1,721,296 research outputs found
KIF21A variant R954W in familial or sporadic cases of CFEOM1
No full textPURPOSE. To demonstrate the clinical characteristics and determine mutations in the KIF21A gene, encoding a kinesin motor protein in patients with congenital fibrosis of the extraocular muscles (CFEOM) type 1. METHODS. Patients of five families with congenital fibrosis syndrome and two simplex patients with CFEOM underwent ophthalmologic examination and mutation analysis in the KIF21A gene. RESULTS. Clinical examination and passive motility testing prior to surgery met criteria for CFEOM. All patients had congenital restrictive ophthalmoplegia primarily affecting muscles innervated by the oculomotor nerve. Complete mutation screening in the KIF21A gene revealed the presence of the known and most common recurrent variant R954W in three families and in two simplex cases. Two families demonstrated linkage to chromosome 16. CONCLUSIONS. The patients included in the study had marked restriction of movement bilaterally with nearly complete loss of vertical ocular motility, graded reduction of horizontal motility, ptosis, and compensatory chin elevation. The phenotype was variable in patients carrying the same mutation. In one family, all patients were diagnosed with mental retardation, indicating that this syndrome might not only affect the development of cranial nerves, but can also be responsible for general neurologic dysfunction. The screening data suggest frequent and exclusive appearance of the R454W variant in sporadic and familial cases of CFEOM1 in Germany. (Eur J Ophthalmol 2009; 19: 667-74
KIF21A variant R954W in familial or sporadic cases of CFEOM1
No full textPURPOSE. To demonstrate the clinical characteristics and determine mutations in the KIF21A gene, encoding a kinesin motor protein in patients with congenital fibrosis of the extraocular muscles (CFEOM) type 1. METHODS. Patients of five families with congenital fibrosis syndrome and two simplex patients with CFEOM underwent ophthalmologic examination and mutation analysis in the KIF21A gene. RESULTS. Clinical examination and passive motility testing prior to surgery met criteria for CFEOM. All patients had congenital restrictive ophthalmoplegia primarily affecting muscles innervated by the oculomotor nerve. Complete mutation screening in the KIF21A gene revealed the presence of the known and most common recurrent variant R954W in three families and in two simplex cases. Two families demonstrated linkage to chromosome 16. CONCLUSIONS. The patients included in the study had marked restriction of movement bilaterally with nearly complete loss of vertical ocular motility, graded reduction of horizontal motility, ptosis, and compensatory chin elevation. The phenotype was variable in patients carrying the same mutation. In one family, all patients were diagnosed with mental retardation, indicating that this syndrome might not only affect the development of cranial nerves, but can also be responsible for general neurologic dysfunction. The screening data suggest frequent and exclusive appearance of the R454W variant in sporadic and familial cases of CFEOM1 in Germany. (Eur J Ophthalmol 2009; 19: 667-74
Thyroid Hormone Receptors Predict Prognosis in BRCA1 Associated Breast Cancer in Opposing Ways.
Full text linkSince BRCA1 associated breast cancers are frequently classified as hormone receptor negative or even triple negative, the application of endocrine therapies is rather limited in these patients. Like hormone receptors that bind to estrogen or progesterone, thyroid hormone receptors (TRs) are members of the nuclear hormone receptor superfamily. TRs might be interesting biomarkers - especially in the absence of classical hormone receptors. The current study aimed to investigate whether TRs may be specifically expressed in BRCA1 associated cancer cases and whether they are of prognostic significance in these patients as compared to sporadic breast cancer cases. This study analyzed TRα and TRβ immunopositivity in BRCA1 associated (n = 38) and sporadic breast cancer (n = 86). Further, TRs were studied in MCF7 (BRCA1 wildtype) and HCC3153 (BRCA1 mutated) cells. TRβ positivity rate was significantly higher in BRCA1 associated as compared to sporadic breast cancers (p = 0.001). The latter observation remained to be significant when cases that had been matched for clinicopathological criteria were compared (p = 0.037). Regarding BRCA1 associated breast cancer cases TRβ positivity turned out to be a positive prognostic factor for five-year (p = 0.007) and overall survival (p = 0.026) while TRα positivity predicted reduced five-year survival (p = 0.030). Activation of TRβ resulted in down-modulation of CTNNB1 while TRα inhibition reduced cell viability in HCC3153. However, only BRCA1 wildtype MCF7 cells were capable of rapidly degrading TRα1 in response to T3 stimulation. Significantly, this study identified TRβ to be up-regulated in BRCA1 associated breast cancer and revealed TRs to be associated with patients' prognosis. TRs were also found to be expressed in triple negative BRCA1 associated breast cancer. Further studies need to be done in order to evaluate whether TRs may become interesting targets of endocrine therapeutic approaches, especially when tumors are triple-negative
Validation of important prognostic marker with ovarian cancer
No full textIn der Doktorarbeit wurden bereits vorliegende microarray-basierte mRNA-Expressionsdaten bzgl. des Gens HOMER2 mit einer unabhängigen Analysetechnik, der quantitativen PCR (qPCR) bestätigt und nachfolgend die Assoziation der Expression mit dem Überleben an einem größeren und unabhängigen Kollektiv validiert. Anschließend wurde die HOMER2-Expression auf Proteinebene untersucht. Als Ergebnis konnte gezeigt werden, dass eine hohe Expression von HOMER2, sowohl auf mRNA-Ebene als auch auf Proteinebene, signifikant mit einem längeren Gesamt- und rezidivfreien Überleben von Ovarialkarzinompatientinnen, die eine adjuvante Chemotherapie erhalten hatten, assoziiert war.This doctoral thesis applied an independent analysis technique, the qPCR, to confirm microarray based mRNA expression data regarding the gene HOMER2. The association between HOMER2 mRNA expression and patient survival was validated in an independent, larger patient cohort. Subsequently, the HOMER2 expression was also examined on protein level. Both examinations, on mRNA as well as protein level, indicated that high HOMER2 expression is significantly associated with a longer overall and progression free patient survival
Incidence and outcome of triple-negative BRCA1-mutation carriers
No full textTripel-negative Tumore, definiert durch die fehlende Expression von Östrogen-, und Progesteronrezeptoren sowie des HER2neu, stellen eine Subgruppe der Mammakarzinome dar, die sich durch eine schlechte Prognose aufgrund fehlender gezielter Therapieoptionen auszeichnen und vor allem junge Frauen betreffen. Da häufig Tumore, die bei BRCA1-Mutationsträgerinnen auftreten eben diesen Phänotyp aufweisen, wird in dieser Untersuchung im Umkehrschluss die Frage nach der tatsächlichen Häufigkeit von Mutationsträgerinnen im unselektierten tripel-negativen Kollektiv gestellt. Die hierzu mittels Schmelzkurvenanalyse durchgeführten Mutationsdiagnostiken konnten eine Mutationsfrequenz von 10% ermitteln. Weiter wurde der Mutationsstatus bei tripel-negativen Patientinnen als prognostischer Parameter untersucht, da bekannt ist, dass aufgrund bestehender BRCA1-Insuffizinez eine eingeschränkte Fähigkeit zur Doppelstrangreperatur und somit möglicherweise eine erhöhte Sensibilität für direkt DNA schädigende chemotherapeutische Substanzen besteht. Eine statistische Relevanz bezüglich eines prognostischen Vorteils, sowohl für das progressionsfreie, als auch für das Gesamtüberleben bei tripel-negativen Mutationsträgerinnen, ergab sich trotz klinischer Hinweise im betrachteten Kollektiv dieser Studie nicht.Triple-negative breast cancer is defined as a cancer type that lacks estrogen, progesterone and Her2-neu receptors. It offers very few available treatment options and has therefore an overall poor prognosis. Furthermore, this phenotype affects especially young women as well as carriers of the BRCA1 mutation. The purpose of this research was to determine the frequency of BRCA1 mutation carriers in an unselect group of women with triple-negative breast cancer. The used high-resolution melting analysis determined a mutation frequency of 10 %. Due to the correlation between BRCA1 and double strand repair as well as possible effects on increased sensibility of chemotherapeutic agents that damage DNA, the purpose was to find out if there is any effect on the outcome. Unfortunately, this research found no benefit for BRCA1 mutation carriers for overall and progression free survival
Methylation analysis of the BRCA1 gene in triple-negative breast cancer
No full textIn dieser Doktorarbeit wurde experimentell an 170 DNA-Proben von tripel-negativen Mammakarzinomen untersucht, ob es in dieser Subgruppe zu gehäuftem Auftreten von Gen inaktivierenden epigenetischen Veränderungen, insbesondere von Promotorhypermethylierung im BRCA1-Gen, kommt. Es wird eine Methylierungshäufigkeit von 15% gefunden. Die Korrelation der experimentellen Ergebnisse mit den Überlebensdaten der Patientinnen zeigt, dass die Promotormethylierung mit einem signifikant längeren rezidivfreien Intervall vergesellschaftet ist.In this experimental study we analyzed 170 DNA probes of triple-negative breast cancers to identify if there is a increased occurrence of gene silencing epigenetic alterations, in particular BRCA1 gene promotorhypermethylation. A methylation frequency of 15% is found. The correlation of the experimental results with the survival data of the affected women shows that a promotorhypermethylation is linked with a significantly longer disease free survival
Tumor suppressor gene KAI1 and its splice variant in ovarian cancer
No full textDiese Arbeit befasst sich mit der prognostischen Relevanz des Tumorsuppressorgens KAI1 und seiner Spleißvariante bei Patientinnen mit Ovarialkarzinom. Es konnte gezeigt werden, dass insbesondere R0 resezierte und platinhaltig-chemotherapierte Patientinnen bei hoher KAI1 mRNA Expression ein längeres Gesamt- sowie rezidivfreies Überleben haben. Zudem zeigte sich für Patientinnen in FIGO Stadium 3 bei hoher Expression der Spleißvariante ein signifikant schlechteres rezidivfreies Überleben.This thesis analyses the prognostic relevance of tumor suppressor gene KAI1 and its splice variant for patients with ovarian cancer. We could show, that especially patients with R0 resection and platin chemotherapy, high KAI1 mRNA expression levels have a longer overall and progression-free survial. Moreover, patients with FIGO stadium 3 and high expression of the splice variant have a significant reduction of progression-free survival
Low-risk variants in familial breast cancer
No full textIn den Studien des GC-HBOC war im Gen LSP1 neben dem, als Risikovariante für das Mammakarzinom bereits bekannten SNP rs3817198, ein weiterer SNP, rs2271439, aufgefallen. Die Validierung dieses SNP in 368 weiteren Proben zeigte einen statistisch signifikanten Zusammenhang mit Brustkrebs, mit einer stärkeren Ausprägung des Effekts in Hochrisikofamilien. Die Sequenzierung des Gens LSP1 zeigte, dass der bekannte SNP rs3817198 und der neu charakterisierte SNP rs2271439 nicht im Kopplungsungleichgewicht, d. h. auf zwei Allelen, liegen. Außerdem wurden in 1501 zusätzlichen DNA-Proben weitere, publizierte oder noch unbekannte, Einzelbasen-polymorphismen, validiert. Dabei konnten bekannte SNPs wie in den Genen RAD51L und FGFR2 bestätigt werden. Aber auch neue SNPs wie z.B. die SNPs rs1175332, rs2378556 und rs400161 im Bereich des Gens TLE1, rs2394829 im Gen CDH23 und rs1610374 zeigten eine signifikante Assoziation. Schließlich wurden zusätzlich ca. 800 SNPs ausgewählt, die im Rahmen der umfassenden iCOGS-Studie untersucht wurden und deren Ergebnisse demnächst zu erwarten sind.In addition to a known low risk variant for breast cancer, the SNP rs3817198 located in the gene LSP1, another one, rs2271439,has been identified in the studies of GC-HBOC. This new SNP was validated within this thesis in further 368 cases. We showed that there is a statistically significant association with breast cancer, with a stronger effect in high-risk families. Sequencing of the gene LSP1 gene showed that the known SNP rs3817198 and the newly characterized SNP rs2271439 are not genetically linked. Additionally, we genotyped further 1501 new cases for published or novel SNPs. Thereby, we were able to confirm known SNPs in the genes RAD51L and FGFR2, but also new SNPs showed a significant associations, like rs1175332, rs2378556, and rs400161 in the gene TLE1, rs2394829 in the gene CDH23, and rs1610374. Finally, we selected approx. 800 SNPs, which have been analyzed within a comprehensive iCOGS-study and whose results will be available soon
Analyses of DPYD-polymorphisms for clarification of 5-FU-associated side effects
No full textPrätherapeutisches Screening auf ein Vorliegen von Risikopolymorphismen im DPYD-Gen wurde als eine Möglichkeit der Identifizierung von Patienten mit hohem Risiko während einer 5-FU-haltigen Chemotherapie diskutiert. Im Mittelpunkt der Analysen stand die Einstufung der bekannten Varianten c.496A>G, IVS10-15T>C und c.1236G>A hinsichtlich ihrer Assoziation mit 5-FU Toxizität. Die Analysen wurden zudem auf ein Vorliegen des Risikofaktors c.1129-5923C>G hin untersucht, da dieser gekoppelt mit c.1236G>A aufzutreten schien. Darüber hinaus fanden wir bei der Abklärung eines Falles hochgradiger Toxizität die neuartige Spleißmutation IVS12-1G>A.Pretherapeutical screening for toxicity-associated polymorphisms in the dihydropyrimidine dehydrogenase gene has been supposed as one possible approach to identify patients at risk during 5-FU-based chemotherapy. It was our central issue to categorize the known single nucleotide polymorphisms c.496A>G, IVS10-15T>C and c.1236G>A regarding their relation to 5-FU toxicity. Our samples were also analyzed for the risk factor c.1129-5923C>G, as it appeared to be linked with c.1236G>A. Moreover, investigating a case of very strong side effects during 5-FU treatment, we found the new splice site mutation IVS12-1G>A
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