Age-dependent performance of BRAF mutation testing in Lynch syndrome diagnostics.

BRAF V600E mutations have been reported as a marker of sporadic microsatellite instability (MSI) colorectal cancer (CRC). Current international diagnostic guidelines recommend BRAF mutation testing in MSI CRC patients to predict low risk of Lynch syndrome (LS). We evaluated the age-specific performance of BRAF testing in LS diagnostics.

Hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome.

Background: Hereditary nonpolyposis colorectal cancer HNPCC, Lynch syndrome) is a genetic disease of autosomal dominant inheritance. It is caused by a mutation in one of four genes of the DNA mismatch repair system and confers a markedly increased risk for various types of cancer, particularly of the colon and the endometrium. Its prevalence in the general population is about 1 in 500, and it causes about 2% to 3% of all colorectal cancers.

Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing Lynch syndrome.

Background: A positive family history, germline mutations in DNA mismatch repair genes, tumours with high microsatellite instability, and loss of mismatch repair protein expression are the hallmarks of hereditary non-polyposis colorectal cancer (Lynch syndrome). However, in ~10-15% of cases of suspected Lynch syndrome, no disease-causing mechanism can be detected.

Methods: Oligo array analysis was performed to search for genomic imbalances in patients with suspected mutation-negative Lynch syndrome with MLH1 deficiency in their colorectal tumours.

Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies.

Missense mutations of the DNA mismatch repair gene MLH1 are found in a significant fraction of patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC) and their pathogenicity often remains unclear. We report here all 88 MLH1 missense variants identified in families from the German HNPCC consortium with clinical details of these patients/families. We investigated 23 MLH1 missense variants by two functional in vivo assays in yeast; seven map to the ATPase and 16 to the protein interaction domain.

Examination of apoptosis signaling in pancreatic cancer by computational signal transduction analysis.

Background: Pancreatic ductal adenocarcinoma (PDAC) remains an important cause of cancer death. Changes in apoptosis signaling in pancreatic cancer result in chemotherapy resistance and aggressive growth and metastasizing. The aim of this study was to characterize the apoptosis pathway in pancreatic cancer computationally by evaluation of experimental data from high-throughput technologies and public data bases.

TLR4 and IL-18 gene variants in chronic periodontitis: impact on disease susceptibility and severity.

The aim of the study was to assess whether genotypes in the Toll-like receptor 4 gene and in the promoter of the interleukin-18 gene are associated with the susceptibility to chronic periodontitis. 108 chronic periodontitis patients and 76 controls were genotyped for c.896A>G/1196C>T (TLR4 gene) and for c.

TLR4 and IL-18 gene variants in aggressive periodontitis.

Aim: We aimed to assess the association of different genotypes with increased aggressive periodontitis susceptibility by studying functional relevant variants in the pathogen-recognition receptor Toll-like receptor 4 (TLR4) and variants in the promoter region of the pro-inflammatory cytokine interleukin-18 (IL-18).

Material And Methods: One hundred and eleven patients with aggressive periodontitis and 80 periodontally healthy controls were genotyped for four functional variants in the TLR4 gene (c.896A>G and c.

Frequent loss of the CDKN2C (p18INK4c) gene product in pituitary adenomas.

Genomic alterations of cyclin-dependent kinase inhibitors have been demonstrated in a variety of tumor types including brain tumors. Among them, the cyclin-dependent kinase inhibitor 2A (CDKN2A or p16(INK4a)) gene has been shown to be frequently deleted or inactivated in astrocytic tumors. The CDKN2C (p18(INK4c)) gene is functionally related to CDKN2A.

Further evidence for heritability of an epimutation in one of 12 cases with MLH1 promoter methylation in blood cells clinically displaying HNPCC.

Germline mutations in mismatch repair (MMR) genes, tumours with high microsatellite instability (MSI-H) and loss of MMR protein expression are the hallmarks of HNPCC (Lynch syndrome). While somatic MLH1 promoter hypermethylation is generally accepted in the tumorigenesis of sporadic tumours, abnormal MLH1 promoter methylation in normal body cells is controversially discussed as a mechanism predisposing patients to HNPCC. In all 94 patients suspected of HNPCC-syndrome with a mean age of onset of 45.

Functional Cathepsin C mutations cause different Papillon-Lefèvre syndrome phenotypes.

Aim: The autosomal-recessive Papillon-Lefèvre syndrome (PLS) is characterized by severe aggressive periodontitis, combined with palmoplantar hyperkeratosis, and is caused by mutations in the Cathepsin C (CTSC) gene. This study aimed to identify CTSC mutations in different PLS phenotypes, including atypical forms and isolated pre-pubertal aggressive periodontitis (PAP).

Material And Methods: Thirteen families with different phenotypes were analysed by direct sequencing of the entire coding region and the regulatory regions of CTSC.

Occult endometrial cancer and decision making for prophylactic hysterectomy in hereditary nonpolyposis colorectal cancer patients.

Background And Objective: Hereditary nonpolyposis colorectal cancer (HNPCC) is the most frequent form of hereditary colorectal cancer. In addition to the high lifetime risk for colorectal cancer in mutation carriers, there is also a remarkably increased risk for endometrial cancer (EC).

Methods: In this retrospective study, clinical and molecular approach to the individual decision making as to whether or not to perform a prophylactic hysterectomy in a subset of HNPCC patients is discussed.

Comparative genetic analysis of metachronous anaplastic oligoastrocytomas with extended recurrence-free interval.

Two metachronous anaplastic oligoastrocytomas with different cerebral locations were analyzed in a 51-year-old patient with an extended recurrence-free interval of 6 years and an a long survival of 9 years. Remarkably, the patient had not undergone adjuvant chemotherapy. Different cytogenetic and molecular techniques were performed including comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), allelic loss analysis, sequencing of p53, p16(INK4a)/CDKN2A and p14(ARF), EGFRamplification studies, investigation of the DNA mismatch repair system as well as tumor clonality.

Meta-analysis of microarray data on pancreatic cancer defines a set of commonly dysregulated genes.

Pancreatic ductal adenocarcinoma is the eighth most common cancer with the lowest overall 5-year relative survival rate of any tumor type today. Expression profiling using microarrays has been widely used to identify genes associated with pancreatic cancer development. To extract maximum value from the available gene expression data, we applied a meta-analysis to search for commonly differentially expressed genes in pancreatic ductal adenocarcinoma.

Therapy of hematogenous melanoma brain metastases with endostatin.

Purpose: Cerebral metastases represent the most common type of brain tumors. This study investigated the effects of endogenous endostatin on hematogenous cerebral melanoma metastases.

Experimental Design: Murine K1735 melanoma cells were transfected with the mouse endostatin cDNA.

Gene expression profiling of microdissected pancreatic ductal carcinomas using high-density DNA microarrays.

Pancreatic ductal adenocarcinoma (PDAC) remains an important cause of malignancy-related death and is the eighth most common cancer with the lowest overall 5-year relative survival rate. To identify new molecular markers and candidates for new therapeutic regimens, we investigated the gene expression profile of microdissected cells from 11 normal pancreatic ducts, 14 samples of PDAC, and 4 well-characterized pancreatic cancer cell lines using the Affymetrix U133 GeneChip set. RNA was extracted from microdissected samples and cell lines, amplified, and labeled using a repetitive in vitro transcription protocol.

An Ambystoma mexicanum EST sequencing project: analysis of 17,352 expressed sequence tags from embryonic and regenerating blastema cDNA libraries.

Background: The ambystomatid salamander, Ambystoma mexicanum (axolotl), is an important model organism in evolutionary and regeneration research but relatively little sequence information has so far been available. This is a major limitation for molecular studies on caudate development, regeneration and evolution. To address this lack of sequence information we have generated an expressed sequence tag (EST) database for A.

Microarray-based gene expression profiling in pancreatic ductal carcinoma: status quo and perspectives.

Background: Pancreatic ductal adenocarcinoma has an extremely poor prognosis. To improve the prognosis, novel molecular markers and targets for earlier diagnosis and adjuvant and/or neoadjuvant treatment need to be identified. One of the key techniques that has been developed to achieve this goal is DNA microarray profiling, which is used to identify the mechanisms of deregulated molecular functions in pancreatic carcinoma cells.

Genetic polymorphisms of drug-metabolizing enzymes and susceptibility to oral cavity cancer.

We investigated the association of polymorphisms of drug-metabolizing enzymes and susceptibility to oral cavity cancer. Polymerase chain reaction (PCR)-based analyses were performed on genomic DNA of 94 Caucasian patients in Germany and 92 healthy German controls to determine genotypes of polymorphisms in CYP1A1, GSTM1 and NAT2. For CYP1A1, the homozygous mutant genotype Val/Val did not occur.

Physical and functional characterization of the human LGI1 gene and its possible role in glioma development.

The human gene termed LGI1 (leucine-rich gene - glioma inactivated) has been isolated recently, and is supposed to be an additional candidate tumor suppressor gene involved in the formation and progression of glioblastoma multiforme [Chernova et al. (1998) Oncogene 17:2873-2881]. To test this hypothesis and to complete the characterization of the gene, we performed various detailed studies on the genomic structure, the mRNA expression level, the integrity of the cDNA, and retroviral gene transfer into LGI1-deficient cell lines.