Gene polymorphism analysis cell cycle control in medullary thyroid carcinoma

Orientadores: Laura Sterian Ward, Lígia Vera Montalli AssumpçãoTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: O câncer de tireoide representa cerca de 2% de todas as neoplasias humanas e a sua incidência está aumentando no mundo todo tendo dobrado nas últimas três décadas. No Brasil, há uma previsão de 6.960 novos casos em 2016, fazendo com que o câncer de tireoide atinja a oitava posição entre as neoplasias malignas mais frequentes na mulher. Os carcinomas medulares da tireoide derivam das células C ou parafoliculares, estes são responsáveis por menos de 3% dos carcinomas tireoidianas. O carcinoma medular é principalmente esporádico (70-80%), mas o padrão hereditário está presente em 20 a 30% dos casos. Devido a isso, nosso grupo vem se empenhando ativamente na busca tanto de marcadores de malignidade quanto de agressividade. Em especial, demonstramos que vários polimorfismos gênicos estão associados ao risco de câncer de tireoide. O ciclo celular representa uma série altamente regulada de eventos que levam à reprodução de células. A fase de progressão do ciclo celular é regulada principalmente por ciclinas, quinases dependentes de ciclina (CDK) e os inibidores de CDK (CDKIs). Ciclinas e CDKs formam complexos que regulam o crescimento celular pela marcação e fosforilação de uma proteína-alvo, enquanto CDKIs inibem a atividade dos complexos e induzem a parada do ciclo celular. Alterações genéticas na via envolvida na manutenção da integridade genômica são importantes contribuintes para a suscetibilidade ao câncer de tireoide. No entanto, a utilidade clínica potencial de CDKIs tem se mostrado bastante discutível. Este trabalho visa ampliar o conhecimento acerca da contribuição de polimorfismos genéticos em CDKIs no risco de câncer de tireoide e no processo de carcinogênese, buscando marcadores diagnósticos e prognósticos. Utilizando um grupo bem caracterizado de 138 pacientes com carcinoma medular hereditário, 45 carcinomas medulares esporádicos e 100 controles normais pareados, investigamos polimorfismos dos genes CDKN1A, CDKN1B, CDKN2A, CDKN2B e CDKN2C. A identificação de um perfil de risco e de agressividade tumoral pode ajudar a delinear novas estratégias de prevenção, diagnóstico, planejamento terapêutico e seguimento dos pacientes com câncer medular de tireoideAbstract: Thyroid cancer accounts for about 2% of all human cancers and its incidence is increasing worldwide having doubled in the last three decades. In Brazil, 6,960 new cases were estimated to occur in 2016, making thyroid cancer the eighth most common malignancy among women. The medullary thyroid carcinomas derived from C or parafollicular cells, they account for less than 3% of thyroid carcinomas. Medullary carcinoma is sporadic primarily (70-80 %), but the inheritance pattern is present in 20 to 30% of cases. Because of that, our group has been working actively in the search for markers of malignancy and aggressiveness. In particular, we have shown that several genetic polymorphisms are associated with the risk of thyroid cancer. The cell cycle is a highly regulated series of successive events leading to cell reproduction. Cell cycle progression is mainly regulated by cyclins, cyclin-dependent kinases (CDK) and CDK inhibitors (CDKIs). Cyclins and CDKs form complexes that regulate cell growth by marking and phosphorylating protein targets, while CDKIs inhibit the activity of the complexes and induce cell cycle disruption. Changes in the genetic pathway involved in the maintenance of genomic integrity are important contributors to the susceptibility to thyroid cancer. However, the potential clinical utility of CDKIs remains controversial. This job aims to expand knowledge on the contribution of genetic polymorphisms on the risk of thyroid cancer and on the process of carcinogenesis, aiming to identify diagnostic and prognostic markers. Using of a very well characterized group of 138 patients with hereditary medullary thyroid carcinomas, 45 sporadic medullary thyroid carcinomas and 100 paired health controls, we will investigate polymorphisms of CDKN1A, CDKN1B, CDKN2A, CDKN2B and CDKN2C genes. The identification of a profile of risk and thyroid cancer aggressiveness may help develop new strategies for the prevention, diagnosis, treatment planning and follow-up of patients with medullary thyroid cancerDoutoradoClinica MedicaDoutora em Ciência

Unraveling Brazilian Indian population prostate good health: clinical, anthropometric and genetic features

To compare dietary, lifestyle, clinical, anthropometric, genetic and prostatic features of Brazilian Indians and non-Indians (Amazon). 315 men, 228 Indians and 89 non-Indians, ≥40 years old were submitted to digital rectal examination, serum prostate specific antigen (PSA), testosterone, TP53 and GSTP1 genotyping, anthropometric, lifestyle, dietary, personal and familial medical history. Prostatic symptoms were evaluated with the International Prostate Symptom Score (IPSS). Macuxis and Yanomamis represented 43.6% and 14.5% of Indians respectively who spontaneously referred no prostate symptoms. Mean IPSS was 7, range 3-19, with only 15% of moderate symptoms (score 8-19); Mean age was 54.7 years, waist circumference 86.6 cm, BMI 23.9 kg/m2. Yanomamis presented both lower BMI (21.4 versus 24.8 and 23.3, p=0,001) and prostate volume than Macuxis and “other ethnic groups” (15 versus 20, p=0.001). Testosterone (414 versus 502 and 512, p=0.207) and PSA (0.48 versus 0.6 and 0.41, p=0.349) were similar with progressive PSA increase with aging. Val/Val correlated with lower PSA (p=0.0361). Indians compared to control population presented: - TP53 super representation of Arg/Arg haplotype, 74.5% versus 42.5%, p<0.0001. -GSTP1 Ile/Ile 35.3% versus 60.9%; Ile/Val 45.9% versus 28.7%; Val/Val 18.8% versus 10.3%; p=0.0003. Observed specific dietary, lifestyle, anthropometric and genetic profile for TP53 and GSTP1 may contribute to Brazilian Indian population prostate good health.41234435

Profile of genetic susceptibility to the development of medullary thyroid carcinoma

Orientadores: Laura Sterian Ward, Janete CeruttiDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: Polimorfismos de genes baixa penetrância têm sido consistentemente associados com a suscetibilidade a uma série de tumores humanos, incluindo o câncer de tireóide. A fim de determinar seu papel no carcinoma medular de tireóide (CMT), foi utilizado o método TaqMan® SNP Genotyping em 138 pacientes com CMTH, 47 pacientes com CMT-s e um grupo controle de 578 indivíduos para genotipagem dos polimorfismos CYP1A2*F (rs762551), CYP1A1m1 (rs4646903), NAT2 C282T (rs1041983), GSTP1 codon 105 (rs1695), TP53 codon 72 (rs1042522). Este estudo demonstrou uma associação entre a presença de alelos polimórficos de CYP1A2*F, GSTP1 e NAT2 e o desenvolvimento de CMTH. A herança do alelo C em homozigose do gene CYP1A 2*F influencia o desenvolvimento de CMTH em mais de 2 vezes. Pacientes que apresentaram o alelo T em homozigose para o gene NAT2 possuem uma probabilidade 3 vezes maior para o desenvolvimento de CMTH e os indivíduos que herdaram o alelo G do gene GSTP1 em homozigose apresentam maior probabilidade de desenvolvimento de CMTH. Uma análise estatística de regressão logística, ajustada para sexo, idade, etnia, tabagismo e os genes CYP1A*F, CYP1A1m1, NAT, GSTP1 e TP53 para os pacientes com CMTH demonstrou que, quando considerado o tamanho do tumor como estimativa de agressividade, o sexo masculino apresentou-se como fator de proteção ao aumento do tamanho do tumor (OR=0,12; p=0,0072). Considerando a recidiva local como estimativa de agressividade, o genótipo alterado do gene GSTP1 apresentou-se como fator de risco para presença de recidiva local (OR=1,17; p=0,035). A análise de regressão logística mostrou que a herança do genótipo C/C dos genes NAT2 (OR=3,87; IC95%=2,11-7,10; p=2,2x10-5) e TP53 (OR=3,87 IC95%=1,78-6,10; p=2,8x10-4) aumentou o risco de CMT-s. Uma análise de regressão indicou que o genótipo C/C do gene TP53 contribui com 8,07% do risco CMT-s. Não foi possível identificar qualquer relação entre os polimorfismos de NAT2 e TP53, sugerindo que são fatores independentes de risco para o CMT-s. Em conclusão, foi demonstrado que os genes de detoxificação e genes de apoptose e controle do ciclo celular estão envolvidos na suscetibilidade ao desenvolvimento de CMT-s e CMTH e podem modular a suscetibilidade à doençaAbstract: Polymorphisms in low penetrance genes have been consistently associated with susceptibility to a variety of human tumors, including thyroid cancer. In order to determine its role in medullary thyroid carcinoma (MTC) TaqMan® SNP Genotyping method was used in 138 patients with HMTC, 47 patients with MTC-s and a control group of 578 for genotyping of polymorphisms CYP1A2*F (rs762551), CYP1A1m1 (rs4646903), NAT2 C282T (rs1041983), GSTP1 codon 105 (rs1695) and TP53 codon 72 (rs1042522). This study demonstrated an association between the presence of polymorphic alleles of CYP1A2 F, GSTP1 and NAT2 and the development of HMTC. The legacy of the C allele in homozygous CYP1A2*F gene influences the development of CMTH in more than two times. Patients who had the T allele in homozygous for the NAT2 gene have a three times more likely to develop HMTC and individuals who have inherited the G allele of GSTP1 gene in homozygous are more likely to develop CMTH. A statistical analysis of logistic regression, adjusted for sex, age, ethnicity, smoking and genes CYP1A*F, CYP1A1m1, NAT, GSTP1, and TP53, in patients with HMTC, showed that, when considering the size of the tumor as an estimate of aggression, sex male presented himself as a protective factor to the increase in tumor size (OR=0.12; p=0.0072). Considering the estimate of local recurrence and aggressiveness, the altered gene GSTP1 genotype appeared as a risk factor for presence of local recurrence (OR=1.17; p=0.035). The logistic regression analysis showed that the genotypes of the NAT2 gene C/C (OR=3.87; 95%CI=2.11-7.10, p=2.2x10-5) and TP53 C/C (OR=3.87; 95%CI=1.78-6.10; p=2.8x10-4) inheritance increased the risk of sporadic MTC. A regression analysis showed that genotype C/C TP53 gene accounts for 8.07% of sporadic MTC risk. In addition, there was no association between the investigated genes and clinical or pathological features of aggressiveness of the tumors or the outcome of MTC patients. In conclusion, we demonstrated that detoxification genes and apoptotic and cell-cycle control genes are involved in the susceptibility of MTC-s and HMTC and may modulate the susceptibility to the diseaseMestradoCiencias BasicasMestre em Clinica Medic

Unraveling Brazilian Indian Population Prostate Good Health: Clinical, Anthropometric And Genetic Features.

To compare dietary, lifestyle, clinical, anthropometric, genetic and prostatic features of Brazilian Indians and non-Indians (Amazon). 315 men, 228 Indians and 89 non-Indians, ≥ 40 years old were submitted to digital rectal examination, serum prostate specific antigen (PSA), testosterone, TP53 and GSTP1 genotyping, anthropometric, lifestyle, dietary, personal and familial medical history. Prostatic symptoms were evaluated with the International Prostate Symptom Score (IPSS). Macuxis and Yanomamis represented 43.6% and 14.5% of Indians respectively who spontaneously referred no prostate symptoms. Mean IPSS was 7, range 3-19, with only 15% of moderate symptoms (score 8-19); Mean age was 54.7 years, waist circumference 86.6 cm, BMI 23.9 kg/m(2). Yanomamis presented both lower BMI (21.4 versus 24.8 and 23.3, p=0,001) and prostate volume than Macuxis and other ethnic groups (15 versus 20, p=0.001). Testosterone (414 versus 502 and 512, p=0.207) and PSA (0.48 versus 0.6 and 0.41, p=0.349) were similar with progressive PSA increase with aging. Val/Val correlated with lower PSA (p=0.0361). Indians compared to control population presented: - TP53 super representation of Arg/Arg haplotype, 74.5% versus 42.5%, p<0.0001. -GSTP1 Ile/Ile 35.3% versus 60.9%; Ile/Val 45.9% versus 28.7%; Val/Val 18.8% versus 10.3%; p=0.0003. Observed specific dietary, lifestyle, anthropometric and genetic profile for TP53 and GSTP1 may contribute to Brazilian Indian population prostate good health.41344-35

CoCoNet: Towards coast to coast networks of marine protected areas (From the shore to the high and deep sea), coupled with sea-based wind energy potential

This volume contains the main results of the EC FP7 "The Ocean of Tomorrow" Project CoCoNet, divided in two sections: 1) a set of guidelines to design networks of Marine Protected Areas in the Mediterranean and the Black Seas; 2) a smart wind chart that will allow evaluating the possibility of installing Offshore Wind Farms in both seas. The concept of Cells of Ecosystem Functioning, based on connectivity, is introduced to define natural units of management and conservation. The definition of Good Environmental Status, as defined in the Marine Strategy Framework Directive, is fully embraced to set the objectives of the project, by adopting a holistic approach that integrates a full set of disciplines, ranging from physics to bio-ecology, economics, engineering and many sub-disciplines. The CoCoNet Consortium involved scientist sfrom 22 states, based in Africa, Asia, and Europe, contributing to build a coherent scientific community

Editorial. A supplement of Scires-it on the COCONET european project

The Supplement to vol. 6, 2016 of SCIRES-IT contains the result of CoCoNet (Towards COast to COast NETworks of marine protected areas, coupled with sea-based wind energy potential), a project of the EU Oceans of Tomorrow programme (http://www.coconet-fp7.eu). The European Union requires Open Access to the results of the projects resulting from its support to scientific advancement. This is in full accordance with the policy of SCIRES-IT, an eco-sustainable open–access journal, which joins the main principles of the Berlin Declaration on Open Access with the aims of the International Convention on Biological Diversity. CoCoNet tackled two problems that are closely linked with each other: the protection of the marine environment and clean energy production. Hence, the Supplement is divided into two parts that, together, form a unicum

CoCoNet: towards coast to coast networks of marine protected areas (from the shore to the high and deep sea), coupled with sea-based wind energy potential

This volume contains the main results of the EC FP7 “The Ocean of Tomorrow” Project CoCoNet, divided in two sections: 1) a set of guidelines to design networks of Marine Protected Areas in the Mediterranean and the Black Seas; 2) a smart wind chart that will allow evaluating the possibility of installing Offshore Wind Farms in both seas. The concept of Cells of Ecosystem Functioning, based on connectivity, is introduced to define natural units of management and conservation. The definition of Good Environmental Status, as defined in the Marine Strategy Framework Directive, is fully embraced to set the objectives of the project, by adopting a holistic approach that integrates a full set of disciplines, ranging from physics to bio-ecology, economics, engineering and many sub-disciplines. The CoCoNet Consortium involved scientist sfrom 22 states, based in Africa, Asia, and Europe, contributing to build a coherent scientific community