Medium levels of transcription and replication related chromosomal instability are associated with poor clinical outcome
| العنوان: | Medium levels of transcription and replication related chromosomal instability are associated with poor clinical outcome |
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| المؤلفون: | Ataaillah Benhaddou, Laetitia Gaston, Gaëlle Pérot, Nelly Desplat, Laura Leroy, Sophie Le Guellec, Mohamed Ben Haddou, Philippe Rochaix, Thibaud Valentin, Gwenaël Ferron, Christine Chevreau, Binh Bui, Eberhard Stoeckle, Axel Le Cesne, Sophie Piperno-Neumann, Françoise Collin, Nelly Firmin, Gonzague De Pinieux, Jean-Michel Coindre, Jean-Yves Blay, Frédéric Chibon |
| المصدر: | Scientific Reports, Vol 11, Iss 1, Pp 1-17 (2021) Scientific Reports |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | DNA Replication, Risk, DNA Repair, Transcription, Genetic, Science, DNA Mutational Analysis, Antineoplastic Agents, Kaplan-Meier Estimate, Chromosomes, Article, Chromosomal Instability, Neoplasms, Humans, Gene Regulatory Networks, Neoplasm Metastasis, Promoter Regions, Genetic, Cancer, Multidisciplinary, Genome, Human, Sarcoma, DNA, Sequence Analysis, DNA, Enhancer Elements, Genetic, Treatment Outcome, Medicine, Algorithms, DNA Damage |
| الوصف: | Genomic instability (GI) influences treatment efficacy and resistance, and an accurate measure of it is lacking. Current measures of GI are based on counts of specific structural variation (SV) and mutational signatures. Here, we present a holistic approach to measuring GI based on the quantification of the steady-state equilibrium between DNA damage and repair as assessed by the residual breakpoints (BP) remaining after repair, irrespective of SV type. We use the notion of Hscore, a BP “hotspotness” magnitude scale, to measure the propensity of genomic structural or functional DNA elements to break more than expected by chance. We then derived new measures of transcription- and replication-associated GI that we call iTRAC (transcription-associated chromosomal instability index) and iRACIN (replication-associated chromosomal instability index). We show that iTRAC and iRACIN are predictive of metastatic relapse in Leiomyosarcoma (LMS) and that they may be combined to form a new classifier called MAGIC (mixed transcription- and replication-associated genomic instability classifier). MAGIC outperforms the gold standards FNCLCC and CINSARC in stratifying metastatic risk in LMS. Furthermore, iTRAC stratifies chemotherapeutic response in LMS. We finally show that this approach is applicable to other cancers. |
| تدمد: | 2045-2322 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7d5b309710d44e74da74336be91660daTest https://doi.org/10.1038/s41598-021-02787-xTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7d5b309710d44e74da74336be91660da |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20452322 |
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