Discovery of clinically relevant fusions in pediatric cancer.

Autor:	LaHaye S; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Fitch JR; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Voytovich KJ; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Herman AC; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Kelly BJ; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Lammi GE; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Arbesfeld JA; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Wijeratne S; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Franklin SJ; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Schieffer KM; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Bir N; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., McGrath SD; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Miller AR; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Wetzel A; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Miller KE; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Bedrosian TA; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Leraas K; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Varga EA; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Lee K; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Gupta A; Division of Hematology, Oncology, Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, OH, USA., Setty B; Division of Hematology, Oncology, Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA., Boué DR; Department of Pathology, The Ohio State University, Columbus, OH, USA.; Department of Pathology, Nationwide Children's Hospital, Columbus, OH, USA., Leonard JR; Department of Pediatrics, The Ohio State University, Columbus, OH, USA.; Section of Neurosurgery, Nationwide Children's Hospital, Columbus, OH, USA., Finlay JL; Division of Hematology, Oncology, Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA., Abdelbaki MS; Division of Hematology, Oncology, Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA., Osorio DS; Division of Hematology, Oncology, Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA., Koo SC; Department of Pathology, The Ohio State University, Columbus, OH, USA.; Department of Pathology, Nationwide Children's Hospital, Columbus, OH, USA., Koboldt DC; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Wagner AH; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA.; Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA., Eisfeld AK; Division of Hematology, The Ohio State University, Columbus, OH, USA.; Clara D. Bloomfield Center for Leukemia Outcomes Research, The Ohio State University, Columbus, OH, USA.; The Ohio State Comprehensive Cancer Center, Columbus, OH, USA., Mrózek K; Clara D. Bloomfield Center for Leukemia Outcomes Research, The Ohio State University, Columbus, OH, USA.; The Ohio State Comprehensive Cancer Center, Columbus, OH, USA., Magrini V; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA., Cottrell CE; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA.; Department of Pathology, The Ohio State University, Columbus, OH, USA., Mardis ER; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA., Wilson RK; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA., White P; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA. peter.white@nationwidechildrens.org.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA. peter.white@nationwidechildrens.org.
Jazyk:	angličtina
Zdroj:	BMC genomics [BMC Genomics] 2021 Dec 04; Vol. 22 (1), pp. 872. Date of Electronic Publication: 2021 Dec 04.
DOI:	10.1186/s12864-021-08094-z
Abstrakt:	Background: Pediatric cancers typically have a distinct genomic landscape when compared to adult cancers and frequently carry somatic gene fusion events that alter gene expression and drive tumorigenesis. Sensitive and specific detection of gene fusions through the analysis of next-generation-based RNA sequencing (RNA-Seq) data is computationally challenging and may be confounded by low tumor cellularity or underlying genomic complexity. Furthermore, numerous computational tools are available to identify fusions from supporting RNA-Seq reads, yet each algorithm demonstrates unique variability in sensitivity and precision, and no clearly superior approach currently exists. To overcome these challenges, we have developed an ensemble fusion calling approach to increase the accuracy of identifying fusions. Results: Our Ensemble Fusion (EnFusion) approach utilizes seven fusion calling algorithms: Arriba, CICERO, FusionMap, FusionCatcher, JAFFA, MapSplice, and STAR-Fusion, which are packaged as a fully automated pipeline using Docker and Amazon Web Services (AWS) serverless technology. This method uses paired end RNA-Seq sequence reads as input, and the output from each algorithm is examined to identify fusions detected by a consensus of at least three algorithms. These consensus fusion results are filtered by comparison to an internal database to remove likely artifactual fusions occurring at high frequencies in our internal cohort, while a "known fusion list" prevents failure to report known pathogenic events. We have employed the EnFusion pipeline on RNA-Seq data from 229 patients with pediatric cancer or blood disorders studied under an IRB-approved protocol. The samples consist of 138 central nervous system tumors, 73 solid tumors, and 18 hematologic malignancies or disorders. The combination of an ensemble fusion-calling pipeline and a knowledge-based filtering strategy identified 67 clinically relevant fusions among our cohort (diagnostic yield of 29.3%), including RBPMS-MET, BCAN-NTRK1, and TRIM22-BRAF fusions. Following clinical confirmation and reporting in the patient's medical record, both known and novel fusions provided medically meaningful information. Conclusions: The EnFusion pipeline offers a streamlined approach to discover fusions in cancer, at higher levels of sensitivity and accuracy than single algorithm methods. Furthermore, this method accurately identifies driver fusions in pediatric cancer, providing clinical impact by contributing evidence to diagnosis and, when appropriate, indicating targeted therapies. (© 2021. The Author(s).)
Databáze:	MEDLINE
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