Search for new loci and low-frequency variants influencing glioma risk by exome-array analysis

To identify protein-altering variants (PAVs) for glioma, we analysed Illumina HumanExome BeadChip exome-array data on 1882 glioma cases and 8079 controls from three independent European populations. In addition to single-variant tests we incorporated information on the predicted functional consequences of PAVs and analysed sets of genes with a higher likelihood of having a role in glioma on the basis of the profile of somatic mutations documented by large-scale sequencing initiatives. Globally there was a strong relationship between effect size and PAVs predicted to be damaging (P=2.29 × 10−49); however, these variants which are most likely to impact on risk, are rare (MAFT, p.(Lys3326Ter), which has been shown to influence breast and lung cancer risk (odds ratio (OR)=2.3, P=4.00 × 10−4 for glioblastoma (GBM)) and IDH2:c.782G>A, p.(Arg261His) (OR=3.21, P=7.67 × 10−3, for non-GBM). Additionally, gene burden tests revealed a statistically significant association for HARS2 and risk of GBM (P=2.20 × 10−6). Genome scans of low-frequency PAVs represent a complementary strategy to identify disease-causing variants compared with scans based on tagSNPs. Strategies to lessen the multiple testing burden by restricting analysis to PAVs with higher priors affords an opportunity to maximise study power

Prediction of Response to Temozolomide in Low-Grade Glioma Patients Based on Tumor Size Dynamics and Genetic Characteristics

International audienceBoth molecular profiling of tumors and longitudinal tumor size data modeling are relevant strategies to predict cancer patients' response to treatment. Herein we propose a model of tumor growth inhibition integrating a tumor's genetic characteristics (p53 mutation and 1p/19q codeletion) that successfully describes the time course of tumor size in patients with low-grade gliomas treated with first-line temozolomide chemotherapy. The model captures potential tumor progression under chemotherapy by accounting for the emergence of tissue resistance to treatment following prolonged exposure to temozolomide. Using information on individual tumors' genetic characteristics, in addition to early tumor size measurements, the model was able to predict the duration and magnitude of response, especially in those patients in whom repeated assessment of tumor response was obtained during the first 3 months of treatment. Combining longitudinal tumor size quantitative modeling with a tumor''s genetic characterization appears as a promising strategy to personalize treatments in patients with low-grade gliomas. WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? þ First-line temozolomide is frequently used to treat low-grade gliomas (LGG), which are slow-growing brain tumors. The duration of response depends on genetic characteristics such as 1p/19q chromosomal codeletion, p53 mutation, and IDH mutations. However, up to now there are no means of predicting, at the individual level, the duration of the response to TMZ and its potential benefit for a given patient. • WHAT QUESTION DID THIS STUDY ADDRESS? þ The present study assessed whether combining longitudinal tumor size quantitative modeling with a tumor's genetic characterization could be an effective means of predicting the response to temozolomide at the individual level in LGG patients. • WHAT THIS STUDY ADDS TO OUR KNOWLEDGE þ For the first time, we developed a model of tumor growth inhibition integrating a tumor's genetic characteristics which successfully describes the time course of tumor size and captures potential tumor progression under chemotherapy in LGG patients treated with first-line temozolomide. The present study shows that using information on individual tumors' genetic characteristics, in addition to early tumor size measurements, it is possible to predict the duration and magnitude of response to temozolomide. • HOW THIS MIGHT CHANGE CLINICAL PHARMACOLOGY AND THERAPEUTICS þ Our model constitutes a rational tool to identify patients most likely to benefit from temozolomide and to optimize in these patients the duration of temozolomide therapy in order to ensure the longest duration of response to treatment. Response evaluation criteria such as RECIST—or RANO for brain tumors—are commonly used to assess response to anticancer treatments in clinical trials. 1,2 They assign a patient's response to one of four categories, ranging from " complete response " to " disease progression. " Yet, criticisms have been raised regarding the use of such categorical criteria in the drug development process, 3,4 and regulatory agencies have promoted the additional analysis of longitudinal tumor size measurements through the use of quantitative modeling. 5 Several mathematical models of tumor growth and response to treatment have been developed for this purpose. 6,7 These analyses have led to th

Noisy Kondo impurities

The anti-ferromagnetic coupling of a magnetic impurity carrying a spin with the conduction electrons spins of a host metal is the basic mechanism responsible for the increase of the resistance of an alloy such as Cu${}_{0.998}$Fe${}_{0.002}$ at low temperature, as originally suggested by Kondo . This coupling has emerged as a very generic property of localized electronic states coupled to a continuum . The possibility to design artificial controllable magnetic impurities in nanoscopic conductors has opened a path to study this many body phenomenon in unusual situations as compared to the initial one and, in particular, in out of equilibrium situations. So far, measurements have focused on the average current. Here, we report on \textit{current fluctuations} (noise) measurements in artificial Kondo impurities made in carbon nanotube devices. We find a striking enhancement of the current noise within the Kondo resonance, in contradiction with simple non-interacting theories. Our findings provide a test bench for one of the most important many-body theories of condensed matter in out of equilibrium situations and shed light on the noise properties of highly conductive molecular devices.Comment: minor differences with published versio

Strong quantum memory at resonant Fermi edges revealed by shot noise

Studies of non-equilibrium current fluctuations enable assessing correlations involved in quantum transport through nanoscale conductors. They provide additional information to the mean current on charge statistics and the presence of coherence, dissipation, disorder, or entanglement. Shot noise, being a temporal integral of the current autocorrelation function, reveals dynamical information. In particular, it detects presence of non-Markovian dynamics, i.e., memory, within open systems, which has been subject of many current theoretical studies. We report on low-temperature shot noise measurements of electronic transport through InAs quantum dots in the Fermi-edge singularity regime and show that it exhibits strong memory effects caused by quantum correlations between the dot and fermionic reservoirs. Our work, apart from addressing noise in archetypical strongly correlated system of prime interest, discloses generic quantum dynamical mechanism occurring at interacting resonant Fermi edges.Comment: 6 pages, 3 figure

Incidence and prognostic value of tumour cells detected by RT–PCR in peripheral blood stem cell collections from patients with Ewing tumour

To retrospectively evaluate the incidence of tumour cell contamination of peripheral blood stem cell (PBSC) collections and to correlate these data with the clinical outcome after high-dose chemotherapy (HDCT) with stem cell rescue in patients with a high-risk Ewing tumour. Peripheral blood stem cell collections obtained from 171 patients were analysed. Tumour contamination was assessed by reverse transcriptase–polymerase chain reaction (RT–PCR). The files of 88 patients who underwent HDCT followed by PBSC reinfusion were reviewed in detail, and their outcome compared to the PBSC RT–PCR results. Seven of 88 PBSC collections (8%) contained tumour cells as detected by RT–PCR. Peripheral blood stem cells were collected after a median of five cycles of chemotherapy. No clinical factor predictive of tumour cell contamination of PBSC harvest could be identified. Event-free survival (EFS) and overall survival (OS) of the whole study population were 45.3 % and 51.8 % at 3 years from the date of the graft, respectively. Forty-five patients relapsed with a median time of 15 months after graft, only four of whom had tumour cell contamination of the PBSC harvest. Tumour cell contamination of PBSC collection is rare and does not seem to be associated with a significantly poorer EFS or OS in this high-risk population

Functional significance may underlie the taxonomic utility of single amino acid substitutions in conserved proteins

We hypothesized that some amino acid substitutions in conserved proteins that are strongly fixed by critical functional roles would show lineage-specific distributions. As an example of an archetypal conserved eukaryotic protein we considered the active site of ß-tubulin. Our analysis identified one amino acid substitution—ß-tubulin F224—which was highly lineage specific. Investigation of ß-tubulin for other phylogenetically restricted amino acids identified several with apparent specificity for well-defined phylogenetic groups. Intriguingly, none showed specificity for “supergroups” other than the unikonts. To understand why, we analysed the ß-tubulin Neighbor-Net and demonstrated a fundamental division between core ß-tubulins (plant-like) and divergent ß-tubulins (animal and fungal). F224 was almost completely restricted to the core ß-tubulins, while divergent ß-tubulins possessed Y224. Thus, our specific example offers insight into the restrictions associated with the co-evolution of ß-tubulin during the radiation of eukaryotes, underlining a fundamental dichotomy between F-type, core ß-tubulins and Y-type, divergent ß-tubulins. More broadly our study provides proof of principle for the taxonomic utility of critical amino acids in the active sites of conserved proteins

Cumulative incidence and risk factors for radiation induced leukoencephalopathy in high grade glioma long term survivors

The incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18–69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity

SU(VAR)3-7 Links Heterochromatin and Dosage Compensation in Drosophila

In Drosophila, dosage compensation augments X chromosome-linked transcription in males relative to females. This process is achieved by the Dosage Compensation Complex (DCC), which associates specifically with the male X chromosome. We previously found that the morphology of this chromosome is sensitive to the amounts of the heterochromatin-associated protein SU(VAR)3-7. In this study, we examine the impact of change in levels of SU(VAR)3-7 on dosage compensation. We first demonstrate that the DCC makes the X chromosome a preferential target for heterochromatic markers. In addition, reduced or increased amounts of SU(VAR)3-7 result in redistribution of the DCC proteins MSL1 and MSL2, and of Histone 4 acetylation of lysine 16, indicating that a wild-type dose of SU(VAR)3-7 is required for X-restricted DCC targeting. SU(VAR)3-7 is also involved in the dosage compensated expression of the X-linked white gene. Finally, we show that absence of maternally provided SU(VAR)3-7 renders dosage compensation toxic in males, and that global amounts of heterochromatin affect viability of ectopic MSL2-expressing females. Taken together, these results bring to light a link between heterochromatin and dosage compensation