Publications by authors named "Jules Kerssemakers"

5 Publications

  • Page 1 of 1

Germline Elongator mutations in Sonic Hedgehog medulloblastoma.

Nature 2020 04 1;580(7803):396-401. Epub 2020 Apr 1.

Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.

Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma. Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MB) ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MB. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U) position. Tumours from patients with ELP1-associated MB were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems. Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.
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http://dx.doi.org/10.1038/s41586-020-2164-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430762PMC
April 2020

mPies: a novel metaproteomics tool for the creation of relevant protein databases and automatized protein annotation.

Biol Direct 2019 11 14;14(1):21. Epub 2019 Nov 14.

Division of Biological and Environmental Sciences, Faculty of Natural Sciences, University of Stirling, Stirling, FK9 4LA, UK.

Metaproteomics allows to decipher the structure and functionality of microbial communities. Despite its rapid development, crucial steps such as the creation of standardized protein search databases and reliable protein annotation remain challenging. To overcome those critical steps, we developed a new program named mPies (metaProteomics in environmental sciences). mPies allows the creation of protein databases derived from assembled or unassembled metagenomes, and/or public repositories based on taxon IDs, gene or protein names. For the first time, mPies facilitates the automatization of reliable taxonomic and functional consensus annotations at the protein group level, minimizing the well-known protein inference issue, which is commonly encountered in metaproteomics. mPies' workflow is highly customizable with regards to input data, workflow steps, and parameter adjustment. mPies is implemented in Python 3/Snakemake and freely available on GitHub: https://github.com/johanneswerner/mPies/. REVIEWER: This article was reviewed by Dr. Wilson Wen Bin Goh.
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http://dx.doi.org/10.1186/s13062-019-0253-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854712PMC
November 2019

Whole genome sequencing puts forward hypotheses on metastasis evolution and therapy in colorectal cancer.

Nat Commun 2018 11 14;9(1):4782. Epub 2018 Nov 14.

Department of Experimental Surgery-Cancer Metastasis, Medical Faculty Mannheim, Ruprecht Karls University Heidelberg, 69120 Mannheim, Germany.

Incomplete understanding of the metastatic process hinders personalized therapy. Here we report the most comprehensive whole-genome study of colorectal metastases vs. matched primary tumors. 65% of somatic mutations originate from a common progenitor, with 15% being tumor- and 19% metastasis-specific, implicating a higher mutation rate in metastases. Tumor- and metastasis-specific mutations harbor elevated levels of BRCAness. We confirm multistage progression with new components ARHGEF7/ARHGEF33. Recurrently mutated non-coding elements include ncRNAs RP11-594N15.3, AC010091, SNHG14, 3' UTRs of FOXP2, DACH2, TRPM3, XKR4, ANO5, CBL, CBLB, the latter four potentially dual protagonists in metastasis and efferocytosis-/PD-L1 mediated immunosuppression. Actionable metastasis-specific lesions include FAT1, FGF1, BRCA2, KDR, and AKT2-, AKT3-, and PDGFRA-3' UTRs. Metastasis specific mutations are enriched in PI3K-Akt signaling, cell adhesion, ECM and hepatic stellate activation genes, suggesting genetic programs for site-specific colonization. Our results put forward hypotheses on tumor and metastasis evolution, and evidence for metastasis-specific events relevant for personalized therapy.
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http://dx.doi.org/10.1038/s41467-018-07041-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235880PMC
November 2018

OTP: An automatized system for managing and processing NGS data.

J Biotechnol 2017 Nov 10;261:53-62. Epub 2017 Aug 10.

Department of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Germany.

The One Touch Pipeline (OTP) is an automation platform managing Next-Generation Sequencing (NGS) data and calling bioinformatic pipelines for processing these data. OTP handles the complete digital process from import of raw sequence data via alignment of sequencing reads to identify genomic events in an automated and scalable way. Three major goals are pursued: firstly, reduction of human resources required for data management by introducing automated processes. Secondly, reduction of time until the sequences can be analyzed by bioinformatic experts, by executing all operations more reliably and quickly. Thirdly, storing all information in one system with secure web access and search capabilities. From software architecture perspective, OTP is both information center and workflow management system. As a workflow management system, OTP call several NGS pipelines that can easily be adapted and extended according to new requirements. As an information center, it comprises a database for metadata information as well as a structured file system. Based on complete and consistent information, data management and bioinformatic pipelines within OTP are executed automatically with all steps book-kept in a database.
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http://dx.doi.org/10.1016/j.jbiotec.2017.08.006DOI Listing
November 2017