Identity by Descent Mapping of Founder Mutations in Cancer Using High-Resolution Tumor SNP Data

Dense genotype data can be used to detect chromosome fragments inherited from a common ancestor in apparently unrelated individuals. A disease-causing mutation inherited from a common founder may thus be detected by searching for a common haplotype signature in a sample population of patients. We present here FounderTracker, a computational method for the genome-wide detection of founder mutations in cancer using dense tumor SNP profiles. Our method is based on two assumptions. First, the wild-type allele frequently undergoes loss of heterozygosity (LOH) in the tumors of germline mutation carriers. Second, the overlap between the ancestral chromosome fragments inherited from a common founder will define a minimal haplotype conserved in each patient carrying the founder mutation. Our approach thus relies on the detection of haplotypes with significant identity by descent (IBD) sharing within recurrent regions of LOH to highlight genomic loci likely to harbor a founder mutation. We validated this approach by analyzing two real cancer data sets in which we successfully identified founder mutations of well-characterized tumor suppressor genes. We then used simulated data to evaluate the ability of our method to detect IBD tracts as a function of their size and frequency. We show that FounderTracker can detect haplotypes of low prevalence with high power and specificity, significantly outperforming existing methods. FounderTracker is thus a powerful tool for discovering unknown founder mutations that may explain part of the “missing” heritability in cancer. This method is freely available and can be used online at the FounderTracker website

Acide folique et prévention des anomalies de fermeture du tube neural (états des lieux des connaissances des pharmaciens officinaux dans le grand Toulouse)

Les anomalies de fermeture du tube neural concernent chaque année en France environ une grossesse sur mille. Ces pathologies sont très lourdes de conséquence pour le fœtus et la famille. Leur seul recours thérapeutique est la prévention. Elle repose sur une supplémentation en acide folique ou vitamine B9, chez la femme désirant concevoir. Médicament peu connu, les pharmaciens officinaux sont en première ligne pour diffuser l'information nécessaire aux patientes afin de leur éviter de connaître une interruption médicale de grossesse ou de mettre au monde un enfant gravement handicapé. Notre travail consiste à dresser un bilan des connaissances des pharmaciens d'officine. Dans un second temps, nous proposons de diffuser l'information sous forme de plaquettes à l'ensemble des officinaux.TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Acide folique et prévention des anomalies de fermeture du tube neural (états des lieux des connaissances des pharmaciens officinaux dans le grand Toulouse)

Les anomalies de fermeture du tube neural concernent chaque année en France environ une grossesse sur mille. Ces pathologies sont très lourdes de conséquence pour le fœtus et la famille. Leur seul recours thérapeutique est la prévention. Elle repose sur une supplémentation en acide folique ou vitamine B9, chez la femme désirant concevoir. Médicament peu connu, les pharmaciens officinaux sont en première ligne pour diffuser l'information nécessaire aux patientes afin de leur éviter de connaître une interruption médicale de grossesse ou de mettre au monde un enfant gravement handicapé. Notre travail consiste à dresser un bilan des connaissances des pharmaciens d'officine. Dans un second temps, nous proposons de diffuser l'information sous forme de plaquettes à l'ensemble des officinaux.TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Comparison of the latest commercial short and long oligonucleotide microarray technologies

Abstract Background We compared the relative precision and accuracy of expression measurements obtained from three different state-of-the-art commercial short and long-oligonucleotide microarray platforms (Affymetrix GeneChip™, GE Healthcare CodeLink™ and Agilent Technologies). The design of the comparison was chosen to judge each platform in the context of a multi-project program. Results All wet-lab experiments and raw data acquisitions were performed independently by each commercial platform. Intra-platform reproducibility was assessed using measurements from all available targets. Inter-platform comparisons of relative signal intensities were based on a common and non-redundant set of roughly 3,400 targets chosen for their unique correspondence toward a single transcript. Despite many examples of strong similarities we found several areas of discrepancy between the different platforms. Conclusion We found a higher level of reproducibility from one-color based microarrays (Affymetrix and CodeLink) compared to the two-color arrays from Agilent. Overall, Affymetrix data had a slightly higher level of concordance with sample-matched real-time quantitative reverse-transcriptase polymerase chain reaction (QRT-PCR) data particularly for detecting small changes in gene expression levels.</p

PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification.

PURPOSE: To improve the risk stratification of patients with rhabdomyosarcoma (RMS) through the use of clinical and molecular biologic data. PATIENTS AND METHODS: Two independent data sets of gene-expression profiling for 124 and 101 patients with RMS were used to derive prognostic gene signatures by using a meta-analysis. These and a previously published metagene signature were evaluated by using cross validation analyses. A combined clinical and molecular risk-stratification scheme that incorporated the PAX3/FOXO1 fusion gene status was derived from 287 patients with RMS and evaluated. RESULTS: We showed that our prognostic gene-expression signature and the one previously published performed well with reproducible and significant effects. However, their effect was reduced when cross validated or tested in independent data and did not add new prognostic information over the fusion gene status, which is simpler to assay. Among nonmetastatic patients, patients who were PAX3/FOXO1 positive had a significantly poorer outcome compared with both alveolar-negative and PAX7/FOXO1-positive patients. Furthermore, a new clinicomolecular risk score that incorporated fusion gene status (negative and PAX3/FOXO1 and PAX7/FOXO1 positive), Intergroup Rhabdomyosarcoma Study TNM stage, and age showed a significant increase in performance over the current risk-stratification scheme. CONCLUSION: Gene signatures can improve current stratification of patients with RMS but will require complex assays to be developed and extensive validation before clinical application. A significant majority of their prognostic value was encapsulated by the fusion gene status. A continuous risk score derived from the combination of clinical parameters with the presence or absence of PAX3/FOXO1 represents a robust approach to improving current risk-adapted therapy for RMS

IBD mapping of founder mutations in recurrent regions of LOH.

<p>This diagram illustrates the principles underlying our method. A founder mutation (red star on the schematic diagram of chromosomes) spreads through a population within a chromosome fragment (in red) inherited from the ancestral founder (A). Due to crossing-overs (dashed lines) between homologous chromosomes at meiosis, this chromosome fragment is shortened over generations, such that mutation carriers (indicated in red) eventually harbor only a short identical by descent (IBD) haplotype around the mutant gene (B). In addition, the wild-type counterpart of germline mutations is frequently lost by LOH in tumors, such that the founder mutation typically lies within a minimal region of LOH (C). As a result, the founder mutation is located within a haplotype conserved in each mutation carrier (peak IBD score), in the minimal region of LOH (D).</p

Power analysis with simulated data.

<p>The performance of FounderTracker was assessed under various conditions, by comparison with the DASH method. The ability of each method to detect conserved haplotypes was established as a function of haplotype length (1 to 5 cM) and prevalence (2 to 10% of the samples). For each condition, the mean ROC curve was established by applying each method to 100 simulated datasets.</p

Detection of a long conserved haplotype around <i>SDHD</i> gene in two paragangliomas.

<p>(A) LOH analysis revealed 10 chromosome arms with LOH frequency >20% in our set of 30 pheochromocytomas and paragangliomas (top). These regions were analyzed using FounderTracker to detect conserved haplotypes, revealing a single significant region on chromosome arm 11q (bottom). (B) Visualization of the significant region identified on chromosome 11 with the Integrative Genomics Viewer <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035897#pone.0035897-Robinson1" target="_blank">[44]</a>. The IBD score is represented as a blue line above tumor haplotypes. Haplotypes are represented as series of blue and yellow vertical lines, corresponding to SNPs with respectively “A” and “B” genotype, according to Illumina nomenclature. The significant region detected by FounderTracker corresponds to the long haplotype that is identical in tumors HS_048 and HS_158, and results in a high IBD score for this segment. This region contains 32 genes, including <i>SDHD</i> (indicated in red).</p