Sequential genomic analysis using a multisample/multiplatform approach to better define rhabdomyosarcoma progression and relapse
Abstract The genomic spectrum of rhabdomyosarcoma (RMS) progression from primary to relapse is not fully understood. In this pilot study, we explore the sensitivity of various targeted and whole-genome NGS platforms in order to assess the best genomic approach of using liquid biopsy in future prospe...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-09-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-023-00445-1 |
| _version_ | 1797454086504710144 |
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| author | Henry de Traux de Wardin Josephine K. Dermawan Marie-Sophie Merlin Leonard H. Wexler Daniel Orbach Fabio Vanoli Gudrun Schleiermacher Birgit Geoerger Stelly Ballet Delphine Guillemot Eléonore Frouin Stacy Cyrille Olivier Delattre Gaelle Pierron Cristina R. Antonescu |
| author_facet | Henry de Traux de Wardin Josephine K. Dermawan Marie-Sophie Merlin Leonard H. Wexler Daniel Orbach Fabio Vanoli Gudrun Schleiermacher Birgit Geoerger Stelly Ballet Delphine Guillemot Eléonore Frouin Stacy Cyrille Olivier Delattre Gaelle Pierron Cristina R. Antonescu |
| author_sort | Henry de Traux de Wardin |
| collection | DOAJ |
| description | Abstract The genomic spectrum of rhabdomyosarcoma (RMS) progression from primary to relapse is not fully understood. In this pilot study, we explore the sensitivity of various targeted and whole-genome NGS platforms in order to assess the best genomic approach of using liquid biopsy in future prospective clinical trials. Moreover, we investigate 35 paired primary/relapsed RMS from two contributing institutions, 18 fusion-positive (FP-RMS) and 17 fusion-negative RMS (FN-RMS) by either targeted DNA or whole exome sequencing (WES). In 10 cases, circulating tumor DNA (ctDNA) from multiple timepoints through clinical care and progression was analyzed for feasibility of liquid biopsy in monitoring treatment response/relapse. ctDNA alterations were evaluated using a targeted 36-gene custom RMS panel at high coverage for single-nucleotide variation and fusion detection, and a shallow whole-genome sequencing for copy number variation. FP-RMS have a stable genome with relapse, with common secondary alterations CDKN2A/B, MYCN, and CDK4 present at diagnosis and impacting survival. FP-RMS lacking major secondary events at baseline acquire recurrent MYCN and AKT1 alterations. FN-RMS acquire a higher number of new alterations, most commonly SMARCA2 missense mutations. ctDNA analyses detect pathognomonic variants in all RMS patients within our collection at diagnosis, regardless of type of alterations, and confirmed at relapse in 86% of FP-RMS and 100% FN-RMS. Moreover, a higher number of fusion reads is detected with increased disease burden and at relapse in patients following a fatal outcome. These results underscore patterns of tumor progression and provide rationale for using liquid biopsy to monitor treatment response. |
| first_indexed | 2024-03-09T15:32:11Z |
| format | Article |
| id | doaj.art-6f1928873e1d41818ff5568e4b5f0d3e |
| institution | Directory Open Access Journal |
| issn | 2397-768X |
| language | English |
| last_indexed | 2024-03-09T15:32:11Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj.art-6f1928873e1d41818ff5568e4b5f0d3e2023-11-26T12:12:31ZengNature Portfolionpj Precision Oncology2397-768X2023-09-017111310.1038/s41698-023-00445-1Sequential genomic analysis using a multisample/multiplatform approach to better define rhabdomyosarcoma progression and relapseHenry de Traux de Wardin0Josephine K. Dermawan1Marie-Sophie Merlin2Leonard H. Wexler3Daniel Orbach4Fabio Vanoli5Gudrun Schleiermacher6Birgit Geoerger7Stelly Ballet8Delphine Guillemot9Eléonore Frouin10Stacy Cyrille11Olivier Delattre12Gaelle Pierron13Cristina R. Antonescu14Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterUniversity of Lorraine, Centre Hospitalier Régional Universitaire (CHRU), Childrens’ Hospital, Department of Pediatric OncologyDepartment of Pediatrics, Memorial Sloan Kettering Cancer CenterSIREDO Oncology Center (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), PSL University, Institut CurieDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterSIREDO Oncology Center (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), PSL University, Institut CurieGustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Université Paris-SaclayUnit of Somatic Genetics, Institut CurieUnit of Somatic Genetics, Institut CurieUnit of Somatic Genetics, Institut CurieDepartment of Biometrics, Institut CurieSIREDO Oncology Center (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), PSL University, Institut CurieUnit of Somatic Genetics, Institut CurieDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterAbstract The genomic spectrum of rhabdomyosarcoma (RMS) progression from primary to relapse is not fully understood. In this pilot study, we explore the sensitivity of various targeted and whole-genome NGS platforms in order to assess the best genomic approach of using liquid biopsy in future prospective clinical trials. Moreover, we investigate 35 paired primary/relapsed RMS from two contributing institutions, 18 fusion-positive (FP-RMS) and 17 fusion-negative RMS (FN-RMS) by either targeted DNA or whole exome sequencing (WES). In 10 cases, circulating tumor DNA (ctDNA) from multiple timepoints through clinical care and progression was analyzed for feasibility of liquid biopsy in monitoring treatment response/relapse. ctDNA alterations were evaluated using a targeted 36-gene custom RMS panel at high coverage for single-nucleotide variation and fusion detection, and a shallow whole-genome sequencing for copy number variation. FP-RMS have a stable genome with relapse, with common secondary alterations CDKN2A/B, MYCN, and CDK4 present at diagnosis and impacting survival. FP-RMS lacking major secondary events at baseline acquire recurrent MYCN and AKT1 alterations. FN-RMS acquire a higher number of new alterations, most commonly SMARCA2 missense mutations. ctDNA analyses detect pathognomonic variants in all RMS patients within our collection at diagnosis, regardless of type of alterations, and confirmed at relapse in 86% of FP-RMS and 100% FN-RMS. Moreover, a higher number of fusion reads is detected with increased disease burden and at relapse in patients following a fatal outcome. These results underscore patterns of tumor progression and provide rationale for using liquid biopsy to monitor treatment response.https://doi.org/10.1038/s41698-023-00445-1 |
| spellingShingle | Henry de Traux de Wardin Josephine K. Dermawan Marie-Sophie Merlin Leonard H. Wexler Daniel Orbach Fabio Vanoli Gudrun Schleiermacher Birgit Geoerger Stelly Ballet Delphine Guillemot Eléonore Frouin Stacy Cyrille Olivier Delattre Gaelle Pierron Cristina R. Antonescu Sequential genomic analysis using a multisample/multiplatform approach to better define rhabdomyosarcoma progression and relapse npj Precision Oncology |
| title | Sequential genomic analysis using a multisample/multiplatform approach to better define rhabdomyosarcoma progression and relapse |
| title_full | Sequential genomic analysis using a multisample/multiplatform approach to better define rhabdomyosarcoma progression and relapse |
| title_fullStr | Sequential genomic analysis using a multisample/multiplatform approach to better define rhabdomyosarcoma progression and relapse |
| title_full_unstemmed | Sequential genomic analysis using a multisample/multiplatform approach to better define rhabdomyosarcoma progression and relapse |
| title_short | Sequential genomic analysis using a multisample/multiplatform approach to better define rhabdomyosarcoma progression and relapse |
| title_sort | sequential genomic analysis using a multisample multiplatform approach to better define rhabdomyosarcoma progression and relapse |
| url | https://doi.org/10.1038/s41698-023-00445-1 |
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