Thesis (Ph. D.)--Case Western Reserve University, 2006. / [School of Medicine] Department of Genetics. Includes bibliographical references. Available online via OhioLINK's ETD Center.

Thesis (Ph.D. in Epidemiology) -- University of Colorado at Denver and Health Sciences Center, 2005. / Typescript. Includes bibliographical references (leaves 95-118). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;

O presente estudo investigou a percepção de risco para o desenvolvimento de neoplasias e os comportamentos preventivos em indivíduos com suspeita de síndromes neoplásicas hereditárias. Teve como objetivos: descrever a percepção de risco e causas das principais neoplasias relacionadas a síndromes de câncer hereditário em usuários de um serviço de aconselhamento genético para câncer; associar comportamentos adotados para prevenção de tumores e história familiar dessa patologia; traçar um panorama da realização de exames preventivos e do acesso a informações sobre os mesmos na população estudada; e descrever o interesse desses indivíduos em ações educativas, no aconselhamento genético e na realização de testes genéticos preditivos para síndromes neoplásicas hereditárias. Foi selecionada uma amostra de conveniência, constituída de 51 usuários atendidos junto ao Ambulatório de Aconselhamento Genético do Câncer da Unidade de Genética Médica do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo. Após aprovação do estudo pelo Comitê de Ética em Pesquisa, realizou-se um estudo-piloto e a coleta de dados propriamente dita, durante o período de maio a outubro de 2009. Os dados foram coletados por meio de um instrumento desenvolvido para ser utilizado junto à população latina norte-americana, adaptado culturalmente para a realidade brasileira, contendo 22 questões e duas escalas tipo Likert, de cinco itens cada. Os dados foram obtidos mediante a aplicação do mesmo durante as consultas de enfermagem em aconselhamento genético oncológico. Utilizou-se estatística descritiva, o teste de Qui-quadrado e o teste não paramétrico Kruskal-Wallis para analisá-los. A maioria da amostra foi composta por sujeitos do sexo feminino (68,6%), com idade variável ente 18 e 40 anos. Os respondentes consideraram seu risco de câncer igual ao da população em geral, independente da história pessoal e/ou familiar dessa patologia. Os fatores emocionais/psicológicos foram apontados como a principal causa de câncer, seguido pela hereditariedade e o tabagismo, sendo que as mulheres consideram que a genética exerce um forte efeito sobre o risco da doença (?2 1=5,38, p=0,02). Não foi encontrada associação estatisticamente significativa entre a realização de exames preventivos e a história familiar de malignidades. A maior parte da amostra (n=38) relatou não ter as informações que necessita sobre o rastreamento de tumores e todos expressaram interesse em obter mais orientações sobre o seu risco pessoal para desenvolver câncer. A busca por esclarecimentos demonstra a preocupação dos clientes acometidos por neoplasias familiais ou hereditárias em compreender melhor os aspectos genéticos de sua doença. Os achados desse estudo evidenciam a necessidade de intervenção dos profissionais de saúde, em especial do enfermeiro, o qual pode desenvolver atividades educativas junto a essa clientela, como um dos componentes essenciais para o cuidado de enfermagem em oncogenética. / This study researched the perception of risk for developing cancer and preventive behaviors of individuals with suspect of hereditary cancer syndromes. It aimed to describe the perception of risk and causes of the main neoplasms related to hereditary cancer syndromes in a sample of users of a genetic counseling service for cancer; to associate behaviors adopted for the prevention of tumors and family history of cancer; to establish prospect of the performance of preventive exams and the access to information about them on the studied population; to describe the individuals\' interest in educative activities, genetic counseling and predictive genetic tests to hereditary cancer syndromes. A convenience sample of 51 individuals was selected in the Cancer Genetic Counseling Outpatient Clinic of the Medical Genetics Unit of the Hospital das Clinicas of the University of São Paulo at Ribeirão Preto Medical School. After the approval of the Research Ethics Committee, a pilot study was carried out and the data collection was performed between May and October 2009. For data collection, an instrument developed to be applied in a Latin North American population, and culturally adapted to the Brazilian reality, was used. It contained 22 questions and two 5-item Likert scales. Data were obtained by applying the instrument during the nursing cancer genetic counseling consultation. For analysis, descriptive statistics was used and the Qui-Square and Kruskal-Wallis tests. Most of the participants were women (68.6%), with an age variation ranging from 18 to 40 years. The respondents considered their own risk as being the same as the population\'s risk, independently of their personal or family history of this disease. Psychological and emotional factors were considered to be the main cause of cancer, followed by heredity and smoking, and women were more likely to believe that genetics has the strongest effect on the risk of cancer (?2 1=5.38, p=0.02). No significant statistical association was found between the accomplishment of preventive exams and family history of cancer. Most of the sample (n=38) reported not to have the information needed concerning tumor screening and all of them expressed interest in obtaining more information about guidance on their personal risk for developing cancer. The search for explanations demonstrates the concern of clients affected by familial or hereditary cancers in better understanding the genetic aspects of their illness. The findings highlight the need for intervention by health professionals, especially nurses, who may conduct educational activities to this population as an essential component of nursing care in cancer genetics.

Orientador: Iscia Teresinha Lopes-Cendes, Carmen Passos Lima / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-06T07:38:24Z (GMT). No. of bitstreams: 1 Viana_DaniloVilela_M.pdf: 17449794 bytes, checksum: 5628cf41f1e3b3dae3d2ad85bb64f5d4 (MD5) Previous issue date: 2006 / Resumo: O câncer de cólon e reto é a quinta causa de mortalidade por câncer no Brasil. Sua taxa de mortalidade vem apresentando um aumento contínuo desde 1979. Entre os fatores de risco mais importantes para essa doença está a história familial de câncer de cólon e reto ou de pólipos adenomatosos. O propósito do presente estudo foi investigar a qualidade das histórias familiais (HF) registradas nos prontuários médicos e estimar a freqüência dos agregados familiais e das síndromes hereditárias de câncer nos pacientes com diagnóstico de câncer de cólon e reto atendidos no Hospital de Clínicas da UNICAMP. Um estudo retrospectivo foi delineado para avaliar os prontuários dos pacientes que tinham confirmação histopatológica do diagnóstico de adenocarcinoma de cólon ou reto. Inicialmente, 415 prontuários que apresentavam codificação para a doença foram selecionados a partir do livro de cirurgias e de uma lista de pacientes atendidos nos ambulatórios de oncologia clínica, radioterapia e proctologia. Foram excluídos 104, sendo realizada a revisão de 311 prontuários. Numa segunda fase do estudo todos esses pacientes foram convocados para um entrevista com médico geneticista para obtenção de nova história familial, e comparação subseqüente dos dados, na qual a história familial previamente registrada foi classificada como completa ou incompleta. Dentre os 311 prontuários revisados, 193 (62%) tinham HF de câncer registrada. No total, 95 pacientes compareceram à entrevista, dos quais 66 tinha HF registrada no seu prontuário para que fosse feita comparação. Dessas 66 HF, 21 (32%) puderam ser consideradas completas e 45 (68%) incompletas. Pelo menos um critério clínico para câncer hereditário foi preenchido por 39 pacientes. Agregação familiar de CCR foi encontrada em 19% dos indivíduos entrevistados. Estes achados demonstram que a coleta e o correto preenchimento das histórias familiais nos prontuários dos pacientes com câncer são freqüentemente negligenciados, o que poderia influenciar negativamente na qualidade da assistência médica a eles prestada. As formas hereditárias de câncer hereditário, em especial a síndrome de Lynch (câncer colorretal hereditário sem polipose - HNPCC), são subdiagnosticadas, impossibilitando que medidas preventivas e diagnóstico precoce sejam oferecidos às suas famílias. / Abstract: Colorectal cancer is the 5th mortality cause by cancer in Brazil, and has been showing a continuous increase in mortality since 1979. Among the most important risk factors for this disease is family history of CRC or adenomatous polyps. The purpose of the present study was to investigate family histories (FH) recorded in medical charts for completeness and accuracy and to estimate the frequency of cancer aggregates and cancer syndromes in colorectal cancer patients treated in a general hospital. A retrospective study was assembled to evaluate archived charts of patients with pathological diagnosis of colorectal adenocarcinoma. Four hundred and fifteen medical records with ICD-10 coding of colorectal cancer were selected from the list of pacients who had had consultation in the clinical oncology, radiation oncology or proctology clinics, from which 104 were excluded because of misclassification or unconfirmed diagnosis. 311 charts were fully reviewed, and these patients invited for a personal interview by a medical geneticist. FH obtained from chart reviews were compared to data obtained from personal interviews and subsequently classified as complete or incomplete. Among the 311 charts, 193 (62%) had FH of cancer recorded. Overall, 95 patients attended the interviews, 66 of whom had a FH recorded in their hospital charts allowing accuracy comparisons. Of these, 21/66 (32%) FH could be considered complete and 45/66 (68%) incomplete. Thirty-nine patients met at least one criterion for hereditary cancer. Familial aggregates of colorectal cancer were found in 18 families (19%). In conclusion, the data in this study showed that FH in medical charts were often flawed or carried important omissions, which could influence negatively medical attention delivered to patients, and that hereditary forms of cancer, especially hereditary non-polyposis colorectal cancer, were underdiagnosed, making it impossible to extend the benefits of early diagnosis and preventive measures to at risk family members. / Mestrado / Genetica Medica / Mestre em Ciências Médicas

Abstract The currently known susceptibility genes account for approximately 25% of familial breast cancer predisposition. Additional factors contributing to the pathogenesis of breast cancer are, therefore, likely to be discovered. Most of the known genes affecting breast cancer predisposition function in the DNA damage response pathway. In this study three genes, TOPBP1, CLSPN and PALB2, involved in this complex process were investigated to reveal potentially pathogenic mutations associated with breast cancer susceptibility. In the analysis of the TOPBP1 gene, one novel putative pathogenic alteration was observed. The Arg309Cys variant was found at an elevated frequency among familial cases (19/125) vs. controls (49/697) (p = 0.002; OR 2.4; 95% CI 1.3–4.2). In addition, altogether 18 other germline alterations were observed in this gene, but they all appeared to be harmless polymorphisms. Investigation of CLSPN alterations among familial breast cancer families revealed altogether seven different changes. No clearly pathogenic alterations were observed. However, a potential modifier effect was discovered for the 1195delGlu change. The obtained results suggest that CLSPN alterations are unlikely to be significant breast cancer susceptibility alleles. In the PALB2 gene, a pathogenic mutation c.1592delT was identified at an elevated frequency among breast cancer patients (0.9%) compared to controls (0.2%) (p = 0.003, OR 3.94, 95% CI 1.5–12.1). Among familial cases the frequency of c.1592delT was even higher (2.7%). This mutation was also functionally deficient. It had a markedly decreased BRCA2-binding affinity and was unable to support homologous recombination or to restore cross link repair in PALB2 knock-down cells. Additionally, this mutation was discovered in a familial prostate cancer family and was found to segregate with the disease, suggesting some association also with prostate cancer. The penetrance and hazard ratio associated with PALB2 c.1592delT were determined in unselected breast cancer families. A substantially increased risk of breast cancer (HR 6.1; 95% CI 2.2–17.2; p = 0.01) was discovered resulting in an estimated 40% (95% CI 17–77) breast cancer risk by age 70 years, comparable to that for carriers of BRCA2 mutations. This markedly increased cancer risk suggests that genetic counselling for carriers is needed and screening for this mutation should be considered.

Abstract Mutations in BRCA1 and BRCA2 explain only about 20% of familial aggregation of breast cancer, suggesting involvement of additional susceptibility genes. In this study five DNA damage response genes, ATM, ATR, MRE11, NBS1 and RAD50, were considered as putative candidates to explain some of the remaining familial breast cancer risk, and were screened for germline mutations in families displaying genetic predisposition. Analysis of ATM indicated that clearly pathogenic mutations seem to be restricted to those reported in ataxia-telangiectasia (A-T). However, a cancer risk modifying effect was suggested for a combination of two ATM polymorphisms, 5557G>A and IVS38-8T>C, as this allele seemed to associate with bilateral breast cancer (OR 10.2, 95% CI 3.1–33.8, p = 0.001). The relevance of ATM mutations, originally identified in Finnish A-T patients, in breast cancer susceptibility was evaluated by a large case-control study. Two such alleles, 6903insA and 7570G>C, in addition to 8734A>G previously associated with breast cancer susceptibility, were observed. The overall mutation frequency in unselected cases (7/1124) was higher than in controls (1/1107), but a significantly elevated frequency was observed only in familial cases (6/541, p = 0.006, OR 12.4, 95% CI 1.5–103.3). These three mutations showed founder effects in their geographical occurrence, and had different functional consequences at protein level. In ATR no disease-related mutations were observed, suggesting that it is not a breast cancer susceptibility gene. The mutation screening of the Mre11 complex genes, MRE11, NBS1 and RAD50, revealed two novel potentially breast cancer associated alleles: NBS1 Leu150Phe and RAD50 687delT were observed in 2.0% (3/151) of the studied families. The subsequent study of newly diagnosed, unselected breast cancer cases indicated that RAD50 687delT is a relatively common low-penetrance susceptibility allele in Northern Finland (cases 8/317 vs. controls 6/1000, OR 4.3, 95% CI 1.5–12.5, p = 0.008). NBS1 Leu150Phe (2/317) together with a novel RAD50 IVS3-1G>A mutation (1/317) was also observed, both being absent from controls. Loss of the wild-type allele was not observed in the tumors of the studied mutation carriers, but they all showed an increase in chromosomal instability of peripheral T-lymphocytes. This suggests an effect for RAD50 and NBS1 haploinsufficiency on genomic integrity and susceptibility to cancer.

The cause for childhood acute lymphoblastic leukemia (ALL) remains unknown, but male gender is a risk factor, and among ethnicities, Hispanics have the highest risk. In this dissertation, we explored correlations among genetic polymorphisms, birth characteristics, and the risk of childhood ALL in a multi-ethnic sample in 161 cases and 231 controls recruited contemporaneously (2007-2012) in Houston, TX. We first examined three lymphoma risk markers, since lymphoma and ALL both stem from lymphoid cells. Of these, rs2395185 showed a risk association in non-Hispanic White males (OR=2.8, P=0.02; Pinteraction=0.03 for gender), but not in Hispanics. We verified previously known risk associations to validate the case-control sample. Mutations of HFE (C282Y, H63D) were genotyped to test whether iron-regulatory gene (IRG) variants known to elevate iron levels increase childhood ALL risk. Being positive for either polymorphism yielded only a modestly elevated OR in males, which increased to 2.96 (P=0.01) in the presence of a particular transferrin receptor (TFRC) genotype for rs3817672 (Pinteraction=0.04). SNP rs3817672 itself showed an ethnicity-specific association (Pinteraction=0.02 for ethnicity). We then examined additional IRG SNPs (rs422982, rs855791, rs733655), which showed risk associations in males (ORs=1.52 to 2.60). A polygenic model based on the number of polymorphic alleles in five IRG SNPs revealed a linear increase in risk (OR=2.00 per incremental change; P=0.002). Having three or more alleles compared with none was associated with increased risk in males (OR=4.12; P=0.004). Significant risk associations with childhood ALL was found with birth length (OR=1.18 per inch, P=0.04), high birth weight (>4,000g) (OR=1.93, P=0.01), and with gestational age (OR=1.10 per week, P=0.04). We observed a negative correlation between HFE SNP rs9366637 and gestational age (P=0.005), again, stronger in males (P=0.001) and interacting with TFRC (PPinteraction=0.05). Our results showed that (i) ALL risk markers do not show universal associations across ethnicities or between genders, (ii) IRG SNPs modify ALL risk presumably by their effects on iron levels, (iii) a negative correlation between an HFE SNP and gestational age exists, which implicates an iron-related mechanism. The results suggest that currently unregulated supplemental iron intake may have implications on childhood ALL development.

Muitos estudos têm sido conduzidos em diferentes populações visando a identificação da proporção da variância fenotípica total atribuída a efeitos genéticos. A herdabilidade de fatores de risco relacionados à Síndrome Metabólica apresenta variações entre populações, tanto por causa da diferente distribuição de fatores de risco ambientais quanto pela variação genética presente em populações distintas. O objetivo desta análise foi avaliar as influências genéticas e ambientais dos componentes da Síndrome Metabólica, usando uma análise de componentes de variância, estimando a herdabilidade destes fatores em uma amostra de extensas famílias. Nós examinamos 1.712 indivíduos de 119 famílias selecionadas randomicamente da população geral de uma cidade do Brasil. Um total de 1.666 indivíduos de 81 famílias foi usado para análises. O tamanho das famílias variou de 3 a 156 indivíduos com uma média de 21 indivíduos por família. Antes de ajustes, as herdabilidades poligênicas da pressão sistólica (PAS) e diastólica (PAD) foram de 15 e 16,4%, circunferência abdominal de 26,1%, glicemia de 32,8%, triglicérides de 25,7% e HDL-c de 31,2%. Ajuste para idade, sexo, idade2 e interação sexo x idade aumentou as estimativas de herdabilidade para todos os traços: PAS (25,9%), PAD (26,2%), circunferência abdominal (40,1%), glicemia de jejum (34,5%), triglicérides (28,8%) e HDL-c (32,0%). Quando os fatores de risco para Síndrome Metabólica foram tratados como traços discretos, utilizando pontos de corte segundo critérios do ATPIII, as estimativas de herdabilidade, após ajuste para covariáveis, foram: 24,5% para SM, 37,5% para pressão arterial, 40,6% para circunferência abdominal, 54,5% para glicemia, 25,5% para triglicérides e 37,8% para HDL-c. Em conclusão, as estimativas de herdabilidade para os traços da síndrome metabólica em uma amostra da população brasileira são altas e não significativamente diferente de outros estudos em populações mundiais / Many studies have been conducted in different populations aiming at the identification of the proportion of total phenotypic variance that is attributable to genetic effects. The heritability of Metabolic Syndrome (MS) factors is expected to differ between populations because of the different distribution of environmental risk factors, as well as the genetic make-up of different human populations. The purpose of this analysis was to evaluate genetic and environmental influences on metabolic syndrome traits, using a variance component analysis, by estimating the heritability of these traits in a sample of extended pedigrees. We examined 1,712 individuals of 119 randomly selected families from the general population of a city of Brazil. A total of 1,666 individuals of 81 families were used for analysis. Family size varied from 3 to 156 individuals with a mean of 21 subjects per family. Before adjustment, polygenic heritability of systolic (SBP) and diastolic (DBP) blood pressure were 15% and 16.4%, waist circumference 26.1%, fasting glucose 32.8%, triglycerides 25.7%, and HDL-c 31.2%. Adjustment for age, sex, age2, age and sex interaction increased polygenic heritability estimates for all traits: SBP (25.9%), DBP (26.2%), waist circumference (40.1%), fasting glucose (34.5%), triglycerides (28.8%), and HDL-c (32,0%). When the Metabolic Syndrome factors were treated as discrete traits, using ATPIII cut off, the estimates of heritability after adjusting for covariates were: 24.5% for MS, 37.5% for blood pressure, 40.6% for abdominal circumference, 54.5% for fasting glucose, 25.5% for triglycerides, and 37.8% for HDL-cholesterol. In conclusion, heritability estimates for metabolic syndrome traits in a sample of Brazilian population are high and not significantly different from other studied worldwide populations

The present study evaluated genetic and metabolic factors influencing the risk of acute cerebrovascular disease (CVD) and internal carotid artery stenosis (ICA stenosis) in a Swedish community. The threonine (T) containing protein of the FABP2 A54T gene polymorphism has a greater affinity for long chain fatty acids (FFAs) than the alanine (A) containing protein. This altered affinity for FFAs has been shown to affect the intestinal absorption of fatty acids and consequently the fatty acid composition of serum lipids, in particularly postprandially. Endothelium derived NO is a potent vasodilator and antiatherogenic agent. Asymmetric dimethyl arginine (ADMA) is an endogenous competitive inhibitor of endothelial nitric oxide synthase (eNOS). ADMA has been shown to be involved in the pathogenesis of atherosclerotic disease, and ADMA inhibits eNOS by displacement of L-arginine from the enzyme, which in turn is believed to affect the amount of NO available within the endothelium. The FABP2 A54T gene polymorphism was analyzed in 407 patients with acute CVD and also in a subset of these patients whose carotids had been evaluated with ultrasound. Both the FABP2 polymorphism and a common polymorphism of the eNOS gene, Glu298Asp, were analyzed in a different population consisting of 54 matched pairs of patients with ICA stenosis and controls. ADMA levels were measured in both study populations. We found that the T54 allele was more frequent in patients with transient ischaemic attacks (TIA), and that the TT genotype was more prevalent in young, non-smoking patients with CVD than in controls. Increased concentrations of ADMA were observed in cardio-embolic infarction and TIA, but not significantly in non-cardio-embolic infarction nor in haemorrhagic stroke. In multivariate logistic regression models, CVD increased across quartiles of ADMA in all subgroups, but this association was only significant in the TIA group. A decreased arginine/ADMA ratio, a measure of NO availability was associated with CVD in the entire study population. Patients with severe carotid stenosis had significantly higher ADMA levels than the controls. Allele and genotype frequencies of the FABP2 and eNOS polymorphisms did not differ between patients with ICA stenosis and controls. Our results indicate that ADMA is a strong marker for TIA and severe ICA stenosis, and that relative defiency of arginine, measured as L-arginine/ADMA, is present in acute CVD. We also conclude that a common polymorphism of the FABP2 gene increases susceptibility to ischaemic stroke and TIA. / Figure 4 on page 17 is publshed with kind permisson from The Journal of Physiology (http://jp.physoc.org/).

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010.