ATM gene mutations in sporadic breast cancer patients from Brazil.

PURPOSE: The Ataxia-telangiectasia mutated (ATM) gene encodes a multifunctional kinase, which is linked to important cellular functions. Women heterozygous for ATM mutations have an estimated relative risk of developing breast cancer of 3.8. However, the pattern of ATM mutations and their role in breast cancer etiology has been controversial and remains unclear. In the present study, we investigated the frequency and spectrum of ATM mutations in a series of sporadic breast cancers and controls from the Brazilian population. METHODS: Using PCR-Single Strand Conformation Polymorphism (SSCP) analysis and direct DNA sequencing, we screened a panel of 100 consecutive, unselected sporadic breast tumors and 100 matched controls for all 62 coding exons and flanking introns of the ATM gene. RESULTS: Several polymorphisms were detected in 12 of the 62 coding exons of the ATM gene. These polymorphisms were observed in both breast cancer patients and the control population. In addition, evidence of potential ATM mutations was observed in 7 of the 100 breast cancer cases analyzed. These potential mutations included six missense variants found in exon 13 (p.L546V), exon 14 (p.P604S), exon 20 (p.T935R), exon 42 (p.G2023R), exon 49 (p.L2307F), and exon 50 (p.L2332P) and one nonsense mutation in exon 39 (p.R1882X), which was predicted to generate a truncated protein. CONCLUSIONS: Our results corroborate the hypothesis that sporadic breast tumors may occur in carriers of low penetrance ATM mutant alleles and these mutations confer different levels of breast cancer risk.

Molecular genetic case-control women investigation from the first Brazilian high-risk study on functional psychosis / Investigação genético-molecular do tipo caso-controle em uma amostra de mulheres portadoras de psicose funcional do primeiro estudo de alto-risco brasileiro

OBJECTIVE: Data from epidemiological studies have demonstrated that genetics is an important risk factor for psychosis. The present study is part of a larger project, pioneer in Brazil, which has been conducted by other researchers who intend to follow a high-risk population (children) for the development of schizophrenia and bipolar disorder. In this first phase of the project, the objective was to investigate the distribution of four candidate genetic polymorphisms for functional psychosis (Ser9Gly DRD3, 5HTTLPR, the VNTR 3'-UTR SLC6A3 and Val66Met BDNF) in a case-control sample. METHOD: A total of 105 women (58 with schizophrenia and 47 with bipolar disorder) and 62 gender-matched controls were investigated. RESULTS: Allele and genotype distributions of all identified functional polymorphisms did not differ statistically between cases and controls. CONCLUSIONS: These results suggest that the investigated polymorphisms were not related to susceptibility to functional psychoses in our Brazilian sample. These findings need to be validated in larger and independent studies.

OBJETIVO: Estudos epidemiológicos demonstram que alterações genéticas são fatores de risco importantes para o desenvolvimento de psicose. O presente estudo é parte um projeto maior, pioneiro no Brasil, realizado com mais pesquisadores, que pretende seguir uma população de alto risco genético para o desenvolvimento de esquizofrenia e transtorno bipolar. Nesta primeira fase, o objetivo foi investigar a distribuição de quatro polimorfismos genéticos candidatos no desenvolvimento de psicose funcional (Ser9Gly DRD3, 5HTTLPR, o VNTR 3'-UTR SLC6A3 e Val66Met BDNF) em uma amostra caso-controle. MÉTODO: O estudo genético respeitou o desenho metodológico do estudo clínico. Um total de 105 mulheres (58 esquizofrenia e 47 transtorno bipolar) e 62 controles sem diagnóstico psiquiátrico foi investigado. RESULTADOS: Nenhuma diferença estatisticamente significante foi observada nas distribuições alélicas e genotípicas entre os grupos investigados. CONCLUSÕES: Os resultados sugerem que estes polimorfismos não estavam relacionados à suscetibilidade para psicose funcional nesta amostra brasileira estudada. Esses achados precisam ser validados em estudos maiores e independentes.

Molecular genetic case-control women investigation from the first Brazilian high-risk study on functional psychosis.

OBJECTIVE: Data from epidemiological studies have demonstrated that genetics is an important risk factor for psychosis. The present study is part of a larger project, pioneer in Brazil, which has been conducted by other researchers who intend to follow a high-risk population (children) for the development of schizophrenia and bipolar disorder. In this first phase of the project, the objective was to investigate the distribution of four candidate genetic polymorphisms for functional psychosis (Ser9Gly DRD3, 5HTTLPR, the VNTR 3'-UTR SLC6A3 and Val66Met BDNF) in a case-control sample. METHOD: A total of 105 women (58 with schizophrenia and 47 with bipolar disorder) and 62 gender-matched controls were investigated. RESULTS: Allele and genotype distributions of all identified functional polymorphisms did not differ statistically between cases and controls. CONCLUSIONS: These results suggest that the investigated polymorphisms were not related to susceptibility to functional psychoses in our Brazilian sample. These findings need to be validated in larger and independent studies.

Association analysis between the C516T polymorphism in the 5-HT2A receptor gene and schizophrenia.

Data from epidemiological studies have demonstrated that genetics is an important risk factor for schizophrenia. Disturbances of serotonergic brain pathways have been implicated in the pathophysiology of schizophrenia. Some studies have suggested that the efficacy of atypical antipsychotics on schizophrenia treatment may be related to the serotonin 2A receptor (5-HT2A), and that serotonergic drugs may induce psychotic symptoms. Thus, the aim of this study was to investigate the association between the C516T polymorphism and schizophrenia in a Brazilian population composed by 246 patients and 315 healthy matched controls in a case-control approach. No statistically differences were observed in allelic (chi2=1.77, 1d.f., p=0.18) or genotypic (chi2=1.69, 2d.f., p=0.42) distributions between cases and controls. The results suggest that the C516T polymorphism of the 5-HT2A receptor gene is not related to the susceptibility for schizophrenia in our Brazilian sample.

Association analysis between the C516T polymorphism in the 5-HT2A receptor gene and schizophrenia

Data from epidemiological studies have demonstrated that genetics is an important risk factor for schizophrenia. Disturbances of serotonergic brain pathways have been implicated in the pathophysiology of schizophrenia. Some studies have suggested that the efficacy of atypical antipsychotics on schizophrenia treatment may be related to the serotonin 2A receptor (5-HT2A), and that serotonergic drugs may induce psychotic symptoms. Thus, the aim of this study was to investigate the association between the C516T polymorphism and schizophrenia in a Brazilian population composed by 246 patients and 315 healthy matched controls in a case-control approach. No statistically differences were observed in allelic (chi2=1.77, 1d.f., p=0.18) or genotypic (chi2=1.69, 2d.f., p=0.42) distributions between cases and controls. The results suggest that the C516T polymorphism of the 5-HT2A receptor gene is not related to the susceptibility for schizophrenia in our Brazilian sample.

Estudos epidemiológicos têm demonstrado que o componente genético é importante fator de risco para o desenvolvimento de esquizofrenia. Alterações nas vias cerebrais serotonérgicas têm sido relacionadas à fisiopatologia da esquizofrenia. Algumas investigações têm sugerido que a eficácia de antipsicóticos atípicos no tratamento da esquizofrenia pode estar relacionada com sua ação no receptor de serotonina subtipo 2A (5-HT2A), e que drogas serotonérgicas podem provocar sintomas psicóticos. Assim, o objetivo desta investigação foi examinar a associação entre o polimorfismo C516T do gene do receptor 5-HT2A e esquizofrenia em uma amostra brasileira composta por 246 pacientes e 315 controles saudáveis e pareados em um estudo tipo caso-controle. Não foram observadas diferenças na distribuição alélica (chi2=1,77, 1d.f., p=0,18, 1d.f.) e genotípica (chi2=1,69, 2d.f., p=0,42) entre os grupos de pacientes e controles. Os resultados sugerem que o polimorfismo C516T gene do receptor 5-HT2A não é fator de susceptibilidade para esquizofrenia na amostra brasileira estudada.

Investigation of possible association between Ser9Gly polymorphism of the D3 dopaminergic receptor gene and response to typical antipsychotics in patients with schizophrenia.

Typical antipsychotics have a high affinity for dopamine receptors. It is therefore of interest to investigate such loci in pharmacogenetic studies on psychosis. We investigated the hypothesis that Ser9Gly polymorphism of the DRD3 gene may play a role in the differences in individual response to typical antipsychotics between schizophrenic patients. The sample was composed of 53 good responders and 59 poor ones. No significant differences between the good and poor responders were found in the allelic distribution (good responders: Ser9 61.32%, Gly9 38.67%; poor responders: Ser9 64.40%, Gly9 35.59%; odds ratio, OR = 0.88, 0.49 < OR < 1.56; chi2 = 0.23, 1 degree of freedom, df, p = 0.63) and genotype distribution (good responders: Ser9/Ser9 37.73%, Ser9/Gly9 47.16%, Gly9/Gly9 15.09%; poor responders: Ser9/Ser9 42.37%, Ser9/Gly9 44.06%, Gly9/Gly9 13.55%; chi2 = 0.25, 2 df, p = 0.88). Nor was there any association with homozygosity (good responders: homozygous: 52.82%, heterozygous: 47.16%; poor responders: homozygous: 55.92%, heterozygous: 44.06%; odds ratio, OR = 0.88, 0.39 < OR < 1.99; chi2 = 0.11, 1 df, p = 0.74). The results did not support the hypothesis that Ser9Gly polymorphism of the DRD3 gene influences the response to typical antipsychotics in our sample of schizophrenics.

Investigation of possible association between Ser9Gly polymorphism of the D3 dopaminergic receptor gene and response to typical antipsychotics in patients with schizophrenia / Investigação da possível associação entre o polimorfismo Ser9Gly do gene do receptor de dopamina D3 e resposta a antipsicóticos típicos em pacientes com esquizofrenia

Typical antipsychotics have a high affinity for dopamine receptors. It is therefore of interest to investigate such loci in pharmacogenetic studies on psychosis. We investigated the hypothesis that Ser9Gly polymorphism of the DRD3 gene may play a role in the differences in individual response to typical antipsychotics between schizophrenic patients. The sample was composed of 53 good responders and 59 poor ones. No significant differences between the good and poor responders were found in the allelic distribution (good responders: Ser9 61.32 percent, Gly9 38.67 percent; poor responders: Ser9 64.40 percent, Gly9 35.59 percent; odds ratio, OR = 0.88, 0.49 < OR < 1.56; chi2 = 0.23, 1 degree of freedom, df, p = 0.63) and genotype distribution (good responders: Ser9/Ser9 37.73 percent, Ser9/Gly9 47.16 percent, Gly9/Gly9 15.09 percent; poor responders: Ser9/Ser9 42.37 percent, Ser9/Gly9 44.06 percent, Gly9/Gly9 13.55 percent; chi2 = 0.25, 2 df, p = 0.88). Nor was there any association with homozygosity (good responders: homozygous: 52.82 percent, heterozygous: 47.16 percent; poor responders: homozygous: 55.92 percent, heterozygous: 44.06 percent; odds ratio, OR = 0.88, 0.39 < OR < 1.99; chi2 = 0.11, 1 df, p = 0.74). The results did not support the hypothesis that Ser9Gly polymorphism of the DRD3 gene influences the response to typical antipsychotics in our sample of schizophrenics.

Antipsicóticos típicos apresentam alta afinidade pelos receptores dopaminérgicos, que são, portanto, regiões de interesse para os estudos de farmacogenética das psicoses. No presente estudo, investigamos a hipótese de que o polimorfismo Ser9Gly do gene do DRD3 possa exercer um papel na diferença de resposta inter-individual ao uso de antipsicóticos típicos em pacientes com esquizofrenia. Nossa amostra foi composta por 53 pacientes bons respondedores e 59 maus respondedores. Não houve diferenças nas distribuições alélicas (bons respondedores: Ser9 61,32 por cento, Gly9 38,67 por cento; maus respondedores: Ser9 64,40 por cento, Gly9 35,59 por cento; odds ratio, OR = 0,88, 0,49 < OR < 1,56; chi2 = 0,23, 1 degree of freedom, d.f., p = 0,63) e genotípica (bons respondedores: Ser9/Ser9 37,73 por cento, Ser9/Gly9 47,16 por cento, Gly9/Gly9 15,09 por cento; maus repondedores: Ser9/Ser9 42,37 por cento, Ser9/Gly9 44,06 por cento, Gly9/Gly9 13,55 por cento; chi2 = 0,25, 2 d.f., p = 0,88) entre os grupos. Não houve também associação com homozigosidade (bons respondedores: homozigotos: 52,82 por cento, heterozigotos: 47,16 por cento; maus repondedores: homozigotos: 55,92 por cento, heterozigotos: 44,06 por cento; odds ratio, OR = 0,88, 0,39 < OR < 1,99); chi2 = 0,11, 1 d.f., p = 0,74). Os resultados não dão suporte à hipótese de que o polimorfismo Ser9Gly do gene do DRD3 possa influenciar a resposta terapêutica aos antipsicóticos típicos na nossa amostra de pacientes com esquizofrenia.

Large-scale transcriptome analyses reveal new genetic marker candidates of head, neck, and thyroid cancer.

A detailed genome mapping analysis of 213,636 expressed sequence tags (EST) derived from nontumor and tumor tissues of the oral cavity, larynx, pharynx, and thyroid was done. Transcripts matching known human genes were identified; potential new splice variants were flagged and subjected to manual curation, pointing to 788 putatively new alternative splicing isoforms, the majority (75%) being insertion events. A subset of 34 new splicing isoforms (5% of 788 events) was selected and 23 (68%) were confirmed by reverse transcription-PCR and DNA sequencing. Putative new genes were revealed, including six transcripts mapped to well-studied chromosomes such as 22, as well as transcripts that mapped to 253 intergenic regions. In addition, 2,251 noncoding intronic RNAs, eventually involved in transcriptional regulation, were found. A set of 250 candidate markers for loss of heterozygosis or gene amplification was selected by identifying transcripts that mapped to genomic regions previously known to be frequently amplified or deleted in head, neck, and thyroid tumors. Three of these markers were evaluated by quantitative reverse transcription-PCR in an independent set of individual samples. Along with detailed clinical data about tumor origin, the information reported here is now publicly available on a dedicated Web site as a resource for further biological investigation. This first in silico reconstruction of the head, neck, and thyroid transcriptomes points to a wealth of new candidate markers that can be used for future studies on the molecular basis of these tumors. Similar analysis is warranted for a number of other tumors for which large EST data sets are available.

Differentially expressed genes and estrogen receptor status in breast cancer.

There is a large and increasing body of experimental and clinical data supporting the involvement of estrogen on the proliferation of hormone-dependent breast tumors. Estrogen acts via its receptor (ER) stimulating cellular proliferation. ER and progesterone receptor (PR), which is regulated by estrogen via ER, have been used as prognostic markers in the clinical management of breast cancer patients. The aim of the present study was the identification of tumor-associated genes differentially expressed in breast tumors regarding the presence or absence of ER and PR. Using the technique of differential display reverse transcriptase-polymerase chain reaction (DDRT-PCR) we have isolated and cloned 127 cDNA fragments that showed differential expression in either ER+/PR+ or ER-/PR- breast tumors. Sequencing analysis of these clones revealed that 119 cDNAs had homology with known sequences in the National Center of Biotechnology Information (NCBI) and 8 were novel, showing no homology to known genes. Among these differentially expressed transcripts are metabolic enzymes, ribosomal proteins, transcription factors, hypothetical proteins, cell cycle regulators, cytoskelectum related genes, cell adhesion and motility genes. Differences in gene expression profiles are likely to explain the phenotypic differences between hormone-responsive and hormone-unresponsive breast tumors.