Intratumoral patterns of clonal evolution in gliomas

Few studies have explored the patterns of clonal evolution in gliomas. Here, we investigate the cytogenetic patterns of intratumoral clonal evolution of gliomas and their impact on tumor histopathology and patient survival. Cytogenetic analysis of 90 gliomas was performed in individual tumor cells (>200 cells/tumor) using multicolor (N = 16 probes) interphase-FISH. Overall, chromosome gains were more frequent than chromosome losses. Gains of chromosome 7 and/or EGFR amplification were detected in 91% of the cases, whereas del(9p21) (77%) and del(10q23) (78%) were the most frequent chromosome losses. Virtually, all cases (99%) showed >/=2 tumor cell clones, with higher numbers among high- versus low-grade gliomas (p = 0.001). Nine different cytogenetic patterns were found in the ancestral tumor clones. In most gliomas, ancestral clones showed abnormalities of chromosome 7, 9p, and/or 10q and cytogenetic evolution consisted of acquisition of additional abnormalities followed by tetraploidization. Conversely, early tetraploidization was associated with low-grade astrocytomas-2/3 pilocytic and 3/6 grade II diffuse astrocytomas-and combined loss of 1p36/19q13 with oligodendrogliomas, respectively; both aberrations were associated with a better patient outcome (p = 0.03). Overall, our results support the existence of different pathways of intratumoral evolution in gliomas

Amplified and Homozygously Deleted Genes in Glioblastoma: Impact on Gene Expression Levels

BACKGROUND: Glioblastoma multiforme (GBM) displays multiple amplicons and homozygous deletions that involve relevant pathogenic genes and other genes whose role remains unknown. METHODOLOGY: Single-nucleotide polymorphism (SNP)-arrays were used to determine the frequency of recurrent amplicons and homozygous deletions in GBM (n = 46), and to evaluate the impact of copy number alterations (CNA) on mRNA levels of the genes involved. PRINCIPAL FINDINGS: Recurrent amplicons were detected for chromosomes 7 (50%), 12 (22%), 1 (11%), 4 (9%), 11 (4%), and 17 (4%), whereas homozygous deletions involved chromosomes 9p21 (52%) and 10q (22%). Most genes that displayed a high correlation between DNA CNA and mRNA levels were coded in the amplified chromosomes. For some amplicons the impact of DNA CNA on mRNA expression was restricted to a single gene (e.g., EGFR at 7p11.2), while for others it involved multiple genes (e.g., 11 and 5 genes at 12q14.1-q15 and 4q12, respectively). Despite homozygous del(9p21) and del(10q23.31) included multiple genes, association between these DNA CNA and RNA expression was restricted to the MTAP gene. CONCLUSIONS: Overall, our results showed a high frequency of amplicons and homozygous deletions in GBM with variable impact on the expression of the genes involved, and they contributed to the identification of other potentially relevant genes

Genomic profiling distinguishes familial multiple and sporadic multiple meningiomas

<p>Abstract</p> <p>Background</p> <p>Meningiomas may occur either as familial tumors in two distinct disorders, familial multiple meningioma and neurofibromatosis 2 (NF2), or sporadically, as either single or multiple tumors in individuals with no family history. Meningiomas in NF2 and approximately 60% of sporadic meningiomas involve inactivation of the <it>NF2 </it>locus, encoding the tumor suppressor merlin on chromosome 22q. This study was undertaken to establish whether genomic profiling could distinguish familial multiple meningiomas from sporadic solitary and sporadic multiple meningiomas.</p> <p>Methods</p> <p>We compared 73 meningiomas presenting as sporadic solitary (64), sporadic multiple (5) and familial multiple (4) tumors using genomic profiling by array comparative genomic hybridization (array CGH).</p> <p>Results</p> <p>Sporadic solitary meningiomas revealed genomic rearrangements consistent with at least two mechanisms of tumor initiation, as unsupervised cluster analysis readily distinguished tumors with chromosome 22 deletion (associated with loss of the <it>NF2 </it>tumor suppressor) from those without chromosome 22 deletion. Whereas sporadic meningiomas without chromosome 22 loss exhibited fewer chromosomal imbalance events overall, tumors with chromosome 22 deletion further clustered into two major groups that largely, though not perfectly, matched with their benign (WHO Grade I) or advanced (WHO Grades II and III) histological grade, with the latter exhibiting a significantly greater degree of genomic imbalance (P < 0.001). Sporadic multiple meningiomas showed a frequency of genomic imbalance events comparable to the atypical grade solitary tumors. By contrast, familial multiple meningiomas displayed no imbalances, supporting a distinct mechanism for the origin for these tumors.</p> <p>Conclusion</p> <p>Genomic profiling can provide an unbiased adjunct to traditional meningioma classification and provides a basis for exploring the different genetic underpinnings of tumor initiation and progression. Most importantly, the striking difference observed between sporadic and familial multiple meningiomas indicates that genomic profiling can provide valuable information for differential diagnosis of subjects with multiple meningiomas and for considering the risk for tumor occurrence in their family members.</p

Phase I pharmacokinetic and pharmacodynamic study of the prenyl transferase inhibitor AZD3409 in patients with advanced cancer

AZD3409 is an orally active double prodrug that was developed as a novel dual prenyltransferase inhibitor. The formation of the active metabolite AZD3409 acid is mediated by esterases in plasma and cells. The aim of this phase I study was to determine the maximum tolerated dose, toxicities, pharmacokinetics and pharmacodynamics of AZD3409. AZD3409 was administered orally to patients with advanced solid malignancies using an interpatient dose-escalation scheme starting at 500 mg AZD3409 once daily. Twenty-nine patients were treated at seven dose levels. The MTD of part A was defined as 750 mg b.i.d. in the fasted state. Adverse events were mainly gastrointestinal and the severity was on average mild to moderate and reversible. The dose-limiting toxicities were vomiting, diarrhoea and uncontrolled nausea. Pharmacokinetic studies of the prodrug and the active metabolite indicated dose proportionality. Pharmacodynamic studies showed that farnesyltransferase (FTase) was inhibited at all dose levels. In conclusion, chronic oral dosing with AZD3409 is feasible and results in significant inhibition of FTase activity. Pharmacodynamic studies revealed that the maximal FTase inhibition, estimated at 49±11%, appeared to be reached at AZD3409 acid plasma concentrations at which the occurrence of drug-related toxicity was low. This study supports the rationale to implement biological effect studies in clinical trials with biologically active anticancer drugs to define optimal dosing regimens

Peripheral refraction in pseudophakic eyes measured by infrared scanning photoretinoscopy.

PURPOSE: To obtain quantitative data of peripheral refractive errors in pseudophakic eyes including measurements up to ±45 degrees on the retina. SETTING: University Eye Hospital, Tübingen, Germany. DESIGN: Population-based cross-sectional study. METHODS: Pseudophakic and phakic subjects were measured with a purpose-built scanning photorefractor. The instrument was improved over previous versions. It permits measurement of semicontinuous peripheral profiles over the central 90-degree field of the retina at a faster speed (4 s/scan). RESULTS: Twenty-four pseudophakic and 43 phakic subjects were enrolled. The intraocular lenses (IOLs) induced a mean myopic shift of 2.00 diopters (D) at ±45 degrees of eccentricity in the vertical pupil meridian. Ray-tracing simulations with phakic eye and pseudophakic eye models agreed well with the experimental data. They showed that changes induced by IOLs were a consequence of an increase in astigmatism with eccentricity and a myopic shift in the spherical equivalent. CONCLUSIONS: The peripheral refractions in pseudophakic eyes were more myopic than in phakic eyes as a consequence of the optical design of the IOLs. Whether a more myopic refraction of approximately 2.00 D at 45 degrees has significant effects on visual performance must be tested. Perhaps there is room for improvement in the peripheral optics of IOLs. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned

Peripheral refraction profiles in subjects with low foveal refractive errors.

PURPOSE: To study the variability of peripheral refraction in a population of 43 subjects with low foveal refractive errors. METHODS: A scan of the refractive error in the vertical pupil meridian of the right eye of 43 subjects (age range, 18 to 80 years, foveal spherical equivalent, &lt; ± 2.5 diopter) over the central ± 45° of the visual field was performed using a recently developed angular scanning photorefractor. Refraction profiles across the visual field were fitted with four different models: (1) "flat model" (refractions about constant across the visual field), (2) "parabolic model" (refractions follow about a parabolic function), (3) "bi-linear model" (linear change of refractions with eccentricity from the fovea to the periphery), and (4) "box model" ("flat" central area with a linear change in refraction from a certain peripheral angle). Based on the minimal residuals of each fit, the subjects were classified into one of the four models. RESULTS: The "box model" accurately described the peripheral refractions in about 50% of the subjects. Peripheral refractions in six subjects were better characterized by a "linear model," in eight subjects by a "flat model," and in eight by the "parabolic model." Even after assignment to one of the models, the variability remained strikingly large, ranging from -0.75 to 6 diopter in the temporal retina at 45° eccentricity. CONCLUSIONS: The most common peripheral refraction profile (observed in nearly 50% of our population) was best described by the "box model." The high variability among subjects may limit attempts to reduce myopia progression with a uniform lens design and may rather call for a customized approach