatal outcomes between normoglycemic and diabetic women. This trial is a prospective, clinic-based, interventional study with a single group. 1066 eligible normoglycaemic women before 12 gestational weeks were assessed. 932 women (32.4 ± 5.2 years old, pre-gestational BMI 22.5 ± 3.5 kg/m2) received a motivational lifestyle interview with emphasis on daily consumption of EVOO and nuts, were followed-up and analysed. Binary regression analyses were used to examine the risk for each pregnancy outcome, pregnancy-induced hypertension, preeclampsia, gestational weight gain (GWG), caesarean-section, perineal trauma, preterm delivery, small (SGA) and large for gestational age (LGA), and Neonatal Intensive Care Unit admissions. GDM was diagnosed in 13.9%. This rate was significantly lower than the CG: RR 0.81 (0.73-0.93), p < 0.001 and no different from the IG: RR 0.96 (0.85-1.07), p = 0.468. GWG was lower in diabetic women (10.88 ± 6.46 vs. 12.30 ± 5.42 Kg; p = 0.013). Excessive weight gain (EWG) was also lower in GDM [RR 0.91 (0.86-0.96); p < 0.001] without a significant increase of insufficient weight gain. LGA were also lower (1 (0.8%) vs. 31 (3.9%); p < 0.05)), and SGA were similar (5 (3.8%) vs. 30 (3.7%)). LGA were associated to EWG (RR 1.61 (1.35-1.91), p < 0.001). Differences in other maternal-foetal outcomes were not found. In conclusions an early MedDiet nutritional intervention reduces GDM incidence and maternal-foetal adverse outcomes and should be universally applied as 1st line therapy. GDM might not be consider as a high risk pregnancy any longer.


Assuntos
Diabetes Gestacional/prevenção & controle , Dieta Mediterrânea , Entrevista Motivacional , Educação de Pacientes como Assunto , Resultado da Gravidez , Adulto , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Gestacional/sangue , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/epidemiologia , Feminino , Hemoglobina A Glicada/metabolismo , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Incidência , Insulina/sangue , Fenômenos Fisiológicos da Nutrição Materna , Estado Nutricional , Valor Nutritivo , Gravidez , Estudos Prospectivos , Recomendações Nutricionais , Medição de Risco , Fatores de Risco , Espanha/epidemiologia
7.
Mol Aspects Med ; 69: 10-26, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30862463

RESUMO

The present article summarizes recent developments in the characterization of genetic predisposition to colorectal cancer (CRC). The main themes covered include new hereditary CRC and polyposis syndromes, non-CRC hereditary cancer genes found mutated in CRC patients, strategies used to identify novel causal genes, and review of candidate genes that have been proposed to predispose to CRC and/or colonic polyposis. We provide an overview of newly described genes and syndromes associated with predisposition to CRC and polyposis, including: polymerase proofreading-associated polyposis, NTHL1-associated polyposis, mismatch repair gene biallelic inactivation-related adenomatous polyposis (including MSH3- and MLH3-associated polyposes), GREM1-associated mixed polyposis, RNF43-associated serrated polyposis, and RPS20 mutations as a rare cause of hereditary nonpolyposis CRC. The implementation of next generation sequencing approaches for genetic testing has exposed the presence of pathogenic germline variants in genes associated with hereditary cancer syndromes not traditionally linked to CRC, which may have an impact on genetic testing, counseling and surveillance. The identification of new hereditary CRC and polyposis genes has not deemed an easy endeavor, even though known CRC-related genes explain a small proportion of the estimated familial risk. Whole-genome sequencing may offer a technology for increasing this proportion, particularly if applied on pedigree data allowing linkage type of analysis. The final section critically surveys the large number of candidate genes that have been recently proposed for CRC predisposition.

8.
Cancer Cell ; 35(2): 256-266.e5, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30753826

RESUMO

Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n = 10) or multiple (n = 16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in female carriers (60%). Mutational signature analysis of 14 tumors from 7 organs revealed that NTHL1 deficiency underlies the main mutational process in all but one of the tumors (93%). These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome.


Assuntos
Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Desoxirribonuclease (Dímero de Pirimidina)/genética , Perfilação da Expressão Gênica , Mutação em Linhagem Germinativa , Síndromes Neoplásicas Hereditárias/genética , Transcriptoma , Adulto , Idoso , Biomarcadores Tumorais/deficiência , Reparo do DNA/genética , Desoxirribonuclease (Dímero de Pirimidina)/deficiência , Europa (Continente) , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Hereditariedade , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/enzimologia , Síndromes Neoplásicas Hereditárias/patologia , Linhagem , Fenótipo , Medição de Risco , Fatores de Risco , Adulto Jovem
9.
Cancer Lett ; 447: 86-92, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30677446

RESUMO

Somatic epigenetic inactivation of the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) is frequent in colorectal cancer (CRC); however, its involvement in CRC predisposition remains unexplored. We assessed the role and relevance of MGMT germline mutations and epimutations in familial and early-onset CRC. Mutation and promoter methylation screenings were performed in 473 familial and/or early-onset mismatch repair-proficient nonpolyposis CRC cases. No constitutional MGMT inactivation by promoter methylation was observed. Of six rare heterozygous germline variants identified, c.346C > T (p.H116Y) and c.476G > A (p.R159Q), detected in three and one families respectively, affected highly conserved residues and showed segregation with cancer in available family members. In vitro, neither p.H116Y nor p.R159Q caused statistically significant reduction of MGMT repair activity. No evidence of somatic second hits was found in the studied tumors. Case-control data showed over-representation of c.346C > T (p.H116Y) in familial CRC compared to controls, but no overall association of MGMT mutations with CRC predisposition. In conclusion, germline mutations and constitutional epimutations in MGMT are not major players in hereditary CRC. Nevertheless, the over-representation of c.346C > T (p.H116Y) in our familial CRC cohort warrants further research.


Assuntos
Neoplasias Colorretais/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Células Germinativas/fisiologia , Mutação em Linhagem Germinativa/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Metilação de DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Adulto Jovem
10.
Ann Nutr Metab ; 74(1): 69-79, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30554220

RESUMO

AIMS: The aim of the study was to evaluate the effect of a Mediterranean diet (MedDiet), enhanced with extra virgin olive oil (EVOO) and nuts, on a composite of adverse maternofoetal outcomes of women with normoglycemia during pregnancy. METHODS: This was a sub-analysis of the St Carlos gestational diabetes mellitus Prevention Study. Only normoglycemic women were analysed (697). They were randomized (at 8-12th gestational weeks) to: standard-care control group (337), where fat consumption was limited to 30% of total caloric intake; or intervention group (360), where a MedDiet, enhanced with EVOO and pistachios (40-42% fats of total caloric intake) was recommended. The primary outcome was a composite of maternofoetal outcomes (CMFOs): at least having 1 event of emergency C-section, perineal trauma, pregnancy-induced hypertension and preeclampsia, prematurity, large-for-gestational-age and small-for gestational-age. RESULTS: Crude relative risk showed that the intervention was associated with a significant reduction in the risk of CMFOs (0.48 [0.37-0.63]; p = 0.0001), with a number-needed-to-treat = 5. Risk of urinary tract infections, emergency C-sections, perineal trauma, large-for-gestational-age and small-for gestational age new-borns were also significantly reduced. CONCLUSION: A MedDiet, enhanced with EVOO and nuts, was associated with a risk reduction of CMFOs in over 50% in normoglycemic pregnant women. Therefore, it might be a potentially adequate diet for pregnant women. TRIAL REGISTRATION: Identifier ISRCTN84389045. The study was registered on September 27, 2013. Last edited on September 26, 2018.

11.
J Pathol ; 247(5): 574-588, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30584801

RESUMO

This article reviews genes and syndromes associated with predisposition to colorectal cancer (CRC), with an overview of gene variant classification. We include updates on the application of preventive and therapeutic measures, focusing on the use of non-steroidal anti-inflammatory drugs (NSAIDs) and immunotherapy. Germline pathogenic variants in genes conferring high or moderate risk to cancer are detected in 6-10% of all CRCs and 20% of those diagnosed before age 50. CRC syndromes can be subdivided into nonpolyposis and polyposis entities, the most common of which are Lynch syndrome and familial adenomatous polyposis, respectively. In addition to known and novel genes associated with highly penetrant CRC risk, identification of pathogenic germline variants in genes associated with moderate-penetrance cancer risk and/or hereditary cancer syndromes not traditionally linked to CRC may have an impact on genetic testing, counseling, and surveillance. The use of multigene panels in genetic testing has exposed challenges in the classification of variants of uncertain significance. We provide an overview of the main classification systems and strategies for improving these. Finally, we highlight approaches for integrating chemoprevention in the care of individuals with genetic predisposition to CRC and use of targeted agents and immunotherapy for treatment of mismatch repair-deficient and hypermutant tumors. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Neoplasias Colorretais/genética , Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/terapia , Genes Neoplásicos/genética , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Humanos , Mutação/genética , Penetrância , Medicina de Precisão/métodos
12.
BMJ Open Diabetes Res Care ; 6(1): e000550, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30397489

RESUMO

Objectives: To assess whether Mediterranean Diet (MedDiet)-based medical nutrition therapy facilitates near-normoglycemia in women with gestational diabetes mellitus (GDMw) and observe the effects on adverse pregnancy outcomes. Research design and methods: This is a secondary analysis of the St Carlos GDM Prevention Study, conducted between January and December 2015 in Hospital Clínico San Carlos (Madrid, Spain). One thousand consecutive women with normoglycemia were included before 12 gestational weeks (GWs), with 874 included in the final analysis. Of these, 177 women were diagnosed with gestational diabetes mellitus (GDM) and 697 had normal glucose tolerance. All GDMw received MedDiet-based medical nutrition therapy with a recommended daily extra virgin olive oil intake ≥40 mL and a daily handful of nuts. The primary goal was comparison of hemoglobin A1c (HbA1c) levels at 36-38 GWs in GDMw and women with normal glucose tolerance (NGTw). Results: GDMw as compared with NGTw had higher HbA1c levels at 24-28 GWs (5.1%±0.3% (32±0.9 mmol/mol) vs 4.9%±0.3% (30±0.9 mmol/mol), p=0.001). At 36-38 GWs values were similar between the groups. Similarly, fasting serum insulin and homeostatic model assessment insulin resitance (HOMA-IR) were higher in GDMw at 24-28 GWs (p=0.001) but became similar at 36-38 GWs. 26.6% of GDMw required insulin for glycemic control. GDMw compared with NGTw had higher rates of insufficient weight gain (39.5% vs 22.0%, p=0.001), small for gestational age (6.8% vs 2.6%, p=0.009), and neonatal intensive care unit admission (5.6% vs 1.7%, p=0.006). The rates of macrosomia, large for gestational age, pregnancy-induced hypertensive disorders, prematurity and cesarean sections were comparable with NGTw. Conclusions: Using a MedDiet-based medical nutrition therapy as part of GDM management is associated with achievement of near-normoglycemia, subsequently making most pregnancy outcomes similar to those of NGTw.

13.
Br J Cancer ; 119(8): 971-977, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30283144

RESUMO

BACKGROUND: Genome-wide association studies on colorectal cancer have identified more than 60 susceptibility loci, but for most of them there is no clear knowledge of functionality or the underlying gene responsible for the risk modification. Expression quantitative trail loci (eQTL) may provide functional information for such single nucleotide polymorphisms (SNPs). METHODS: We have performed detailed eQTL analysis specific for colon tissue on a series of 97 colon tumours, their paired adjacent normal mucosa and 47 colon mucosa samples donated by healthy individuals. R package MatrixEQTL was used to search for genome-wide cis-eQTL and trans-eQTL fitting linear models adjusted for age, gender and tissue type to rank transformed expression data. RESULTS: The cis-eQTL analyses has revealed 29,073 SNP-gene associations with permutation-adjusted P-values < 0.01. These correspond to 363 unique genes. The trans-eQTL analysis identified 10,665 significant SNP-gene associations, most of them in the same chromosome, further than 1 Mb of the gene. We provide a web tool to search for specific SNPs or genes. The tool calculates Pearson or Spearman correlation, and allows to select tissue type for analysis. Data and plots can be exported. CONCLUSIONS: This resource should be useful to prioritise SNPs for further functional studies and to identify relevant genes behind identified loci.


Assuntos
Neoplasias do Colo/genética , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Colo/patologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos
14.
Gac Med Mex ; 154(3): 302-309, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30047939

RESUMO

Introducción: En el Estado de México no existen investigaciones que proporcionen información para toma de decisiones y administración de recursos relacionados con la atención de las lesiones por causa externa (LCE). Objetivo: Describir las LCE en un servicio de urgencias durante un periodo de cinco años. Método: Se diseñó un estudio retrospectivo con pacientes que ingresaron al servicio de urgencias (2010-2015) por diagnóstico de LCE. Se realizó análisis descriptivo y de clúster. Resultados: En el servicio de urgencias, 16.59 % de las atenciones derivaron de LCE. Se incluyeron 16 567 pacientes de 14 a 99 años (media o promedio = 37.7, DE = 17.28), 69.2 % fue del sexo masculino. Las LCE principalmente ocurrieron en la vía pública (26.3 %) y en el hogar (23.7 %). Las causas más frecuentes fueron agresiones fuera del hogar (32.7 %), en promedio a los 34 años; caídas (25 %) en promedio a los 45 años; accidentes ocasionados por vehículos de motor (9.7 %), en promedio a los 33 años. El análisis por clúster identificó cuatro grupos: agresiones fuera del hogar 32.7 % (5417), contactos traumáticos 26.30 % (4363), accidentes de tránsito 15.9 % (2,640) y caídas 25 % (4147). Conclusión: Las LCE relacionadas con vehículos de motor mostraron consecuencias más severas. Background: In the State of Mexico there are no investigations that provide information for decision-making and administration of resources related to the care of externally-caused injuries (ECI). Objective: To describe ECIs seen in an emergency department over a 5-year period. Method: A retrospective study was designed with patients admitted to emergency department (2010-2015) with ECI diagnosis. Descriptive and cluster analyses were performed. Results: At the emergency department, 16.59% of emergency care was related to ECI. A total of 16,567 patients of 14 to 99 years of age (average = 37.7; SD = 17.28) were included; 69.2% were males. ECIs occurred mainly in public places (26.3%) and at home (23.7%). The main causes were aggression outside the home (32.7%), on average at 34 years of age, falls (25%) on average at 45 years, and motor vehicle accidents (9.7%) on average at 33 years. The cluster analysis identified four groups: aggression outside the home 32.7% (5,417), traumatic contacts, 26.30% (4,363), road traffic accidents 15.9% (2,640) and falls 25% (4,147). Conclusions: Motor vehicle accident-related ECIs showed the most severe consequences.


Assuntos
Serviço Hospitalar de Emergência , Ferimentos e Lesões/epidemiologia , Ferimentos e Lesões/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Adulto Jovem
15.
Biochim Biophys Acta Mol Basis Dis ; 1864(9 Pt B): 2992-3000, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29908233

RESUMO

Telomeres are repetitive sequences (TTAGGG) located at the end of chromosomes. Telomeres progressively shorten with each cell replication cycle, ultimately leading to chromosomal instability and loss of cell viability. Telomere length anomaly appears to be one of the earliest and most prevalent genetic alterations in malignant transformation. Here we aim to estimate telomere length from whole-exome sequencing data in colon tumors and normal colonic mucosa, and to analyze the potential association of telomere length with clinical factors and gene expression in colon cancer. Reads containing at least five repetitions of the telomere sequence (TTAGGG) were extracted from the raw sequences of 42 adjacent normal-tumor paired samples. The number of reads from the tumor sample was normalized to build the Tumor Telomere Length Ratio (TTLR), considered an estimation of telomere length change in the tumor compared to the paired normal tissue. We evaluated the associations between TTLR and clinical factors, gene expression and copy number (CN) aberrations measured in the same tumor samples. Colon tumors showed significantly shorter telomeres than their paired normal samples. No significant association was observed between TTLR and gender, age, tumor location, prognosis, stromal infiltration or molecular subtypes. The functional gene set enrichment analysis showed pathways related to immune response significantly associated with TLLR. By extracting a relative measure of telomere length from whole-exome sequencing data, we have assessed that colon tumor cells predominantly shorten telomeres, and this alteration is associated with expression changes in genes related to immune response and inflammation in tumor cells.


Assuntos
Neoplasias do Colo/genética , Encurtamento do Telômero/genética , Telômero/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Instabilidade Cromossômica/genética , Colo/imunologia , Colo/patologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Variações do Número de Cópias de DNA/imunologia , Conjuntos de Dados como Assunto , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Encurtamento do Telômero/imunologia , Sequenciamento Completo do Exoma
16.
Hum Mutat ; 39(9): 1214-1225, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29900613

RESUMO

The causal association of NUDT1 (=MTH1) and OGG1 with hereditary colorectal cancer (CRC) remains unclear. Here, we sought to provide additional evidence for or against the causal contribution of NUDT1 and OGG1 mutations to hereditary CRC and/or polyposis. Mutational screening was performed using pooled DNA amplification and targeted next-generation sequencing in 529 families (441 uncharacterized MMR-proficient familial nonpolyposis CRC and 88 polyposis cases). Cosegregation, in silico analyses, in vitro functional assays, and case-control associations were carried out to characterize the identified variants. Five heterozygous carriers of novel (n = 1) or rare (n = 4) NUDT1 variants were identified. In vitro deleterious effects were demonstrated for c.143G>A p.G48E (catalytic activity and protein stability) and c.403G>T p.G135W (protein stability), although cosegregation data in the carrier families were inconclusive or nonsupportive. The frequency of missense, loss-of-function, and splice-site NUDT1 variants in our familial CRC cohort was similar to the one observed in cancer-free individuals, suggesting lack of association with CRC predisposition. No OGG1 pathogenic mutations were identified. Our results suggest that the contribution of NUDT1 and OGG1 germline mutations to hereditary CRC and to polyposis is inexistent or, at most, negligible. The inclusion of these genes in routine genetic testing is not recommended.


Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , DNA Glicosilases/genética , Enzimas Reparadoras do DNA/genética , Monoéster Fosfórico Hidrolases/genética , Polipose Adenomatosa do Colo/patologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo do DNA/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética/genética , Genótipo , Mutação em Linhagem Germinativa/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação com Perda de Função/genética , Masculino , Mutação de Sentido Incorreto/genética , Estresse Oxidativo , Isoformas de Proteínas/genética
17.
Oncotarget ; 9(13): 11170-11179, 2018 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-29541405

RESUMO

Highly penetrant cancer syndromes account for less than 5% of all cases with familial colorectal cancer (CRC), and other genetic contribution explains the majority of the genetic contribution to CRC. A CRC susceptibility locus on chromosome 9q has been suggested. In this study, families where risk of CRC was linked to the region, were used to search for predisposing mutations in all genes in the region. No disease-causing mutation was found. Next, haplotype association studies were performed in the region, comparing Swedish CRC cases (2664) and controls (4782). Two overlapping haplotypes were suggested. One 10-SNP haplotype was indicated in familial CRC (OR 1.4, p = 0.00005) and one 25-SNP haplotype was indicated in sporadic CRC (OR 2.2, p = 0.0000012). The allele frequencies of the 10-SNP and the 25-SNP haplotypes were 13.7% and 2.5% respectively and both included one RNA, RP11-332M4.1 and RP11-l80l4.2, in the non-overlapping regions. The sporadic 25-SNP haplotype could not be studied further, but the familial 10-SNP haplotype was analyzed in 61 additional CRC families, and 6 of them were informative for all markers and had the risk haplotype. Targeted sequencing of the 10-SNP region in the linked families identified one variant in RP11-332M4.1, suggestive to confer the increased CRC risk on this haplotype. Our results support the presence of two loci at 9q22.32, each with one RNA as the putative cause of increased CRC risk. These RNAs could exert their effect through the same, or different, genes/pathways, possibly through the regulation of neighboring genes, such as PTCH1, FANCC, DKFZP434H0512, ERCC6L2 or the processed transcript LINC00046.

18.
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
20.
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
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