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In: Journal of Carcinogenesis, 2003, Vol.2(1), p.5-5

Description: Background: Germline mutations in BRCA1/2 greatly elevate risks of breast and ovarian cancers, but the role of these genes in tumourigenesis of other cancer types is still being investigated. Objective: We report on an investigation of BRCA1/2 mutations and their loss of heterozygosity (LOH) in a patient with a strong family history of breast cancer who was diagnosed with consecutive primary cervical, ovarian and lung carcinomas. Methods and Results: BRCA1/2 mutation screening of the proband revealed a common familial breast- and ovarian cancer-associated germline BRCA2 mutation (3034del4bp). We then performed LOH analysis for BRCA2 in lung adenocarcinoma tissue of the patient. Using the laser-capture microdissection (LCM) technique, we obtained pure populations of neoplastic cells from which DNA could be extracted. Mutation analysis by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing revealed loss of the mutant allele in the adenocarcinoma tumour tissue. Conclusion: To our knowledge, this is the first report of investigation for LOH for BRCA2 in primary lung adenocarcinoma tissue of a patient with multiple primary tumours related to a familial germline BRCA2 mutation. Interestingly, it was the mutant, not the wild-type, allele which was lost in the lung adenocarcinoma tissue.

Keywords: loss of heterozygosity (LOH); germline mutation; lung adenocarcinoma; cancer genetics; familial breast cancer

ISSN: 1477-3163

DOI: 10.1186/1477-3163-2-5

URL: View record in Medknow Publications

In: Nature Genetics, 2002, Vol.31(2), p.171

Description: Familial hypomagnesemia with secondary hypocalcemia (OMIM 602014) is an autosomal recessive disease that results in electrolyte abnormalities shortly after birth. Affected individuals show severe hypomagnesemia and hypocalcemia, which lead to seizures and tetany. The disorder has been thought to be caused by a defect in the intestinal absorption of magnesium, rather than by abnormal renal loss of magnesium. Restoring the concentrations of serum magnesium to normal values by high-dose magnesium supplementation can overcome the apparent defect in magnesium absorption and in serum concentrations of calcium. Life-long magnesium supplementation is required to overcome the defect in magnesium handling by these individuals. We previously mapped the gene locus to chromosome 9q in three large inbred kindreds from Israel. Here we report that mutation of TRPM6 causes hypomagnesemia with secondary hypocalcemia and show that individuals carrying mutations in this gene have abnormal renal magnesium excretion.

Keywords: DNA Mutational Analysis–Etiology ; Humans–Genetics ; Hypocalcemia–Genetics ; Hypocalcemia–Blood ; Ion Channels–Blood ; Magnesium–Blood ; Molecular Sequence Data–Blood ; Mutation–Blood ; Pedigree–Blood ; Sequence Analysis, DNA–Blood ; Trpm Cation Channels–Blood ; Ion Channels ; Trpm Cation Channels ; Trpm6 Protein, Human ; Magnesium;

ISSN: 1061-4036

E-ISSN: 1546-1718

DOI: 10.1038/ng901

URL: View this record in Nature

Language: English

In: International Journal of Cancer, 10 August 2003, Vol.106(1), pp.78-80

Description: Very recently, mutations were found in about 2/3 of malignant melanomas and at lower frequencies in other human cancers. The gene codes for a protein in the mitogen‐activated protein kinase (MAPK) pathway. All mutations identified to date are within the kinase domain, with a single missense mutation (V599E) accounting for 80%. We investigated the hypothesis that this common somatic mutation (V599E) would contribute to melanoma predisposition in familial and polygenic malignant melanoma if occuring as a germ‐line mutation. We performed comprehensive mutational screening of exon 15 of using DHPLC (denaturing high‐performance liquid chromatography) and DNA sequencing techniques. No V599E mutation could be detected in 172 melanoma patients comprising 46 familial cases, 21 multiple melanoma patients and 106 cases with at least one first‐degree relative suffering from other cancers. We therefore conclude that the common somatic mutation V599E does not contribute to polygenic and familial melanoma predisposition. © 2003 Wiley‐Liss, Inc.

Keywords: Melanoma ; Genetics ; Braf

ISSN: 0020-7136

E-ISSN: 1097-0215

DOI: 10.1002/ijc.11199

Language: English

In: International Journal of Cancer, 01 October 2006, Vol.119(7), pp.1736-1737

Description: Variants in the tumor suppressor gene (ADP‐ribosylation factor‐like tumor‐suppressor gene 1) have been shown to influence familial cancer risk. Both Cys148Arg and Trp149Stop were associated with an increased risk of familial or high‐risk familial breast cancer, respectively. We studied the impact of these gene variants on melanoma risk, investigating 351 melanoma patients and 804 control subjects. While ARLTS1 Trp149Stop did not influence melanoma risk (OR = 0.83, 95% CI = 0.37–1.88, = 0.65), Cys148Arg revealed a statistically significant association with an increased risk for heterozygous carriers (OR = 1.43, 95% CI = 1.05–1.95, = 0.02). An additional risk enhancement, though statistically non‐significant, was observed in individuals with multiple melanomas (OR = 2.33, 95% CI = 0.87–6.26, = 0.08). © 2006 Wiley‐Liss, Inc.

Keywords: Melanoma ; Multiple Melanomas ; Tumor Suppressor Gene ; Cancer Risk ; Polymorphism

ISSN: 0020-7136

E-ISSN: 1097-0215

DOI: 10.1002/ijc.22008

In: Journal of Carcinogenesis, 2003, Vol.2, p.5-5

Description: Background Germline mutations in BRCA1/2 greatly elevate risks of breast and ovarian cancers, but the role of these genes in tumourigenesis of other cancer types is still being investigated. Objective We report on an investigation of BRCA1/2 mutations and their loss of heterozygosity (LOH) in a patient with a strong family history of breast cancer who was diagnosed with consecutive primary cervical, ovarian and lung carcinomas. Methods and results BRCA1/2 mutation screening of the proband revealed a common familial breast- and ovarian cancer-associated germline BRCA2 mutation (3034del4bp). We then performed LOH analysis for BRCA2 in lung adenocarcinoma tissue of the patient. Using the laser-capture microdissection (LCM) technique, we obtained pure populations of neoplastic cells from which DNA could be extracted. Mutation analysis by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing revealed loss of the mutant allele in the adenocarcinoma tumour tissue. Conclusion To our knowledge, this is the first report of investigation for LOH for BRCA2 in primary lung adenocarcinoma tissue of a patient with multiple primary tumours related to a familial germline BRCA2 mutation. Interestingly, it was the mutant, not the wild-type, allele which was lost in the lung adenocarcinoma tissue.

Keywords: Short Paper ; Loss Of Heterozygosity (Loh) ; Germline Mutation ; Lung Adenocarcinoma ; Cancer Genetics ; Familial Breast Cancer

E-ISSN: 1477-3163

DOI: 10.1186/1477-3163-2-5

Source: U.S. National Library of Medicine (NIH/NLM)

Language: English

In: Cancer research, 01 September 2007, Vol.67(17), pp.8406-11

Description: DNA pooling in combination with high-throughput sequencing was done as a part of the Sequenom-Genefinder project. In the pilot study, we tested 83,715 single nucleotide polymorphisms (SNP), located primarily in gene-based regions, to identify polymorphic susceptibility variants for lung cancer. For this pilot study, 369 male cases and 287 controls of both sexes (white Europeans of Southern German origin) were analyzed. The study identified a candidate region in 22q12.2 that contained numerous SNPs showing significant case-control differences and that coincides with a region that was shown previously to be frequently deleted in lung cancer cell lines. The candidate region overlies the seizure 6-like (SEZ6L) gene. The pilot study identified a polymorphic Met430Ile substitution in the SEZ6L gene (SNP rs663048) as the top candidate for a variant modulating risk of lung cancer. Two replication studies were conducted to assess the association of SNP rs663048 with lung cancer risk. The M. D. Anderson Cancer Center study included 289 cases and 291 controls matched for gender, age, and smoking status. The Liverpool Lung Project (a United Kingdom study) included 248 cases and 233 controls. Both replication studies showed an association of the rs663048 with lung cancer risk. The homozygotes for the variant allele had more than a 3-fold risk compared with the wild-type homozygotes [combined odds ratio (OR), 3.32; 95% confidence interval (95% CI), 1.81-7.21]. Heterozygotes also had a significantly elevated risk of lung cancer from the combined replication studies with an OR of 1.15 (95% CI, 1.04-1.59). The effect remained significant after adjusting for age, gender, and pack-years of tobacco smoke. We also compared expression of SEZ6L in normal human bronchial epithelial cells (n = 7), non-small cell lung cancer (NSCLC; n = 52), and small cell lung cancer (SCLC; n = 22) cell lines by using Affymetrix HG-U133A and HG-U133B GeneChips. We found that the average expression level of SEZ6L in NSCLC cell lines was almost two times higher and in SCLC cell lines more than six times higher when compared with normal lung epithelial cell lines. Using the National Center for Biotechnology Information Gene Expression Omnibus database, we found a approximately 2-fold elevated and statistically significant (P = 0.004) level of SEZ6L expression in tumor samples compared with normal lung tissues. In conclusion, the results of these studies representing 906 cases compared with 811 controls indicate a role of the SEZ6L Met430Ile polymorphic variant in increasing lung cancer risk.

Keywords: Carcinoma, Non-Small-Cell Lung -- Genetics ; Carcinoma, Small Cell -- Genetics ; Lung Neoplasms -- Genetics ; Membrane Proteins -- Genetics

ISSN: 0008-5472

E-ISSN: 15387445

DOI: 10.1158/0008-5472.CAN-06-4784

URL: View this record in MEDLINE/PubMed

Language: English

In: Journal of pediatric ophthalmology and strabismus, 2004, Vol.41(4), pp.247-8

Description: A 5-year-old boy presented with ocular anomalies including microphthalmos, colobomas of the iris, choroid, and optic nerve head, and strabismus. Magnetic resonance imaging of the head showed multiple bilateral asymmetric high signal intensity foci in the subcortical and periventricular white matter. Genetic counseling disclosed a 47,XXY karyotype.

Keywords: Abnormalities, Multiple ; Magnetic Resonance Imaging ; Brain -- Pathology ; Choroid -- Abnormalities ; Coloboma -- Diagnosis ; Iris -- Abnormalities ; Klinefelter Syndrome -- Diagnosis

ISSN: 0191-3913

E-ISSN: 19382405

DOI: 10.3928/0191-3913-20040701-17

URL: View this record in MEDLINE/PubMed

Language: German

In: Klinische Monatsblätter für Augenheilkunde, 1999, Vol.215(09), pp.203-204

Description: Zusammenfassung Hintergrund Frischer Saft von Euphorbiaceen führt zu Verätzungen der Augen und der Haut. Von Alters her wurde der Saft für die Verätzung von Warzen eingesetzt. Patienten Nach dem Kontakt mit Wolfsmilchsaft (Saft von der Gartenpflanze Euphorbia myrsinites) kam es bei drei Kindern zu einer toxischen Dermatitis. Beim jüngsten Kind bestand zusätzlich eine Konjunktivitis und eine Okklusion des rechten Auges. Bei allen drei Kindern kam es zur völligen Abheilung. Phorbolester werden für die Zytotoxizität des Milchsaftes der Euphorbiaceen verantwortlich gemacht. Schlußfolgerung Die Gefahren dieser Gartenpflanze und die möglichen Verätzungen am Auge sind noch wenig bekannt.

Description: SummaryBackground Fresh sap of euphorbiaceae leads to a toxic burn of the skin and the eyes. Since years the sap of euphorbiaceae has been used in the treatment of different kinds of verrucas.Patients After contact with the sap of Euphorbia myrsinites three children developped a toxic dermatitis. In addition, the youngest girl showed a conjunctivitis and an occlusion of the right eye. Phorbolesters are considered to be responsible for the toxicity of the euphorbiaceae. All three children have resulted in a restitutio ad integrum.Conclusion This case report is demonstrating the danger of toxic burn of this kind of plant.

Keywords: Wolfsmilch ; Euphorbia ; Toxische Konjunktivitis ; Sap Of Euphorbiaceae ; Toxic Conjunctivitis

ISSN: 0023-2165

E-ISSN: 1439-3999

DOI: 10.1055/s-2008-1034700

URL: View record in Thieme (Access to full text may be restricted)

Language: German

In: Klinische Monatsblätter für Augenheilkunde, 2000, Vol.217(1), pp.55-58

Description: Zusammenfassung Hintergrund Gangliogliome sind seltene Hirntumoren. Im Nervus opticus wurden sie in lediglich sieben Fällen beschrieben. In zwei dieser Fälle bestand zusätzlich eine Neurofibromatose (NF). Ein pathogenetischer Zusammenhang zwischen Optikus-Gangliogliomen und NF ist allerdings umstritten. Patient Wir berichten über einen 71-jährigen Patienten mit einem Gangliogliom der Sehnerven und einer NF Typ 1. Bei der Autopsie wurden multiple Neurofibrome sowie Nävuszellnävi der Haut, multiple Neurofibrome des Nervus vagus und des linken Nervus femoralis, multiple subseröse Schwannome des proximalen Jejunums und Lisch-Knötchen beider Irides gefunden. Es fand sich eine deutliche spindelförmige Auftreibung des rechten Sehnervs im intrakraniellen Anteil, während der linke Sehnerv keine sichtbare Verdickung aufwies. Ergebnis Der Tumor setzte sich aus zwei verschiedenen Zelltypen zusammen, einerseits aus hoch differenzierten, teils sternförmigen teils pilozytisch geformten Astrozyten, andererseits fanden sich am Rande der Axonbündel des Sehnervs Ganglienzellen. Sie ließen sich für Synaptophysin- und Neurofilamente-Antigene gut markieren. Kernteilungen wurden weder in der neuronalen noch in der glialen Zellpopulation beobachtet. Trotz des ausgeprägten tumoralen Befalls der Sehnerven lagen keine Sehstörungen vor. Schlussfolgerung Optikus-Tumoren bei NF Typ 1 sind fast ausschliesslich Gliome (Astrozytome bzw. pilozytische Astrozytome). Unser Patient illustriert die seltene Variante eines glioneuronalen Tumors bei nachgewiesener NF Typ 1.

Description: Background Gangliogliomas are rare tumors of the central nervous system. In only seven cases they have been found within the optic nerve. Two of these cases were associated with neurofibromatosis (NF), but a pathogenic link between gangliogliomas of the optic nerve and NF still remains controversial.Patient Here we report on a 71-year-old patient with a ganglioglioma of the optic nerves and NF type 1. Post mortem examination revealed multiple neurofibromas of the vagal and left femoral nerves, multiple schwannomas of the small bowel and Lisch noduli of both irides. In addition, a spindle shaped thickening of the right optic nerve was observed in its intracranial portion. The left optic nerve was normal on gross inspection.Result Histologically, tumoral tissue was found in both optic nerves. The tumor was composed of two cell types: highly differentiated, partly stellate, partly pilocytic astrocytes and, at the rim of the axon bundles of the optic nerve, fully developped synaptophysin- and neurofilament-antigen-positive ganglion cells with short corkskrew-shaped processes. No mitosis could be found in the neuronal or in the glial cell population. In spite of the tumoral involvement of the optic nerves, there has been no evidence of visual disturbance.Conclusion Optic nerve tumors in NF most often are of glial origin (astrocytomas, pilocytic astrocytomas). Our case illustrates the rare condition of a glioneuronal tumor associated with neurofibromatosis type 1.

Keywords: Gangliogliom ; Nervus Opticus ; Neurofibromatose ; Ganglioglioma ; Nervus Opticus ; Neurofibromatosis

ISSN: 0023-2165

E-ISSN: 1439-3999

DOI: 10.1055/s-2000-10384

URL: View record in Thieme (Access to full text may be restricted)

In: Melanoma Research, 2007, Vol.17(2), pp.109-116

Description: The aim of this study was to investigate the role of NBS1 in the pathogenesis of malignant melanoma of the skin. To exclude the common 657del5 founder mutation, a total of 376 melanoma patients from Southern Germany were analyzed for sequence alterations in exon 6 of NBS1 by direct sequencing. Analyses revealed one 657del5 mutation and three nonsynonymous sequence variations in exon 6 of NBS1 (V210F, R215W, and F222L). Analysis of an additional sample of 629 melanoma patients and 604 controls revealed no F222L mutation, indicating that this newly identified sequence alteration is not a common polymorphism. In a case–control association study including 632 melanoma patients and 615 cancer-free control participants from Southern Germany, three publicly known single nucleotide polymorphisms located in the NBS1 gene region were analyzed. No significant associations between single nucleotide polymorphisms (rs9995, rs867185 and rs1063045) or referring calculated haplotypes and melanoma risk were identified. These results suggest that NBS1 does not play a major role in predisposition to melanoma in the Southern German population but that alterations of this gene might contribute to the risk of this cancer.

Keywords: Genetic Predisposition to Disease ; Cell Cycle Proteins -- Genetics ; DNA Mutational Analysis -- Methods ; Melanoma -- Genetics ; Nuclear Proteins -- Genetics ; Skin Neoplasms -- Genetics;

ISSN: 0960-8931

DOI: 10.1097/CMR.0b013e3280dec638

URL: View record at Wolters Kluwer Health Ovid Technologies