NDRG1 prognosticates the natural course of disease in WHO grade II glioma.

There is a lack of relevant prognostic and predictive factors in neurooncology besides mutation of isocitrate dehydrogenase 1, codeletion of 1p/19q and promoter hypermethylation of O (6) -methylguanine-DNA-methyltransferase. More importantly, there is limited translation of these factors into clinical practice. The cancer genome atlas data and also clinical correlative analyses suggest a pivotal role for the epidermal growth factor receptor /protein kinase B/mammalian target of rapamycin (mTOR) pathway in both biology and the clinical course of gliomas. However, attempts to stratify gliomas by activating alterations in this pathway have failed thus far. The tumors of 40 patients with WHO grade II gliomas without immediate postoperative genotoxic treatment and known progression and survival status at a median follow-up of 12.2 years were analyzed for expression of the mTOR complex 2 downstream target N-myc downstream regulated gene (NDRG)1 using immunohistochemistry. Baseline characteristics for NDRG1 absent/low versus moderate/high patients were similar. Time to reintervention was significantly longer in the NDRG1 group (P = 0.026). NDRG1 may become a novel biomarker to guide the decision which WHO°II glioma patients may be followed without postsurgical intervention and which patients should receive genotoxic treatment early on. Validation of this hypothesis will be possible with the observational arm of the RTOG 9802 and the pretreatment step of the EORTC 22033/26032 trials.

Gross total but not incomplete resection of glioblastoma prolongs survival in the era of radiochemotherapy.

BACKGROUND: This prospective multicenter study assessed the prognostic influence of the extent of resection when compared with biopsy only in a contemporary patient population with newly diagnosed glioblastoma. PATIENTS AND METHODS: Histology, O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, and clinical data were centrally analyzed. Survival analyses were carried out with the Kaplan-Meier method. Prognostic factors were assessed with proportional hazard models. RESULTS: Of 345 patients, 273 underwent open tumor resection and 72 biopsies; 125 patients had gross total resections (GTRs) and 148, incomplete resections. Surgery-related morbidity was lower after biopsy (1.4% versus 12.1%, P = 0.007). 64.3% of patients received radiotherapy and chemotherapy (RT plus CT), 20.0% RT alone, 4.3% CT alone, and 11.3% best supportive care as an initial treatment. Patients ≤60 years with a Karnofsky performance score (KPS) of ≥90 were more likely to receive RT plus CT (P < 0.01). Median overall survival (OS) (progression free survival; PFS) ranged from 33.2 months (15 months) for patients with MGMT-methylated tumors after GTR and RT plus CT to 3.0 months (2.4 months) for biopsied patients receiving supportive care only. Favorable prognostic factors in multivariate analyses for OS were age ≤60 years [hazard ratio (HR) = 0.52; P < 0.001], preoperative KPS of ≥80 (HR = 0.55; P < 0.001), GTR (HR = 0.60; P = 0.003), MGMT promoter methylation (HR = 0.44; P < 0.001), and RT plus CT (HR = 0.18, P < 0.001); patients undergoing incomplete resection did not better than those receiving biopsy only (HR = 0.85; P = 0.31). CONCLUSIONS: The value of incomplete resection remains questionable. If GTR cannot be safely achieved, biopsy only might be used as an alternative surgical strategy.

Association of transcobalamin c. 776C>G with overall survival in patients with primary central nervous system lymphoma.

BACKGROUND: Chemotherapy for primary central nervous system lymphoma (PCNSL) is based on methotrexate (MTX), which interferes with both nucleic acid synthesis and methionine metabolism. We have reported previously that genetic variants with influence on methionine metabolism are associated with MTX side effects, that is, the occurrence of white matter lesions as a sign of MTX neurotoxicity. Here, we investigated whether such variants are associated with MTX efficacy in terms of overall survival in MTX-treated PCNSL patients. METHODS: We analysed seven genetic variants influencing methionine metabolism in 68 PCNSL patients treated with systemic and facultative intraventricular MTX-based polychemotherapy (Bonn protocol). RESULTS: Median age at diagnosis was 59 years (range: 28-77), 32 patients were female. Younger age (Wald=8.9; P=0.003) and the wild-type C (CC) allele of the genotype transcobalamin c (Tc2). 776C>G (Wald=6.7; P=0.010) were associated with longer overall survival in a multivariate COX regression analysis. CONCLUSION: This observation suggests that the missense variant Tc2. 776C>G influences both neurotoxicity and efficacy of MTX in the Bonn PCNSL protocol.

The prognostic value of IDH mutations and MGMT promoter status in secondary high-grade gliomas.

Reports about the prognostic value of IDH mutations and the promoter region of the O6-Methyl-guanyl-methyl-transferase gene in secondary high-grade gliomas (sHGG) are few in number. We investigated the prognostic value of IDH mutations and methylation of the promoter region of the MGMT gene in 99 patients with sHGG and analyzed the clinical course of those tumors. Patients with sHGG were screened for IDH mutations by direct sequencing, and, for promoter status of MGMT gene, by the methylation-specific polymerase chain reaction. A total of 48 of 99 patients (48.5 %) had secondary anaplastic gliomas (Group 1), while 51 patients had secondary glioblastomas (Group 2). The median survival time after malignant progression of all patients with sHGG and with an IDH mutation was 4 years, which is significantly longer than in patients with wild-type IDH (1.2 years, p = 0.009). Patients' survival was not significantly influenced by the tumors' MGMT promoter status, both in Group 1- 9.7 years vs. 6.1 years, methylated vs. unmethylated promoter (p = 0.330)-as well as in Group 2-1.5 years vs. 1.6 years, methylated versus unmethylated promoter (p = 0.829). In our population, the IDH mutation status was not associated with increased PFS or median survival time in sGBM patients. However, patients with secondary anaplastic glioma and IDH mutation had a significantly improved outcome. In addition, IDH mutations are a more powerful prognostic marker concerning both PFS and MS than the MGMT promoter status in those patients.

Rosette-forming glioneuronal tumor of the fourth ventricle in an elderly patient.

Rosette-forming glioneuronal tumor of the fourth ventricle (RGNT) is a rare condition, which previously has been described predominantly in middle-aged patients. There is limited experience with this kind of tumor in the elderly. Clinical, neuroimaging, and histological features of an example in a 70-year-old male who presented initially with vertigo are detailed and compared with published cases. Neuroimaging studies demonstrated a 4-cm cystic lesion in posterior fossa containing a 1-cm contrast-enhancing nodule on its lateral margin. The lesion was confined to the fourth ventricle and initially thought to be a hemangioblastoma until angiography clarified the minimal tumor vascularization. Gross total resection was achieved. Pathological examination showed a rosette-forming low grade tumor with a cell proliferation rate of 2% being consistent with RGNT. The postoperative course was uneventful and clinical symptoms resolved completely. There was no tumor recurrence after 2 years follow-up. We confirm that the rare and only recently characterized tumor entity of RGNT can also be found in elderly patients; furthermore, it can be associated with a benign course. The main differential diagnosis of RGNT resulting from CNS-imaging modalities in elderly patients are pilocytic astrocytoma and hemangioblastoma of the posterior fossa, which after metastasis are the most common primary adult intra-axial posterior fossa tumors. Therefore, a subtle preoperative radiological diagnosis is warranted and surgery should be performed by experienced hands to avoid neurological deterioration.

A MDR1 (ABCB1) gene single nucleotide polymorphism predicts outcome of temozolomide treatment in glioblastoma patients.

BACKGROUND: Some patients with glioblastoma multiform do not respond to temozolomide even though they have aberrant promoter methylation of the DNA repair enzyme O(6)-methylguanine methyltransferase (MGMT). This suggests that additional factors hamper temozolomide cytotoxicity. We aimed to confirm first that temozolomide is a target for the multidrug resistance transporter MDR1/ABCB1 and second to investigate whether genetic variants of the MDR1 gene are associated with the survival of glioblastoma patients treated with temozolomide. MATERIALS AND METHODS: Temozolomide-mediated cytotoxicity was determined by the colorimetric methyl-thiazol-tetrazolium assay in MDR-expressing and MDR-nonexpressing cell lines. Genotypes of three single nucleotide polymorphisms (SNPs) of the MDR1 gene (C1236T, G2677T, and C3435T), MDR1 mRNA expression levels, and the MGMT promoter methylation status were analyzed in 112 glioblastoma patients who had been treated either by surgery plus radiotherapy alone or by additional temozolomide chemotherapy. RESULTS: In vitro analysis revealed that temozolomide-mediated cytotoxicity is dependent on MDR1 expression. Multivariate analysis of MDR1 genotypes showed that the C/C variant of the exon12 C1236T SNP is predictive for survival of patients treated with temozolomide. This effect was independent of the MGMT methylation status. Patients with the C/C genotype had a 2-year overall survival of 37% compared with 8% and 10% for patients with C/T and T/T genotypes, respectively (P=0.02). No influence was seen in the group of patients with radiotherapy only. CONCLUSION: The genotype of the MDR1 exon12 C1236T SNP is a novel independent predictive factor for outcome of temozolomide treatment in glioblastoma patients.

DNA methylation, transcriptome and genetic copy number signatures of diffuse cerebral WHO grade II/III gliomas resolve cancer heterogeneity and development.

BACKGROUND: Diffuse lower WHO grade II and III gliomas (LGG) are slowly progressing brain tumors, many of which eventually transform into a more aggressive type. LGG is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the heterogeneity of the DNA methylome, its function in tumor biology, coupling with the transcriptome and tumor microenvironment and its possible impact for tumor development. METHODS: We here present novel DNA methylation data of an LGG-cohort collected in the German Glioma Network containing about 85% isocitrate dehydrogenase (IDH) mutated tumors and performed a combined bioinformatics analysis using patient-matched genome and transcriptome data. RESULTS: Stratification of LGG based on gene expression and DNA-methylation provided four consensus subtypes. We characterized them in terms of genetic alterations, functional context, cellular composition, tumor microenvironment and their possible impact for treatment resistance and prognosis. Glioma with astrocytoma-resembling phenotypes constitute the largest fraction of nearly 60%. They revealed largest diversity and were divided into four expression and three methylation groups which only partly match each other thus reflecting largely decoupled expression and methylation patterns. We identified a novel G-protein coupled receptor and a cancer-related 'keratinization' methylation signature in in addition to the glioma-CpG island methylator phenotype (G-CIMP) signature. These different signatures overlap and combine in various ways giving rise to diverse methylation and expression patterns that shape the glioma phenotypes. The decrease of global methylation in astrocytoma-like LGG associates with higher WHO grade, age at diagnosis and inferior prognosis. We found analogies between astrocytoma-like LGG with grade IV IDH-wild type tumors regarding possible worsening of treatment resistance along a proneural-to-mesenchymal axis. Using gene signature-based inference we elucidated the impact of cellular composition of the tumors including immune cell bystanders such as macrophages. CONCLUSIONS: Genomic, epigenomic and transcriptomic factors act in concert but partly also in a decoupled fashion what underpins the need for integrative, multidimensional stratification of LGG by combining these data on gene and cellular levels to delineate mechanisms of gene (de-)regulation and to enable better patient stratification and individualization of treatment.

[Chronic subdural hematoma in the elderly]. / Das chronische Subduralhämatom im Alter.

Chronic subdural hematoma (cSDH) is a common condition, the frequency of which further increases due to an aging population and more frequent use of antithrombotic drugs. It leads to unspecific symptoms and neurological deficits and is usually treated surgically. Burr hole trepanation and twist drill craniostomy have become the therapeutic standards with craniotomy being rarely used for recurrent cases. Although recurrences are relatively common, in most cases a good outcome can be achieved even in the elderly; however, as cSDH is associated with other comorbidities, it is indicative of an increased morbidity and mortality. Controlled trials need to be carried out to determine whether pharmacological therapies can also be beneficial in addition to surgical treatment.

Macrophage infiltration into experimental brain metastases: occurrence through an intact blood-brain barrier.

The purpose of this study was to examine the nature of the blood-brain barrier in experimental brain metastases. Syngeneic fibrosarcoma or melanoma cells were injected into the internal carotid arteries of mice. Several weeks later, once the experimental brain metastases were established, the mice were given injections iv of sodium fluorescein. The capillaries within the metastatic foci were enlarged and irregular, but there was no leakage of sodium fluorescein, showing that the blood-brain barrier was intact. The neoplastic lesions were infiltrated by mononuclear phagocytes, which were identified by immunohistochemical localization of the macrophage-specific antigen F4/80, class II major histocompatibility complex (MHC) antigens, and the macrophage product interleukin-1 (IL-1). The metastatic foci contained numerous stellate macrophages that expressed F4/80 and MHC class II antigens, but little IL-1. Round, monocyte-like F4/80 and MHC class II-positive cells were also observed within the tumor lesions and adhering to walls of the tumor microvasculature. Mice with fibrosarcoma brain metastases also had edematous lesions at sites remote from the metastatic foci that contained numerous astrocytes expressing class II MHC but not F4/80 antigens. In conclusion, the blood-brain barrier is intact within experimental brain metastases, yet macrophages of blood monocyte origin can infiltrate the lesions.

Site-specific metastasis of mouse melanomas and a fibrosarcoma in the brain or meninges of syngeneic animals.

Different subpopulations of cells from two different murine melanomas (K-1735 and B16) and a fibrosarcoma (UV-2237) were injected into the internal carotid artery of anesthetized syngeneic mice. Despite the common route of tumor cell injection, tumor lesions in the brain were unique to each tumor type and developed at different sites in the brain. Gross and histological examinations revealed that different subpopulations of cells derived from the K-1735 melanoma produced only parenchymal lesions, cells of the B16 melanoma produced lesions in the meninges and ventricles, and cells of the UV-2237 fibrosarcoma produced lesions throughout the brain. This site specificity for tumor growth was not due to the initial tumor cell arrest in the microvasculature of different regions-areas in the brain as evidenced by detailed studies with radiolabeled cells. The site specificity of this experimental brain metastasis was not random and correlated well with the clinical situation. The exact interactions of tumor cells with different microenvironments in the brain need further elucidation.

Malignant potential of cells isolated from lymph node or brain metastases of melanoma patients and implications for prognosis.

We studied the correlation between the formation of brain metastasis and the malignant growth potential of seven human melanoma cell lines, isolated from lymph node metastases (A375-SM, TXM-1, DM-4) or from brain metastases (TXM-13, TXM-18, TXM-34, TXM-40), and the potential of three variants of the mouse K-1735 melanoma. Growth rates in different concentrations of fetal bovine serum and colony-forming efficiency in semisolid agarose were measured, and the tumorigenicity and metastatic ability were determined in nude mice (for the human melanoma cell lines) or in C3H/HeN mice (for the K-1735 variants). The ability to form brain metastasis was tested by injection of cells into the carotid artery. A high colony-forming efficiency in agarose, especially at concentrations of agarose greater than 0.6%, corresponded with high tumor take rates, rapid tumor growth rates, and metastatic colonization of the lungs of the recipient mice. For the human melanomas, the lymph node metastasis-derived cells were more tumorigenic and metastatic than the brain metastasis-derived cells. In the K-1735 mouse melanoma, the tumorigenic and metastatic behavior of the cells after i.v. and s.c. injection corresponded with growth in agarose cultures. However, for growth in the brain after intracarotid injection, the different melanoma cell lines showed similar frequencies of tumor take, regardless of tumorigenicity in other sites of the recipient mice, although mice given injections of brain metastasis-derived cells survived longer than mice given injections of lymph node metastasis (human melanoma) or lung metastasis (K-1735 M-2)-derived cell lines. The results from the human and mouse melanoma cell lines show that the brain metastasis-derived cell lines were not more malignant than the lymph node or lung metastasis-derived cells. These data imply that the production of brain metastasis is not always the final stage of a metastatic cascade.

Metastatic potential of cloned murine melanoma cells transfected with activated c-Ha-ras.

We sought to determine whether the transfection of tumorigenic but not metastatic cells with the activated c-Ha-ras oncogene was invariably associated with acquisition of the metastatic phenotype. Three clonally derived lines of the K-1735 murine melanoma, characterized as nonmetastatic or poorly metastatic, were transfected with plasmids containing the 6.6-kilobase BamHI fragment of the mutant human c-Ha-ras gene and the neo gene, that confers resistance to neomycin (pSV2neoEJ). Cells transfected with pSV2neo, a plasmid containing the neo gene, served as controls for the procedure of Polybrene-mediated transfection. All cell lines were injected into syngeneic C3H/HeN and into athymic mice, and the results were compared with those produced by highly metastatic K-1735 M-2 cells. Although the pSV2neoEJ-transfected cells produced more rapidly growing s.c. tumors than the control cell lines did, the incidence of spontaneous metastasis was not increased. Following i.v. inoculation, the c-Ha-ras transfectants were retained in lung vasculature in greater proportions than pSV2neo counterpart transfectants were. The c-Ha-ras transfectants also produced significantly more lung tumor colonies, which grew faster than the few lung tumor colonies in mice given injections of control melanoma cells. We concluded that transfection of the activated c-Ha-ras oncogene into nonmetastatic K-1735 melanoma cells leads to accelerated tumor growth in vivo and can confer the ability to form lung colonies after i.v. injection but not the ability to metastasize from a primary s.c. tumor.

The putative tumor suppressor gene FHIT at 3p14.2 is rarely affected by loss of heterozygosity in primary human brain tumors.

To elucidate the role of the recently identified FHIT gene, located at 3p14.2 in human brain tumor carcinogenesis, a total of 259 tumors were analyzed for loss of heterozygosity (LOH) at microsatellite loci D3S1313, D3S1234, D3S1300, and D3S1481. In primary brain tumors, LOH was detected at a frequency of 8.4% (n = 214). Low-grade gliomas exhibited insignificantly lower LOH rates in comparison to high-grade gliomas (5.3%, n = 19, versus 11.1%, n = 90). Notably, no allelic loss was observed in 12 recurrent glioblastomas analyzed in comparison to their corresponding primary tumor lesions and in two astrocytomas with progression to higher grades of malignancy. Our data indicate that allelic loss of the FHIT gene is neither a critical event in carcinogenesis of primary brain tumors nor tumor grade-associated in astrocytic tumors. In contrast, observed LOH rate for brain metastases was as high as 54.5% (n = 45), in accordance with data thus far accumulated from analyses of corresponding primary tumors.

[Surgery for metastases, anatomical and ethical limits. Special aspect: oligometastases]. / Metastasenchirurgie - anatomische und ethische Grenzen. Besonderer Aspekt: Oligometastasierung.

The surgical resection of metastases is nowadays feasible in selected patients with multifocal metastatic disease due to the implementation of interdisciplinary multimodal therapeutic options. Anatomical limitations do not seem to represent obstacles which cannot be overcome because of the development of new surgical techniques. The cornerstone of the selection of patients is the correct staging diagnosis achieved through modern diagnostic tools; however, surgery alone does not always offer acceptable survival and recurrence-free rates. Furthermore, in every complex surgical procedure there is the risk of morbidity and mortality; therefore, parameters such as alternative therapeutic modalities, the individual situation of the patient and tumor biology have to be considered in order to make the correct selection of patients. This is one of the major future challenges and should never be driven by unfounded hopes and expectations of the patients. The same principle also applies for brain metastases, which represent the most common brain tumors. Approximately 70 % of patients with brain metastases have 1-3 lesions (oligometastases). Treatment is now individualized and the goal of therapy has shifted towards long-term survival (≥ 24 months) and improved quality of life. Under this aspect surgery is one of the important treatment options, particularly in patients with a single metastasis or oligometastases. Furthermore, approximately 20 % of patients who have recurrent brain metastases, successfully undergo a complete resection of tumors and with a Karnofsky performance status (KPS) score > 70 show a long-term survival of ≥ 24 months.

[Importance of preoperative and intraoperative imaging for operative strategies]. / Bedeutung der prä- und intraoperativen Bildgebung für die operative Strategie.

Recent advances in preoperative and postoperative imaging have an increasing influence on surgical decision-making and make more complex surgical interventions possible. This improves the possibilities for frequently occurring challenges and promoting improved functional and oncological outcome. This manuscript reviews the role of preoperative and intraoperative imaging in surgery. Various techniques are explained based on examples from hepatobiliary surgery and neurosurgery, in particular real-time procedures, such as the online use of augmented reality and in vivo fluorescence, as well as new and promising optical techniques including imaging of intrinsic signals and vibrational spectroscopy.

Low-level microsatellite instability phenotype in sporadic glioblastoma multiforme.

PURPOSE: Genetic instability is a hallmark of glioblastoma multiforme (GBM). Microsatellite instability (MSI) is a significant event in the tumorigenesis of many sporadic malignancies. The aim of our investigation was to study microsatellite instability in newly diagnosed glioblastomas. METHODS: MSI was investigated in 109 GBMs with 15 microsatellite markers. Immunohistochemistry was performed for the mismatch repair (MMR) proteins hMLH1, hMSH2, hPMS2, and hMSH6 in cases showing MSI. Sequence and promoter methylation status of hMLH1 were analyzed in the case of a decreased hMLH1 protein expression as well. To further investigate MSI(+) GBMs we carried out studies of LOH at selected chromosome regions, EGFR amplification, and sequence of p53 and PTEN. RESULTS: MSI was observed in six GBMs (5.5%) and it was more frequent in GBMs with a previous lower grade astrocytoma (18.8% vs. 3.2%). MMR protein staining was positive in all MSI(+) GBMs except in one case, which showed an aberrant expression of hMLH1 and hPMS2 without hMLH1 inactivation. Among MSI(+) GBMs, one tumor corresponded to the GBM molecular type 1 (p53 mutation, no EGFR amplification), another tumor to type 2 (wild-type p53, EGFR amplification), and four tumors to neither type (wild-type p53, no EGFR amplification). None of the six tumors carried a PTEN mutation. CONCLUSIONS: MSI in GBM might be caused by inactivation of minor MMR genes rather than by a deficiency of hMLH1 or hMSH2 and it appears not to play a decisive role in the pathogenesis of these tumors. MSI(+) GBMs predominantly showed a profile which included wild-type of p53 and PTEN and absence of EGFR amplification but MSI occurred in all GBM molecular subtypes.

Loss of heterozygosity accumulation in primary breast carcinomas and additionally in corresponding distant metastases is associated with poor outcome.

The occurrence of distant metastases is the most feared manifestation of breast cancer, often occurring years after the primary surgery and associated with poor survival. The dominant metastatic clone is characterized by an accumulation of genetic alterations, but it is not actually known at what stage of the metastatic cascade these alterations have occurred. We investigated allelic losses during breast cancer progression in a series of 17 primary breast carcinomas and 22 corresponding brain, liver, lung, and bone metastases (mean metastasis-free interval, 31 months) by analyzing 19 microsatellite markers on seven breast cancer- or metastasis-related chromosomal regions and correlated the incidence of combined loss of heterozygosity (LOH) with metastasis-free and postmetastatic survival. We found that, in comparison with the corresponding primary tumor, additional LOH events are frequently found in metastases and that the incidence of combined LOH in the primary tumor, plus the occurrence of additional LOH events in the distant metastases, correlated significantly with decreased postmetastatic survival. Combined LOH of the three breast cancer-related chromosomal regions alone or in combination with allelic loss at the p53 gene region seems to have a specific influence on the aggressive behavior of metastases. We hypothesize that the occurrence of additional LOH events is either involved in termination of dormancy of micrometastatic tumor cells at distant organ sites or acquired during further progression of metastases.

Genetic alterations of the tumor suppressor gene PTEN/MMAC1 in human brain metastases.

The high mutation rate in advanced brain tumors, recent functional studies, and the high frequency of mutations in prostate metastases all strongly suggest that PTEN/MMAC1 alterations are involved in the formation of metastases. We searched for genetic alterations in the PTEN/MMAC1 gene in 56 consecutive brain metastases from various primary tumors by loss of heterozygosity (LOH), direct sequence analysis, and differential PCR analysis. The highest LOH rates were detected in metastases deriving from lung (67%) and breast (64%) cancers. Three (25%) of the eight detected inactivating mutations (one nonsense mutation, one splice-site mutation, one 11-bp deletion, and five homozygous deletions) were found in metastases originating from 12 different lung carcinomas, suggesting that PTEN/MMAC1 alterations may play a role in the progression of this tumor. With the exception of lung carcinomas, our findings indicate that genetic abnormalities of the PTENM/MMAC1 gene are only involved in a relatively small subset of brain metastases. However, the discrepancy between the high overall LOH rate (50%) and the low frequency of PTEN/MMAC1 mutation detection rate (14%) suggests the presence of one or more additional tumor suppressor genes on chromosome 10q.

Lack of association between endoglin intron 7 insertion polymorphism and intracranial aneurysms in a white population: evidence of racial/ethnic differences.

BACKGROUND AND PURPOSE: Endoglin is a component of the transforming growth factor-beta receptor complex and is predominantly expressed on cell surfaces of endothelial cells. A polymorphism of the endoglin gene has previously been found to be associated with the occurrence of intracranial aneurysms in a Japanese population. In our study, we investigated whether this polymorphism is associated with the development of cerebral aneurysm in a white population. METHODS: The study population consisted of 121 white patients who had been treated for intracranial aneurysms, 124 healthy white blood donors, and 15 Japanese volunteers. Exon 7 of the endoglin gene and adjacent intronic sequences were amplified by polymerase chain reaction and analyzed by using an automated laser fluorescence detection system. RESULTS: A well-known insertion polymorphism (5'-TCCCCC-3', starting 23 bp distal from the 3' end of exon 7) was identified. The allele frequencies of the polymorphism were 35 (14.5%) of 242 alleles in the aneurysm group and 35 (14.1%) of 248 alleles in the white control group, which does not represent a statistically significant difference (P>0.85). The sequence of the polymorphism is complementary to that reported in the previously mentioned Japanese study. However, the 2 polymorphisms are identical. Under this assumption, the allele frequencies differ significantly among the Japanese controls in that particular study and the white controls in our study (27.8% versus 14.1%, respectively; P=0.0003). CONCLUSIONS: The genetic polymorphism in the vicinity of 3' end of exon 7 in the endoglin gene was not significantly associated with the occurrence of intracranial aneurysms in the white population. There are ethnic-related differences of allele frequencies between our white controls and the previously reported Japanese controls.