Hans K. Schackert

Genesis of cerebral aneurysms--an update.

Summary To elucidate the molecular pathogenesis of diseases has become a crucial step in the development of new treatment strategies. Although the pathogenesis of cerebral aneurysms has been studied intensively, it is poorly understood. Endogenous factors like elevated arterial blood pressure, the special anatomy of the Circle of Willis or the effect of haemodynamic factors, particularly originating at vessel bifurcation, are all known to be involved in the growth and rupture of an aneurysm. There is an ongoing discussion as to whether these factors also contribute to the very early steps of pathogenesis. Arteriosclerosis and secondary inflammatory reactions are thought to be elementary preconditions. Exogenous factors like cigarette smoking, heavy alcohol consumption or certain medications known to help generate arteriosclerosis and elevated blood pressure have also been found to be related to the occurrence of cerebral aneurysms. Furthermore, there has been a long-lasting debate on whether aneurysms might develop as a result of an inborn genetic defect. First-degree relatives of patients with cerebral aneurysms have a higher risk of having an aneurysm. In addition, the elevated prevalence of cerebral aneurysms in patients suffering from various inherited diseases points to a genetic background in the development of an aneurysm. Recent advances in molecular biology provide evidence that genetic variants of different candidate genes are associated with the occurrence of cerebral aneurysms. The aim of this review is to expose the current status of these various hypotheses and their contribution to the pathogenesis of cerebral aneurysms in order to provide a basis for future investigations in this field.

Involvement of hMSH6 in the development of hereditary and sporadic colorectal cancer revealed by immunostaining is based on germline mutations, but rarely on somatic inactivation

Germline mutations in human mismatch repair (MMR) genes yield a predisposition for the hereditary nonpolyposis colon cancer (HNPCC) syndrome. In contrast to hMLH1 and hMSH2, little is known about the overall involvement of hMSH6 in colorectal cancer. We investigated 82 tumors from patients who fulfilled the Bethesda guidelines for HNPCC as well as 146 sporadic tumors, analyzing microsatellite instability and expression of the 4 MMR proteins hMSH6, hMSH2, hMLH1 and hPMS2. Four tumors with lost expression and 1 tumor with cytoplasmic expression of hMSH6 were identified. Sequence analysis revealed germline mutations in 4 of the 5 patients, including 1 patient with sporadic disease. The lost or reduced expression of hMSH2 and hMLH1 was always identical to its heterodimerization partners, hMSH6 and hPMS2, respectively. Furthermore, hMSH2 expression was reduced upon hMSH6 deficiency. Abnormal expression of 1 or more of the 4 proteins was always associated with a high level of microsatellite instability (MSI‐H). Conversely, all but 1 of the 44 MSI‐H tumors had abnormal expression of 1 or more of the proteins, basically excluding additional genes associated with the MSI‐H phenotype. We conclude that the involvement of somatic or epigenetic hMSH6 inactivation in colorectal cancer is rare.

Identification of uncommon chromosomal aberrations in the neuroglioma cell line H4 by spectral karyotyping.

To elucidate the reasons why mRNA expression of the LGI1 candidate tumor-suppressor gene was severely reduced in the glioma-derived cell line H4, as demonstrated in a previous study, we performed a cytogenetic analysis of this cell line using conventional methods and fluorescence in situ hybridization (FISH) techniques [spectral karyotyping (SKY), interphase- and chromosome FISH of metaphases (I- and C-FISH)]. Cell line H4 is monoclonal and near triploid (±3n). SKY enabled us to detect 24 structural aberrations: unbalanced translocations, n = 12; deletions, n = 10; insertion, n = 1; duplication, n = 1. The results were confirmed by I- and C-FISH analysis using chromosome-specific paints, centromer-specific probes and locus-specific probes for p53, PTEN/MMAC1, LGI1, Cyclin D1, EGR1, ETV6/TEL, AML1, and the genomic region 13q14.3 containing the Rb locus. We found loss of one copy of p53 as well as of one copy of Rb. Complete loss of PTEN/MMAC1 was detected, while all copies of LGI1 and Cyclin D1 were preserved. Interestingly, there was a gain of ETV6/TEL and EGR1, which were each present in quadruplicate. Additionally, the AML1 locus revealed mosaicism of cells with three and four copies, respectively. Additionally, a 5q-chromosome [del(5)(q13q33)] was found, which is one of the common features in hematological malignancies, and der(12)t(1;12) was found, suggesting that there might be an additional ETV6/TEL fusion protein.The combination of SKY, I- and C-FISH demonstrates that the neuroglioma cell line H4 harbors cytogenetic aberrations that are reported to occur in glioma-derived cell lines and additional chromosomal aberrations that have so far not been reported to occur in these cell lines. The complex aberrant karyotype and possibly generation of transcription factors by fusion proteins might be reasons for the impaired mRNA expression of the LGI1 candidate tumor-suppressor gene in cell line H4.

Albright's hereditary osteodystrophy associated with cerebellar pilocytic astrocytoma: coincidence or genetic relationship?

Albright’s hereditary osteodystrophy (AHO) is a rare inherited disease characterized by skeletal abnormalities, short stature, and, in some cases, resistance to parathyroid hormone, resulting in pseudohypoparathyroidism (PHP). Heterozygous inactivating mutations of the GNAS1 gene are responsible for reduced activity of the alpha subunit of the Gs protein (GSα), a protein that mediates hormone signal transduction across cell membranes. Gsα is also known to have oncogenic potentials, leading to the development of human pituitary tumors and Leydig cell tumors. Here, we report the 1st case, a 3.5-year-old girl, with classic AHO phenotype and PHP type 1A associated with a cerebellar pilocytic astrocytoma. Coincidence or genetic relationships of both diseases are discussed according to molecular findings and current literature.

Genomische Analyse des Matrix Metalloproteinase-2 Gens (MMP-2) als potentieller ätiologischer Faktor spontaner Aortenaneurysmen

Variable expression patterns of the matrix metalloproteinase-2 (MMP-2) gene in the wall of spontaneous aortic aneurysms suggest that the phenotype may be associated with functional genetic variants of this gene. Thus, we have analyzed the coding sequence of the MMP-2 gene in a group of 51 patients with abdominal aortic aneurysm and in a control group of 48 healthy individuals. We have identified ten new single nucleotide polymorphisms (SNP) and established a weak association of the SNP c.2122C > G with the phenotype. Our findings do not exclude a potential role for SNPs or haplotypes of the MMP-2 gene in the etiology of spontaneous abdominal aortic aneurysms.