H3 G34-mutant high-grade gliomas: integrated clinical, imaging and pathological characterisation of a single-centre case series.

BACKGROUND: Diffuse hemispheric glioma, H3 G34-mutant, is a novel paediatric tumour type in the fifth edition of the WHO classification of CNS tumours associated with an invariably poor outcome. We present a comprehensive clinical, imaging and pathological review of this entity. METHODS: Patients with confirmed H3 G34R-mutant high-grade glioma were included in a single-centre retrospective cohort study and examined for clinical, radiological and histo-molecular data. RESULTS: Twelve patients were enrolled in the study - 7 males/5 females; the mean age was 17.5 years (10-57 years). Most patients presented with signs of raised intracranial pressure (8/12). The frontal lobe (60%) was the prevalent location, with a mixed cystic-nodular appearance (10/12) and presence of vascular flow voids coursing through/being encased by the mass (8/12), and all tumours showed cortical invasion. Nine patients had subtotal resection limited by functional margins, two patients underwent supra-total resection, and one patient had biopsy only. 5-ALA was administered to 6 patients, all of whom showed positive fluorescence. Histologically, the tumours showed a marked heterogeneity and aggressive spread along pre-existing brain structures and leptomeninges. In addition to the diagnostic H3 G34R/V mutation, pathogenic variants in TP53 and ATRX genes were found in most cases. Potential targetable mutations in PDGFRA and PIK3CA genes were detected in five cases. The MGMT promoter was highly methylated in half of the samples. Methylation profiling was a useful diagnostic tool and highlighted recurrent structural chromosome abnormalities, such as PDGFRA amplification, CDKN2A/B deletion, PTEN loss and various copy number changes in the cyclin D-CDK4/Rb pathway. Radiochemotherapy was the most common adjuvant treatment (9/12), and the average survival was 19.3 months. CONCLUSIONS: H3 G34R-mutant hemispheric glioma is a distinct entity with characteristic imaging and pathological features. Genomic landscaping of individual tumours can offer an opportunity to adapt individual therapies and improve patient management.

Pseudoprogression in children, adolescents and young adults with non-brainstem high grade glioma and diffuse intrinsic pontine glioma.

Pseudoprogression (PsP) is a treatment-related phenomenon which hinders response interpretation. Its prevalence and clinical impact have not been evaluated in children/adolescents. We assessed the characteristics, risk factors and prognosis of PsP in children/adolescents and young-adults diagnosed with non-brainstem high grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG). Patients aged 1-21 years diagnosed with HGG or DIPG between 1995 and 2012 who had completed radiotherapy were eligible. PsP was assessed according to study-specific criteria and correlated with first-line treatment, molecular biomarkers and survival. Ninety-one patients (47 HGG, 44 DIPG) were evaluable. Median age: 10 years (range, 2-20). Eleven episodes of PsP were observed in 10 patients (4 HGG, 6 DIPG). Rates of PsP: 8.5 % (HGG); 13.6 % (DIPG). Two episodes of PsP were based on clinical findings alone; nine episodes had concurrent radiological changes: increased size of lesions (n = 5), new focal enhancement (n = 4). Temozolomide, MGMT methylation or H3F3A mutations were not found to be associated with increased occurrence of PsP. For HGG, 1-year progression-free survival (PFS) was 41.9 % no-PsP versus 100 % PsP (p = 0.041); differences in 1-year overall survival (OS) were not significant. For DIPG, differences in 1-year PFS and OS were not statistically significant. Hazard ratio (95 %CI) of PsP for OS was 0.551 (0.168-1.803; p = 0.325) in HGG; and 0.308 (0.107-0.882; p = 0.028) in DIPG. PsP occurred in both pediatric HGG and DIPG patients at a comparable rate to adult HGG. PsP was associated with improved 1-yr PFS in HGG patients. PsP had a protective effect upon OS in DIPG patients.

Comparative analysis of genome-wide association studies signals for lipids, diabetes, and coronary heart disease: Cardiovascular Biomarker Genetics Collaboration.

AIMS: To evaluate the associations of emergent genome-wide-association study-derived coronary heart disease (CHD)-associated single nucleotide polymorphisms (SNPs) with established and emerging risk factors, and the association of genome-wide-association study-derived lipid-associated SNPs with other risk factors and CHD events. METHODS AND RESULTS: Using two case-control studies, three cross-sectional, and seven prospective studies with up to 25 000 individuals and 5794 CHD events we evaluated associations of 34 genome-wide-association study-identified SNPs with CHD risk and 16 CHD-associated risk factors or biomarkers. The Ch9p21 SNPs rs1333049 (OR 1.17; 95% confidence limits 1.11-1.24) and rs10757274 (OR 1.17; 1.09-1.26), MIA3 rs17465637 (OR 1.10; 1.04-1.15), Ch2q36 rs2943634 (OR 1.08; 1.03-1.14), APC rs383830 (OR 1.10; 1.02, 1.18), MTHFD1L rs6922269 (OR 1.10; 1.03, 1.16), CXCL12 rs501120 (OR 1.12; 1.04, 1.20), and SMAD3 rs17228212 (OR 1.11; 1.05, 1.17) were all associated with CHD risk, but not with the CHD biomarkers and risk factors measured. Among the 20 blood lipid-related SNPs, LPL rs17411031 was associated with a lower risk of CHD (OR 0.91; 0.84-0.97), an increase in Apolipoprotein AI and HDL-cholesterol, and reduced triglycerides. SORT1 rs599839 was associated with CHD risk (OR 1.20; 1.15-1.26) as well as total- and LDL-cholesterol, and apolipoprotein B. ANGPTL3 rs12042319 was associated with CHD risk (OR 1.11; 1.03, 1.19), total- and LDL-cholesterol, triglycerides, and interleukin-6. CONCLUSION: Several SNPs predicting CHD events appear to involve pathways not currently indexed by the established or emerging risk factors; others involved changes in blood lipids including triglycerides or HDL-cholesterol as well as LDL-cholesterol. The overlapping association of SNPs with multiple risk factors and biomarkers supports the existence of shared points of regulation for these phenotypes.

Case Report: Brainstem angiocentric glioma presenting in a toddler child-diagnostic and therapeutic challenges.

Introduction: Angiocentric gliomas (AG) in brainstem location are exceedingly rare and might cause differential diagnostic problems and uncertainty regarding the best therapeutic approach. Hereby, we describe the clinicopathological findings in a brainstem AG presenting in a toddler child and review the literature. Case report: A 2-year-old boy presented with 5 weeks history of gait disturbances, frequent falls, left-sided torticollis and swallowing problems. MRI head showed a T2-hyperintense, partly exophytic mass lesion centred in the pontomedullary region, raising the possibility of diffuse midline glioma. The exophytic component was partially resected by suboccipital craniotomy, leaving intact the infiltrative component. Ventriculoperitoneal shunt was implanted due to postoperative hydrocephalus. Histological examination revealed a moderately cellular tumour consisted of bland glial cells infiltrating the brain parenchyma and radially arranged around the blood vessels. By immunohistochemistry, the tumour strongly expressed S100 and GFAP in addition to intense nestin positivity, while OLIG2 was negative in the perivascular tumour cells. DNA methylation array profiled the tumour as "methylation class diffuse astrocytoma, MYB or MYBL1-altered subtype B (infratentorial)" and an in-frame MYB::QKI fusion was identified by RNA sequencing, confirming the diagnosis of angiocentric glioma. The patient has been initially treated with angiogenesis inhibitor and mTOR inhibitor, and now he is receiving palliative vinblastine. He is clinically stable on 9 months follow-up. Conclusion: Brainstem AG may cause a diagnostic problem, and the surgical and oncological management is challenging due to unresectability and lack of response to conventional chemo-radiation. In the future, genetically-tailored therapies might improve the prognosis.

MGMT Promoter Methylation: Prognostication beyond Treatment Response.

MGMT promoter methylation is related to the increased sensitivity of tumour tissue to chemotherapy with temozolomide (TMZ) and thus to improved patient survival. However, it is unclear how the extent of MGMT promoter methylation affects outcomes. In our study, a single-centre retrospective study, we explore the impact of MGMT promoter methylation in patients with glioblastoma who were operated upon with 5-ALA. Demographic, clinical and histology data, and survival rates were assessed. A total of 69 patients formed the study group (mean age 53.75 ± 15.51 years old). Positive 5-ALA fluorescence was noted in 79.41%. A higher percentage of MGMT promoter methylation was related to lower preoperative tumour volume (p = 0.003), a lower likelihood of 5-ALA positive fluorescence (p = 0.041) and a larger extent of resection EoR (p = 0.041). A higher MGMT promoter methylation rate was also related to improved progression-free survival (PFS) and overall survival (OS) (p = 0.008 and p = 0.006, respectively), even when adjusted for the extent of resection (p = 0.034 and p = 0.042, respectively). A higher number of adjuvant chemotherapy cycles was also related to longer PFS and OS (p = 0.049 and p = 0.030, respectively). Therefore, this study suggests MGMT promoter methylation should be considered as a continuous variable. It is a prognostic factor that goes beyond sensitivity to chemotherapy treatment, as a higher percentage of methylation is related not only to increased EoR and increased PFS and OS, but also to lower tumour volume at presentation and a lower likelihood of 5-ALA fluorescence intraoperatively.

A role of matrix metalloproteinase-8 in atherosclerosis.

RATIONALE: Atherosclerotic lesions express matrix metalloproteinase (MMP)8, which possesses proteolytic activity on matrix proteins particularly fibrillar collagens and on nonmatrix proteins such as angiotensin (Ang) I. OBJECTIVE: We studied whether MMP8 plays a role in atherogenesis. METHODS AND RESULTS: In atherosclerosis-prone apolipoprotein E-deficient mice, inactivating MMP8 resulted in a substantial reduction in atherosclerotic lesion formation. Immunohistochemical examinations showed that atherosclerotic lesions in MMP8-deficient mice had significantly fewer macrophages but increased collagen content. In line with results of in vitro assays showing that Ang I cleavage by MMP8 generated Ang II, MMP8 knockout mice had lower Ang II levels and lower blood pressure. In addition, we found that products of Ang I cleavage by MMP8 increased vascular cell adhesion molecule (VCAM)-1 expression and that MMP8-deficient mice had reduced VCAM-1 expression in atherosclerotic lesions. Intravital microscopy analysis showed that leukocyte rolling and adhesion on vascular endothelium was reduced in MMP8 knockout mice. Furthermore, we detected an association between MMP8 gene variation and extent of coronary atherosclerosis in patients with coronary artery disease. A relationship among MMP8 gene variation, plasma VCAM-1 level, and atherosclerosis progression was also observed in a population-based, prospective study. CONCLUSIONS: These results indicate that MMP8 is an important player in atherosclerosis.

Coronary artery disease-related genetic variant on chromosome 10q11 is associated with carotid intima-media thickness and atherosclerosis.

OBJECTIVE: To investigate whether chromosome 10q11.21 influences common carotid intima-media thickness (IMT) and atherosclerosis and whether it is associated with stromal cell-derived factor-1α (SDF-1α) plasma levels. METHODS AND RESULTS: Variation on chromosome 10q11.21 has been consistently associated with coronary artery disease. The genetic variant lies upstream of the gene encoding SDF-1α. We genotyped 3 population cohorts (Bruneck [age range, 45 to 94 years; 50.0% men; n=738], Health2000 [age range, 46 to 76 years; 55.4% men; n=1237], and essential hypertension in families collected in the region of Oxford [HTO] [age range, 19 to 88 years; 47.9% men; n=770]) for single-nucleotide polymorphism rs501120 at the 10q11.21 locus and conducted a meta-analysis in these cohorts to ascertain a relationship between the polymorphism and carotid IMT. The analysis showed that individuals with the T/T genotype had a significantly higher carotid IMT than individuals with the C/T or C/C genotype (pooled weighted mean difference, 23 µm [95% CI, 9 to 37 µm], P=0.0014 under a fixed-effects model; and 23 µm [95% CI, 6 to 41 µm], P=0.009 under a random-effects model). In the Bruneck cohort, in which data for carotid atherosclerosis and plasma SDF-1α levels were available, we observed an association of the T/T genotype with a higher burden of atherosclerosis and increased susceptibility to the development of atherosclerosis during a 5-year follow-up (multivariable odds ratio, 1.73 [95% CI, 1.18 to 2.52]; P=0.005 for the recessive model) and an association between the T/T genotype and lower SDF-1α levels (2.62 ng/mL for T/T versus 2.74 ng/mL for C/C or C/T; P=0.023). CONCLUSIONS: The coronary heart disease-related variant at the 10q11.21 locus is associated with carotid IMT and atherosclerosis.

Transformation of Grade II to Grade III Rhabdoid-Papillary Meningioma: Is Stereotactic Radiosurgery the Culprit? A Case Report and Literature Review.

BACKGROUND: In the management of meningiomas, single-fraction stereotactic radiosurgery (SRS) is an established alternative treatment to surgical resection. However, its effects on tumorigenesis and malignant transformation are still uncertain. CASE DESCRIPTION: We have described a grade II parafalcine meningioma that was initially surgically resected (Simpson 2 clearance) and then managed with a single dose of SRS on recurrence. The tumor recurred again 7 years later, with histological features of a grade III rhabdoid-papillary lesion, with local brain invasion. CONCLUSION: To the best of our knowledge, this is the first report to describe malignant transformation of a grade II to grade III meningioma after SRS to date.

Advanced glycation end-product of low density lipoprotein activates the toll-like 4 receptor pathway implications for diabetic atherosclerosis.

OBJECTIVE: Diabetes is a major risk factor for coronary heart disease. Accumulation of advanced glycation end-products (AGEs) attributable to hyperglycemia in diabetics promotes the development of atherosclerosis. However, the underlying mechanisms remain unclear. METHODS AND RESULTS: The advanced glycation end-product of low-density-lipoprotein (AGE-LDL) induced proinflammatory cytokine production in human coronary artery endothelial cells and human- and mouse-macrophages. AGE-LDL stimulated cytokine synthesis was markedly reduced in mouse macrophages with a TLR4 loss-of-function mutation. Coimmunoprecipitation experiments indicated AGE-LDL interacts with TLR4, RAGE, and CD36. Incubation of cultured macrophages with TLR4, RAGE, or CD36 antibodies inhibited AGE-LDL stimulation of tumor necrosis factor (TNF)alpha production. A competitive binding inhibitor of TLR4 blocked AGE-LDL binding to the receptor. After transfection of a HEK293 cell system with wild-type TLR4, AGE-LDL activated a signaling pathway including p38 alpha, JNK, and ERK1 kinases and AP1, Elk1, and NF-kappaB transcription factors; the net result being increased cytokine production. These effects were absent when cells were transfected with empty plasmid. Two common polymorphisms in TLR4, D299G and T399I, reduced the response of TLR4 to lipopolysaccharide (LPS) but had no effect on AGE-LDL signaling. CONCLUSIONS: These results indicate that AGE-LDL activates a TLR4-mediated signaling pathway, thus inducing proinflammatory cytokine production. This mechanism may partly explain the increased risk of atherosclerosis observed in diabetics.

Haplotype effects on matrix metalloproteinase-1 gene promoter activity in cancer cells.

Increased expression of matrix metalloproteinase-1 (MMP1) is associated with poor prognosis in cancers. Several single nucleotide polymorphisms (-1607GG>G, -839G>A, -755G>T, -519A>G, -422T>A, -340C>T, and 320C>T) in the MMP1 gene promoter have recently been identified. In this study, we assessed the functional effects of these polymorphisms on MMP1 gene promoter activity in cell lines of melanoma (A2058 and A375), breast cancer (MCF7 and MDA-MB-231), lung cancer (A549 and H69), and colorectal cancer (HT-29, SW-620) by comparing the promoter strengths of 10 most common haplotypes deriving from these polymorphisms. In A2058 cells, the GG-G-G-A-T-T-T and GG-G-G-A-C-T haplotypes had 2-fold higher promoter activity than the GG-G-T-A-T-T-C, GG-G-G-A-A-T-T, GG-G-G-A-T-T-C, and GG-G-G-A-A-C-T haplotypes, which in turn, had 3-fold higher promoter activity than the G-G-T-A-A-C-T, G-A-T-G-T-T-T, G-A-T-G-A-C-T, and G-A-T-G-A-T-G haplotypes. In A375 and MDA-MB-231 cells, high expression haplotypes include not only the -1607GG-bearing haplotypes but also the G-A-T-G-A-T-T haplotype containing the -1607G allele. A similar trend was detected in A549 cells. In addition, in A549 cells, the GG-G-G-A-T-T-T haplotype had >2-fold higher promoter activity than several other -1607GG-bearing haplotypes. In MCF7 cells, the GG-G-G-A-T-T-T and G-G-T-A-A-C-T haplotypes had 1.5- to 4-fold higher promoter activity than the other haplotypes. These results suggest that the polymorphisms exert haplotype effects on the transcriptional regulation of the MMP1 gene in cancer cells, and indicate a need to examine haplotypes rather than any single polymorphism in genetic epidemiologic studies of the MMP1 gene in cancers.

Primary intracerebral INI1-deficient rhabdoid tumor with CD34 immunopositivity in a young adult.

BACKGROUND: Primary CNS malignant rhabdoid tumors are very rare in adults and much less is known about their biological behavior than in children. Recently, two adult cases of SMARCB1 (also known as INI1)-deficient tumor with rhabdoid cells have been described, suggesting an emerging group of primary meningeal SMARCB1-deficient tumors. We have recently encountered a case of INI1-deficient tumor with similar histology and immunophenotype to the above cases, but with a superficial cerebral, yet apparent intra-axial origin. CASE DESCRIPTION: A 22-year-old woman presented with approximately one year history of focal sensorimotor right upper limb seizures and recently developed a slowly progressive weakness in her right hand. An MRI of the brain demonstrated an avidly enhancing lesion centered on the left perirolandic region with no definite dural involvement. The patient underwent a complete surgical excision. Histology revealed a tumor with monotonous epithelioid and spindle-shaped cells in a mucoid/myxoid background. There was focal mitotic activity and a few necrotic areas, in addition to many rhabdoid cells. The immunohistochemistry was negative for INI1 and there was strong positivity with CD34, while focal smooth muscle actin (SMA) and epithelial membrane antigen (EMA) immunoreactivity were also noted. CONCLUSIONS: As an addition to the two cases of adult SMARCB1-deficient tumors recently described, we present a further adult case with a similar immunohistochemical profile but with an apparent intra-axial origin, questioning the necessary meningeal origin of this type of tumor. The prognosis of this adult INI1/SMARCB1-deficient tumor is to be determined, but may be better than the pediatric atypical/teratoid tumor (AT/RT).

Neuropathology and brain weight in traumatic-crush asphyxia.

Traumatic (crush) asphyxia is a rare condition caused by severe compression of the chest and trunk leading to often extreme so-called asphyxial signs, including cyanosis in head and neck regions, multiple petechiae, and subconjunctival haemorrhage as well as neurological manifestations. AIMS: To investigate the neuropathology and brain weight in traumatic asphyxia caused by different accidents such as industrial accidents and road traffic collision. MATERIAL AND METHODS: Post mortem records of 20 cases of traumatic asphyxia (TA) resulting from different causes of which four brains are available for comprehensive neuropathological examination. The expected brain weights for given body height and associated 95% confidence range were calculated according to the following formula: baseline brain weight (BBW) + body height x rate (g/cm). The 95% confidence range was calculated by adding and subtracting the standard error (SE) x 1.96 (7-8). RESULTS: There was a trend for higher brain weight in the TA cohort but it was not significant (1494 g vs 1404 g, p = 0.1). The upper limits of the brain weight of 95% confidence was 1680 g vs 1660 g, p = 0.9. The neuropathological examination of four available brains from the TA cohort showed severe congestion of blood vessels, perivascular haemorrhages and occasional ßAPP deposits consistent with early axonal disruption. CONCLUSION: Brain examination is informative as part of investigation of TA. Developing ischaemic changes and an increase in brain weight are the most likely indicators of a prolonged period of patient's survival.

Gliomatosis cerebri type 1 with extensive involvement of the spinal cord and BRAF V600E mutation.

Gliomatosis cerebri (GC) is a rare neoplasm in which there is a diffuse cerebral infiltration by malignant glial cells with relative conservation of the underlying structures. A 67-year-old lady was admitted complaining of balance problems, troubled breathing, stuttered speech, decreased mobility, progressive ataxia and also some mild cognitive problems. MRI demonstrated ill defined T2 hyperintensity with mild mass effect mainly involving the brain stem and cerebellar hemispheres, with minor signal abnormalities extending supratentorially along the corticospinal tracts. The imaging appearances were static over a year. No biopsy was performed. The patient received palliative care and died 2 years after initial presentation. Macroscopic examination of the brain showed an extensive firm white-grey lesion predominantly in the cerebellar white matter, the brainstem, spreading to the full length of the spinal cord and invading the sensory ganglia. Histology revealed an extensively infiltrating diffuse glioma with small elongated fusiform nuclei. Diagnosis of GC type 1 was made. Molecular genetic tests revealed BRAF V600E mutation, while no IDH1 & IDH2 mutations were found. GC should be taken into account in the differential diagnoses mainly when there is rapid clinical deterioration without clear evidence of radiological progression. Extensive spinal cord infiltration has been reported only in 9% and BRAF V600E mutation was detected only in one case in GC previously. Future clinical trials should address whether BRAF V600E mutant brain tumour patients will benefit from BRAF V600E-directed targeted therapies.

Two cases of multinodular and vacuolating neuronal tumour.

An unusual multinodular and vacuolating neuronal tumour (MVNT) has been described in the cerebral hemispheres of ten patients with adult-onset seizures. We report the findings in two cases with similar features, a surgical resection and the other an autopsy specimen.Case 1, a 34-year-old female, underwent surgical resection for a multinodular non-enhancing frontal white matter lesion causing intractable epilepsy. Case 2, presented with motor neurone disease (MND) at the age of 71 and MRI scanning revealed extensive multinodular non-enhancing white matter lesions in the temporal lobe. There was no history of epilepsy and post mortem histology confirmed MND.Macroscopically multiple small grey well-formed, discrete and coalescent nodules were seen in the deep cortex and subcortical white matter. On histology, mature-looking neurons with large cytoplasmic vacuoles were distributed in a fibrillary background, where vacuoles were also noted. In the resected tumour scattered oligodendroglia-like cells were present. No ganglion cells were seen. The vacuolated cells exhibited immunopositivity for synaptophysin, HuC/HuD and p62 but were negative for NeuN, neurofilament, GFAP, IDH1, nestin and CD34. Electron microscopy showed non-membrane bound cytoplasmic vacuoles in the neurons and in some neuronal processes. The seizures recurred in Case 1.Some clinicopathological features of this lesion suggest a possible relationship with dysembryoplastic neuroepithelial tumour (DNT) although the morphological features are not typical of DNT. Case 2 demonstrates that MVNT may remain asymptomatic.

IDH1-associated primary glioblastoma in young adults displays differential patterns of tumour and vascular morphology.

Glioblastoma is a highly aggressive tumour with marked heterogeneity at the morphological level in both the tumour cells and the associated highly prominent vasculature. As we begin to develop an increased biological insight into the underlying processes driving the disease, fewer attempts have thus far been made to understand these phenotypic differences. We sought to address this by carefully assessing the morphological characteristics of both the tumour cells and the associated vasculature, relating these observations to the IDH1/MGMT status, with a particular focus on the early onset population of young adults who develop primary glioblastoma. 276 primary glioblastoma specimens were classified into their predominant cell morphological type (fibrillary, gemistocytic, giant cell, small cell, oligodendroglial, sarcomatous), and assessed for specific tumour (cellularity, necrosis, palisades) and vascular features (glomeruloid structures, arcades, pericyte proliferation). IDH1 positive glioblastomas were associated with a younger age at diagnosis, better clinical outcome, prominent oligodendroglial and small cell tumour cell morphology, pallisading necrosis and glomeruloid vascular proliferation in the absence of arcade-like structures. These features widen the phenotype of IDH1 mutation-positive primary glioblastoma in young adults and provide correlative evidence for a functional role of mutant IDH1 in the differential nature of neo-angiogenesis in different subtypes of glioblastoma.

Distinct phenotypic differences associated with differential amplification of receptor tyrosine kinase genes at 4q12 in glioblastoma.

Gene amplification at chromosome 4q12 is a common alteration in human high grade gliomas including glioblastoma, a CNS tumour with consistently poor prognosis. This locus harbours the known oncogenes encoding the receptor tyrosine kinases PDGFRA, KIT, and VEGFR2. These receptors are potential targets for novel therapeutic intervention in these diseases, with expression noted in tumour cells and/or associated vasculature. Despite this, a detailed assessment of their relative contributions to different high grade glioma histologies and the underlying heterogeneity within glioblastoma has been lacking. We studied 342 primary high grade gliomas for individual gene amplification using specific FISH probes, as well as receptor expression in the tumour and endothelial cells by immunohistochemistry, and correlated our findings with specific tumour cell morphological types and patterns of vasculature. We identified amplicons which encompassed PDGFRA only, PDGFRA/KIT, and PDGFRA/KIT/VEGFR2, with distinct phenotypic correlates. Within glioblastoma specimens, PDGFRA amplification alone was linked to oligodendroglial, small cell and sarcomatous tumour cell morphologies, and rare MGMT promoter methylation. A younger age at diagnosis and better clinical outcome in glioblastoma patients is only seen when PDGFRA and KIT are co-amplified. IDH1 mutation was only found when all three genes are amplified; this is a subgroup which also harbours extensive MGMT promoter methylation. Whilst PDGFRA amplification was tightly linked to tumour expression of the receptor, this was not the case for KIT or VEGFR2. Thus we have identified differential patterns of gene amplification and expression of RTKs at the 4q12 locus to be associated with specific phenotypes which may reflect their distinct underlying mechanisms.

Primary glioblastoma with oligodendroglial differentiation has better clinical outcome but no difference in common biological markers compared with other types of glioblastoma.

BACKGROUND: Glioblastoma multiforme with an oligodendroglial component (GBMO) has been recognized in the World Health Organization classification-however, the diagnostic criteria, molecular biology, and clinical outcome of primary GBMO remain unclear. Our aim was to investigate whether primary GBMO is a distinct clinicopathological subgroup of GBM and to determine the relative frequency of prognostic markers such as loss of heterozygosity (LOH) on 1p and/or 19q, O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and isocitrate dehydrogenase 1 (IDH1) mutation. METHODS: We examined 288 cases of primary GBM and assessed the molecular markers in 57 GBMO and 50 cases of other primary GBM, correlating the data with clinical parameters and outcome. RESULTS: GBMO comprised 21.5% of our GBM specimens and showed significantly longer survival compared with our other GBM (12 mo vs 5.8 mo, P = .006); there was also a strong correlation with younger age at diagnosis (56.4 y vs 60.6 y, P = .005). Singular LOH of 19q (P = .04) conferred a 1.9-fold increased hazard of shorter survival. There was no difference in the frequencies of 1p or 19q deletion, MGMT promoter methylation, or IDH1 mutation (P = .8, P = 1.0, P = 1.0, respectively). CONCLUSIONS: Primary GBMO is a subgroup of GBM associated with longer survival and a younger age group but shows no difference in the frequency of LOH of 1p/19q, MGMT, and IDH1 mutation compared with other primary GBM.

Association between the chromosome 9p21 locus and angiographic coronary artery disease burden: a collaborative meta-analysis.

OBJECTIVES: This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD. BACKGROUND: Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability. METHODS: We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects. RESULTS: We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele. CONCLUSIONS: The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.

Association of MMP8 gene variation with an increased risk of malignant melanoma.

Matrix metalloproteinases (MMPs) are implicated in the development of cancers including malignant melanoma (MM) and breast cancer. We tested the possible association of MMP1 and MMP8 gene variation with these two types of cancer. We genotyped 300 unselected patients with MM, 300 consecutive breast cancer cases, 300 controls for melanoma, and 300 controls for breast cancer (age-matched and sex-matched healthy adults with negative cancer family histories). Our study showed that the MMP8 gene rs11225395 polymorphism was associated with the risk of developing MM (odds ratio: 1.69; 95% confidence interval: 1.02-2.80; P=0.040) for the A/A genotype and 1.49 (95% confidence interval: 1.03-2.17; P=0.035) for the A/G genotype compared with the G/G genotype. The A allele was over-represented among MM cases compared with controls (odds ratio=1.54; P=0.017). In-vitro assays showed that the A allele had a higher promoter activity than the G allele in melanoma cells. No association was detected between this variant and breast cancer susceptibility. We found no strong association between MMP1 variation and the risk of MM or breast cancer. The finding of this study indicates an influence of MMP8 gene variation on melanoma susceptibility.

Association of variation at the ABO locus with circulating levels of soluble intercellular adhesion molecule-1, soluble P-selectin, and soluble E-selectin: a meta-analysis.

BACKGROUND: Circulating levels of soluble intercellular adhesion molecule-1, soluble P-selectin, and soluble E-selectin have been associated with variation at the ABO locus. To evaluate these associations and the effect sizes, we performed a meta-analysis with new and previous reported data for polymorphism rs579459. METHODS AND RESULTS: Compared with major allele homozygotes, heterozygotes and minor allele homozygotes had 4.6% (95% CI, 3.4%-5.8%, P=7.3 × 10(-14)) and 7.2% (95% CI, 4.7%-9.7%, P=1.5 × 10(-8)), respectively, lower soluble intercellular adhesion molecule-1 levels (n=33 671). An allele dose-dependent association also was observed for soluble P-selectin (n=4921) with heterozygotes and minor allele homozygotes having 11.5% (95% CI, 7.2%-15.8%, P=1.7 × 10(-7)) and 18.6% (95% CI, 9.1%-28.1%, P=1.2 × 10(-4)), respectively, lower levels than in major allele homozygotes. A larger effect size, again consistent with an additive genetic model, was seen for soluble E-selectin (n=2860) whose level was 25.6% (95% CI, 19.0%-32.2%, P=2.1 × 10(-14)) lower in heterozygotes and 43.3% (95% CI, 36.9%-49.3%, P=4.3 × 10(-42)) lower in minor allele homozygotes than in major allele homozygotes. CONCLUSIONS: The data support the association of variation at the ABO locus with soluble intercellular adhesion molecule-1, soluble P-selectin, and soluble E-selectin levels.