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PubMed2006

Epidemiological studies in the information and genomics era: experience of the Clinical Genome of Cancer Project in São Paulo, Brazil.

Genomics is expanding the horizons of epidemiology, providing a new dimension for classical epidemiological studies and inspiring the development of large-scale multicenter studies with the statistical power necessary for the assessment of gene-gene and gene-environment interactions in cancer etiology and prognosis. This paper describes the methodology of the Clinical Genome of Cancer Project in São Paulo, Brazil (CGCP), which includes patients with nine types of tumors and controls. Three major epidemiological designs were used to reach specific objectives: cross-sectional studies to examine gene expression, case-control studies to evaluate etiological factors, and follow-up studies to analyze genetic profiles in prognosis. The clinical groups included patients' data in the electronic database through the Internet. Two approaches were used for data quality control: continuous data evaluation and data entry consistency. A total of 1749 cases and 1509 controls were entered into the CGCP database from the first trimester of 2002 to the end of 2004. Continuous evaluation showed that, for all tumors taken together, only 0.5% of the general form fields still included potential inconsistencies by the end of 2004. Regarding data entry consistency, the highest percentage of errors (11.8%) was observed for the follow-up form, followed by 6.7% for the clinical form, 4.0% for the general form, and only 1.1% for the pathology form. Good data quality is required for their transformation into useful information for clinical application and for preventive measures. The use of the Internet for communication among researchers and for data entry is perhaps the most innovative feature of the CGCP. The monitoring of patients' data guaranteed their quality.

Adult↗
PubMed2006

Germline mutations of BRCA1 in two Korean hereditary breast/ovarian cancer families.

Testing for cancer susceptibility gene, in particular mutations in the BRCA1 gene in association with hereditary breast/ovarian cancer has been extensively studied. We investigated germline mutations in the BRCA1 gene from two Korean hereditary breast/ovarian cancer families using direct DNA sequencing. Blood samples of the thirteen family members were studied. We found three missense mutations; 3232 Aright curved arrow G, 2731 Cright curved arrow T, 3667 Aright curved arrow G. These mutations were involved in the altered coding of amino acids. According to the BIC database, clinical significance of these mutations is regarded as favor polymorphisms. Therefore, these genetic variations are not believed to be involved in the development of the disease, but may be associated with breast/ovarian cancers in another yet undefined way. For further clinical significance of these variations, additional study such as a case-controlled haplotyping study is needed.

BRCA1 Protein↗
PubMed2006

Pharmacogenomic data sample collection and storage: ethical issues and policy approaches.

This perspective report will focus on the ethical, legal and social issues raised by pharmacogenomic research using large population-based databases. Access to databases established or developed at the level of whole populations or communities (e.g., the Estonian Genome Project, the UK Biobank, CARTaGENE, GenomEUtwin, and so on) will become increasingly important in pharmacogenomic research for the purpose of confirming associations between genetic variations and drug-related effects. The capacity of database creators and managers, along with that of researchers, to meet the ethical issues raised by such vast public projects will determine the integration of pharmacogenomics into mainstream clinical practice.

Computer Security↗
PubMed2026

Pharmacogenomic and drug interactions risk in cardio-oncology: A precision medicine perspective for India.

Cardio-oncology patients may face complex treatment regimens due to the concurrent existence of cancer and cardiovascular disease, leading to a considerable polypharmacy burden. This significantly increases the prospect of drug-drug interactions (DDIs) and gene-drug interactions. The majority of these interactions arise from comparable pharmacokinetic and pharmacological pathways associated with drug transporters and cytochrome P450 enzymes. The significance of pharmacogenomics in tailored treatment strategies are emphasised by the fact that genetic variability enhances individual differences in drug response, safety, and efficacy. This narrative review focus on the effects of key genetic polymorphisms (e.g., DPYD, CYP2C19, and CYP2C9) on the metabolism and efficacy of commonly prescribed anticancer and cardiovascular medications such as fluoropyrimidines, clopidogrel, and warfarin. In addition it explore the role of pharmacogenomic variants on drug-drug interactions within the field of cardio-oncology. The study ultimately emphasizes the necessity of precision medicine in India to address the genetic diversity and underrepresentation in global genomic databases. The absence of pharmacogenomic testing, infrastructural deficiencies, financial constraints, and insufficient clinical integration hinder the widespread use of this technology in India. The Genome India Project and other national initiatives establish the foundation for pharmacogenomic-guided therapy. Utilizing genetic data, together with artificial intelligence-based predictive tools, for clinical decision-making may enhance medication safety and yield optimal outcomes in Indian cardio-oncology patients.

Humans↗
PubMed2006

Genotyping of human Campylobacter jejuni isolates in Greece by pulsed-field gel electrophoresis.

BACKGROUND: Pulsed-field gel electrophoresis (PFGE) typing has been recognized by several groups as a relatively simple and quick method for genotyping of Campylobacter jejuni (C. jejuni). The present study was carried out to determine the genetic variations among clinical isolates of C. jejuni from Greece and to establish a database, which could be used for future epidemiological and clinical studies. METHODS: A total of 93 C. jejuni clinical isolates of known flagellin subunit A (flaA) genotype, serotype, and antimicrobial susceptibility pattern, were collected from a general hospital in the Attica region of Greece, between the years 2000 and 2003. The PFGE profiles of SmaI DNA digests of each strain were compared using a bin analysis based on 44 molecular size intervals. RESULTS: Forty-three different PFGE types, designated as C. jejuni (C. j.) 1 Greece (GR) to C. j. 43 GR, were identified. There was no statistically significant association of PFGE type with flaA genotype, serotype, or antimicrobial susceptibility pattern. However, PFGE typing did show a remarkable discriminatory ability within the non-serotypable group. CONCLUSION: Evaluating our results, we observed that (i) there was no statistically significant clonality of a certain PFGE type among the strains examined, and (ii) the discriminatory ability of PFGE typing was much better than that of the other typing methods. This is the first report of the use of bin patterns to compare the PFGE genotypes identified.

Animals↗
PubMed1998

Clinical study of primary progressive multiple sclerosis in Northern Ireland, UK.

OBJECTIVE: To investigate the clinical and demographic characteristics of primary progressive multiple sclerosis (PPMS) in Northern Ireland and to establish a database of such patients for genetic and immunological studies and future therapeutic trials. METHODS: Diagnosis and categorisation were performed by two neurologists, potential cases being identified from the following sources: neurology outpatient clinics; neurology inpatients; a review of hospital discharges; and an ongoing epidemiological study of multiple sclerosis in Northern Ireland. Only those with a progressive course from onset and a clear history of no prior relapses were accepted. Potential cases were invited for interview and assessment, the minimal record of disability (MRD) being established. RESULTS: One hundred and eleven cases of PPMS have been identified, 63 women and 48 men (ratio 1.3:1), with a mean age at onset of 39.5 (SD 11.0) (range 17-66)years, and mean disease duration of 13.6 (SD 9.3)years. The mean interval between onset and diagnosis was 4.7 (SD 4.2) years. Nineteen patients (17.1%) did not satisfy the requirements for any category in the Poser criteria. Motor disturbance was the commonest mode of onset (67.6%) with visual loss occurring only rarely at onset (3.6%). Kurtzke EDSS scores were concentrated at the upper end of the scale with a median of 6.0 and levels of unemployment and financial dependence were high. CONCLUSIONS: PPMS in Northern Ireland has a generally later age at onset, lower female preponderance, and predominantly motor onset compared with other subgroups of multiple sclerosis. The delay to diagnosis reflects the often insidious onset and the nature of the clinical course makes application of the Poser criteria difficult. Levels of neurological impairment, disability, and handicap as measured by the MRD are high.

Activities of Daily Living↗
PubMed2005

Pediatric disorders with autonomic dysfunction: what role for PHOX2B?

Hirschsprung disease, neuroblastomas, and congenital central hypoventilation syndrome can occur in combination, and familial cases have been reported in all three conditions. This suggests variable expression of a single genetic abnormality as the common cause to these neural crest disorders. Because the PHOX2B gene is pivotal in the development of most relays of the autonomic nervous system, including all autonomic neural crest derivatives, it was considered a candidate gene for the above conditions. Recent studies have shown that 1) PHOX2B is the main disease-causing gene for congenital central hypoventilation syndrome, an autosomal dominant disorder with incomplete penetrance; 2) PHOX2B is the first gene for which germline mutations have been demonstrated to predispose to neuroblastoma; and 3) Hirschsprung disease was associated with an intronic single-nucleotide polymorphism of the PHOX2B gene in a case-control study. For clarifying the variable clinical expression of the autonomic nervous system dysfunction observed in neural crest disorders, international databases of clinical symptoms and molecular test results should be established. Furthermore, the development of genetic mouse models should help to improve our understanding of the molecular mechanisms underlying neural crest disorders.

Animals↗
PubMed1998

[Identification of marker chromosomes and translocations in man using a computerized diagnostic database and fluorescent in situ hybridization].

Cytogenetic analysis revealed five carriers of supernumerary marker chromosomes and two carriers of unbalanced chromosome translocations in patients of the medical genetic consultation clinic. A new method for exact identification of such chromosome rearrangements requiring additional molecular cytogenetic diagnosis was proposed. The method involves computer analysis of abnormal phenotypic traits with the use of diagnostic databases and fluorescent in situ hybridization (FISH) to DNA probes specific for the most probable computer-selected chromosome syndromes. On average, the method allowed the number of necessary DNA probes to be decreased four times. In the tested patients, supernumerary marker chromosomes were shown to be derived from chromosomes 2, 9, and 15, and translocations were identified as dic(Y;18) and ins(6;21). Limited possibilities of using the method when (1) a chromosome syndrome is not clearly defined in a diagnostic system or (2) phenotypic expression of a marker chromosome is not significant are discussed. Presumably, the method will allow a reliable estimation of the efficiency of various diagnostic systems.

Adolescent↗
PubMed2005

ATM sequence variants are predictive of adverse radiotherapy response among patients treated for prostate cancer.

PURPOSE: To examine whether the presence of sequence variants in the ATM (mutated in ataxia-telangiectasia) gene is predictive for the development of radiation-induced adverse responses resulting from (125)I prostate brachytherapy for early-stage prostate cancer. MATERIALS AND METHODS: Thirty-seven patients with a minimum of 1-year follow-up who underwent (125)I prostate brachytherapy of early-stage prostate cancer were screened for DNA sequence variations in all 62 coding exons of the ATM gene using denaturing high-performance liquid chromatography. The clinical course and postimplant dosimetry for each genetically characterized patient were obtained from a database of 2,020 patients implanted at Mount Sinai Hospital after 1990. RESULTS: Twenty-one ATM sequence alterations located within exons, or in short intronic regions flanking each exon, were found in 16 of the 37 patients screened. For this group, 10 of 16 (63%) exhibited at least one form of adverse response. In contrast, of the 21 patients who did not harbor an ATM sequence variation, only 3 of 21 (14%) manifested radiation-induced adverse responses (p = 0.005). Nine of the patients with sequence alterations specifically possessed missense mutations, which encode for amino acid substitutions and are therefore more likely to possess functional importance. For this group, 7 of 9 (78%) exhibited at least one form of adverse response. In contrast, of the 28 patients who did not have a missense alteration, only 6 of 28 (21%) manifested any form of adverse response to the radiotherapy (p = 0.004). Of the patients with missense variants, 5 of 9 (56%) exhibited late rectal bleeding vs. 1 of 28 (4%) without such alterations (p = 0.002). Of those patients who were at risk for developing erectile dysfunction, 5 of 8 (63%) patients with missense mutations developed prospectively evaluated erectile dysfunction as opposed to 2 of 20 (10%) without these sequence alterations (p = 0.009). CONCLUSIONS: Possession of sequence variants in the ATM gene, particularly those that encode for an amino acid substitution, is predictive for the development of adverse radiotherapy responses among patients treated with (125)I prostate brachytherapy.

Aged↗
PubMed2001

Prenatal diagnosis from cystic hygroma fluid: the value of fluorescence in situ hybridization.

OBJECTIVE: We sought to determine the optimal approach to the prenatal chromosome analysis of cystic hygroma fluid using traditional cytogenetic analysis and fluorescence in situ hybridization. STUDY DESIGN: A retrospective evaluation of our experience with traditional cytogenetic and fluorescence in situ hybridization analysis on cystic hygroma fluid was performed through a systematic review of the Genzyme Genetics database from January 1995 to July 2000. Information on gestational age, sample volume, clinical ultrasound findings (including fetal viability), cytogenetic results, fluorescence in situ hybridization results, and turn-around-time were queried. RESULTS: Eighty-three specimens were included in the investigation. The mean gestational age was 18.1 weeks (range, 13-27 weeks), and the mean sample volume was 20.7 mL (range, 0.1-101 mL). Of the 72 samples in which > 5 mL of cystic hygroma fluid was available, the success rate for cytogenetic analysis was 76% (55/72 samples). In 11 specimens of < or = 5 mL of cystic hygroma fluid, cytogenetic analysis was successful in only 1 case (9%). Fluorescence in situ hybridization was attempted on 23 samples, 18 of which were successful (78%), including 6 of 9 cases of cell culture failure (67%). Both traditional cytogenetic analysis and fluorescence in situ hybridization were performed in 21 instances when a sample of > 5 mL was available. A successful result was obtained by either cytogenetic testing or fluorescence in situ hybridization analysis or both in 19 of 21 of these cases (90%). Samples of > 5 mL from viable fetuses had a higher cytogenetic success rate (80%) and fluorescence in situ hybridization success rate (89%) than samples from fetuses with intrauterine death (38% and 50% cytogenetic and fluorescence in situ hybridization success rates, respectively.) The mean turn-around time was 8.2 days (range, 4-17 days). Results were available in < or = 12 days in 91% of cases. There was a 91% aneuploidy rate identified, with 45,X occurring in 86% of the samples. CONCLUSION: We conclude that the optimal approach for the prenatal diagnosis of chromosome abnormalities from cystic hygroma samples is to perform both traditional cytogenetic studies and interphase prenatal fluorescence in situ hybridization evaluation for the most common aneuploidies that involve chromosomes 13, 18, 21, X, and Y. With this combined approach, our data indicate that, in viable pregnancies with a fluid sample of >5 mL, a 90% diagnostic success rate can be achieved.

Congenital Abnormalities↗
PubMed2003

Pharmacogenomics, genetic testing and ethnic variability: tackling the ethical questions.

Dr Winkelmann is the Head of the Cooperation Unit for Pharmacogenomics and Applied Genomics in Heidelberg, which was founded in 2001 by the Department of Internal Medicine VI and the Coordination Centre for Clinical Trials at the University of Heidelberg. His main interests are sophisticated phenotyping procedures for patient characterization and the conduct of multicenter clinical trials according to international standards with state-of-the-art data management. He currently applies new genomic tools in order to achieve progress in personalized medicine using collaborating networks of general practitioners for patient enrollment. The focus of his research group is on the common complex genetic cardiovascular and metabolic diseases ranging from coronary artery disease, dyslipidemia and hypertension, to metabolic syndrome and diabetes mellitus. In collaboration with partners from biotech, the genomic techniques used in clinical studies include haplotyping of candidate genes, gene expression profiling of peripheral leucocytes and proteomics in order to identify new biomarkers of effect in therapeutic studies or pathway/target gene identification in disease-specific family studies using microarray-based linkage approaches. An innovative web-based remote data entry system with an integrated pedigree drawing tool is used in the family studies. Dr Winkelmann is also involved as the clinical database coordinator for a European Framework VI research initiative of leading European centers in cardiovascular genetics for identification of risk genes for atherothrombosis in coronary artery disease by transcriptome and proteome analysis and high throughput exon resequencing at the Wellcome Trust Sanger Institute, Cambridge, UK.

Cardiovascular Diseases↗
PubMed2002

A patient database application for Hereditary Deafness Epidemiology and Clinical Research (H.E.A.R.): an effort for standardization in multiple languages.

One of the most challenging and neglected issues in medicine is the effective recording of the data obtained from the patients. The "European Work Group on the Genetics of Hearing Impairment," which has been working since 1996, proposed a few questionnaires to collect data regarding the phenotype, ENT findings, audiological examination findings and other special investigations. In this study, a computerized patient database application named "Izmir H.E.A.R version 1.0," written in Delphi 4.0 for Windows for recording the patients with hearing problems, is presented. The application consists of a modular form, including information about identity, genetic condition, proband query, audiology and vestibular tests, phenotype, pedigree and special examinations, which allows data entry on all these issues. It has been developed by using the guidelines of Hereditary Deafness Epidemiology and Clinical Research (H.E.A.R.) and by the experience gained within the last 10 years by the authors. The target population of the program is the ENT clinicians, audiologists, epidemiologists, geneticists and researchers in the field. The main idea is to create a program serving the needs of both the daily routine work and research purposes and to distribute this program to the above-mentioned specialists, to encourage them to try the first version and to find a standard and/or better way to collect data. For this reason, the program aims to be multilingual, and the currently available languages are English, German, Spanish and Turkish.

Biomedical Research↗
PubMed2004

The role of genetics in pediatric endocrinology.

Information on the genetics of endocrine disorders and genetic testing is increasing rapidly. This makes it important for endocrinologists to be able to efficiently search for clinically relevant information and to access specialized laboratory testing and genetics professionals to assist with diagnosis, education, counseling and management of patients and families. Because new findings are reported in many different publications, current comprehensive information on clinical and laboratory findings of and genetic testing for endocrine disorders cannot be found in any single journal or text. Electronic databases provide rapid access to such information. Endocrinologists need to develop a working understanding of these databases. This review examines principles of inheritance, types of genetic variation and the genetic aspects of selected endocrine disorders. It demonstrates how information on genetics and genetic testing can be obtained and discusses how endocrinologists and geneticists can work together to strengthen the clinical applications of genetics to pediatric endocrinology.

Child↗