Publications by authors named "Angelina Legros"

Article Synopsis
  • Solving mRNA transcript structures is challenging with traditional methods, but long-read sequencing addresses this by providing direct sequence information.
  • A new targeted enrichment method was developed to capture transcripts of genes related to hereditary breast and ovarian cancer, leading to the identification of 1,231 unique transcripts in eight patients.
  • The SOSTAR pipeline successfully annotated transcript structures and discovered key splicing events, including the identification of a retrotransposon related to unexplained inheritance cases.
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Article Synopsis
  • - The study aims to improve access to testing for homologous recombination deficiency (HRD) in ovarian cancer by developing a new academic test called GIScar, which is based on a targeted gene panel analysis.
  • - GIScar was validated using tumor samples from a clinical trial and showed a strong correlation with an existing HRD test, Myriad Genetics MyChoice, while identifying more HRD-positive tumors and yielding fewer inconclusive results.
  • - The results indicate that GIScar is an effective diagnostic tool that not only detects HRD reliably but also predicts treatment response to the drug olaparib, making it a practical option for labs in need of rapid testing solutions.
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Up to 80% of BRCA1 and BRCA2 genetic variants remain of uncertain clinical significance (VUSs). Only variants classified as pathogenic or likely pathogenic can guide breast and ovarian cancer prevention measures and treatment by PARP inhibitors. We report the first results of the ongoing French national COVAR (cosegregation variant) study, the aim of which is to classify BRCA1/2 VUSs.

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Article Synopsis
  • Branch points (BPs) are crucial for the splicing of pre-mRNA and are located in short motifs upstream of acceptor splice sites (3'ss); several bioinformatics tools for detecting BPs have been developed recently.
  • In a study utilizing a large dataset of human 3'ss, Branchpointer was found to be the most accurate tool for identifying BPs, showing 99.48% accuracy for constitutive and 65.84% for alternative 3'ss.
  • Additionally, BPP was the best performer for predicting the impact of variants in BP regions on mRNA splicing, achieving an accuracy of 89.17%.
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Purpose: Integration of gene panels in the diagnosis of hereditary breast and ovarian cancer (HBOC) requires a careful evaluation of the risk associated with pathogenic or likely pathogenic variants (PVs) detected in each gene. Here we analyzed 34 genes in 5131 suspected HBOC index cases by next-generation sequencing.

Methods: Using the Exome Aggregation Consortium data sets plus 571 individuals from the French Exome Project, we simulated the probability that an individual from the Exome Aggregation Consortium carries a PV and compared it to the estimated frequency within the HBOC population.

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Interpretation of variants of unknown significance (VUS) is a major challenge for laboratories performing molecular diagnosis of hereditary breast and ovarian cancer (HBOC), especially considering that many genes are now known to be involved in this syndrome. One important way these VUS can have a functional impact is through their effects on RNA splicing. Here we present a custom RNA-Seq assay plus bioinformatics and biostatistics pipeline to analyse specifically alternative and abnormal splicing junctions in 11 targeted HBOC genes.

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Highlighting tumoral mutations is a key step in oncology for personalizing care. Considering the genetic heterogeneity in a tumor, software used for detecting mutations should clearly distinguish real tumor events of interest that could be predictive markers for personalized medicine from false positives. OutLyzer is a new variant-caller designed for the specific and sensitive detection of mutations for research and diagnostic purposes.

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Germline allele specific expression (ASE), resulting in a lowered expression of one of the BRCA1 alleles, has been described as a possible predisposition marker in Hereditary Breast or Ovarian Cancer (HBOC), usable for molecular diagnosis in HBOC. The main objective of this prospective case-control study was to compare the proportion of ASE between controls without familial history of breast or ovarian cancer, and HBOC cases without BRCA1 or BRCA2 deleterious mutation. BRCA1 ASE evaluated on three SNPs among controls and HBOC patients without deleterious mutation were assessed by pyrosequencing.

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Cancer treatment is facing major evolution since the advent of targeted therapies. Building genetic profiles could predict sensitivity or resistance to these therapies and highlight disease-specific abnormalities, supporting personalized patient care. In the context of biomedical research and clinical diagnosis, our laboratory has developed an oncogenic panel comprised of 226 genes and a dedicated bioinformatic pipeline to explore somatic mutations in cervical carcinomas, using high-throughput sequencing.

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To optimize the molecular diagnosis of hereditary breast and ovarian cancer (HBOC), we developed a next-generation sequencing (NGS)-based screening based on the capture of a panel of genes involved, or suspected to be involved in HBOC, on pooling of indexed DNA and on paired-end sequencing in an Illumina GAIIx platform, followed by confirmation by Sanger sequencing or MLPA/QMPSF. The bioinformatic pipeline included CASAVA, NextGENe, CNVseq and Alamut-HT. We validated this procedure by the analysis of 59 patients' DNAs harbouring SNVs, indels or large genomic rearrangements of BRCA1 or BRCA2.

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For the majority of breast and/or ovarian cancer patients tested for BRCA1/2 genes, mutation screening of the coding regions remains negative. MicroRNAs which negatively regulate mRNA translation by binding to 3' untranslated region (3'UTR) are implicated in cancer. Genetic changes in the 3'UTR of several genes were reported to be associated with higher susceptibility to particular tumor types.

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