de Traux de Wardin Henry, Dermawan Josephine K, Merlin Marie-Sophie, Wexler Leonard H, Orbach Daniel, Vanoli Fabio, Schleiermacher Gudrun, Geoerger Birgit, Ballet Stelly, Guillemot Delphine, Frouin Eléonore, Cyrille Stacy, Delattre Olivier, Pierron Gaelle, Antonescu Cristina R
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Unit of Somatic Genetics, Institut Curie, Paris, France.
NPJ Precis Oncol. 2023 Sep 20;7(1):96. doi: 10.1038/s41698-023-00445-1.
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.
横纹肌肉瘤（RMS）从原发肿瘤进展到复发的基因组谱尚未完全明确。在这项初步研究中，我们探索了各种靶向和全基因组NGS平台的敏感性，以评估在未来前瞻性临床试验中使用液体活检的最佳基因组方法。此外，我们通过靶向DNA或全外显子测序（WES）研究了来自两个合作机构的35对原发性/复发性RMS，其中18例为融合阳性（FP-RMS），17例为融合阴性RMS（FN-RMS）。在10例病例中，分析了多个时间点通过临床护理和疾病进展获得的循环肿瘤DNA（ctDNA），以评估液体活检监测治疗反应/复发的可行性。使用一个针对36个基因的定制RMS panel在高覆盖度下评估ctDNA改变，以检测单核苷酸变异和融合，并用浅层全基因组测序检测拷贝数变异。FP-RMS复发时基因组稳定，常见的继发性改变CDKN2A/B、MYCN和CDK4在诊断时即存在并影响生存。基线时缺乏主要继发性事件的FP-RMS会出现复发性MYCN和AKT1改变。FN-RMS获得的新改变数量更多，最常见的是SMARCA2错义突变。ctDNA分析在我们收集的所有RMS患者诊断时均检测到特征性变异，无论改变类型如何，在复发时，86%的FP-RMS和100%的FN-RMS得到证实。此外，随着疾病负担增加以及致命结局患者复发时，检测到的融合读数更多。这些结果强调了肿瘤进展模式，并为使用液体活检监测治疗反应提供了理论依据。
