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. Author manuscript; available in PMC: 2025 Apr 1.
Published in final edited form as: Genes Chromosomes Cancer. 2024 Apr;63(4):e23232. doi: 10.1002/gcc.23232

FGFR1 Fusions as a Novel Molecular Driver in Rhabdomyosarcoma

Henry de Traux De Wardin 1,2,*, Joanna Cyrta 3,*, Josephine K Dermawan 4, Delphine Guillemot 5, Daniel Orbach 6, Isabelle Aerts 6, Gaelle Pierron 5,*, Cristina R Antonescu 1,*
PMCID: PMC11385681  NIHMSID: NIHMS2013096  PMID: 38607246

Abstract

The wide application of RNA sequencing in clinical practice has allowed the discovery of novel fusion genes, which have contributed to a refined molecular classification of rhabdomyosarcoma (RMS). Most fusions in RMS result in aberrant transcription factors, such as PAX3/7::FOXO1 in alveolar RMS (ARMS) and fusions involving VGLL2 or NCOA2 in infantile spindle cell RMS. However, recurrent fusions driving oncogenic kinase activation have not been reported in RMS. Triggered by an index case of an unclassified RMS (overlapping features between ARMS and sclerosing RMS) with a novel FGFR1::ANK1 fusion, we reviewed our molecular files for cases harboring FGFR1-related fusions. One additional case with an FGFR1::TACC1 fusion was identified in a tumor resembling embryonal RMS (ERMS) with anaplasia, but with no pathogenic variants in TP53 or DICER1 on germline testing. Both cases occurred in males, aged 7 and 24, and in the pelvis. The 2nd case also harbored additional alterations, including somatic TP53 and TET2 mutations. Two additional RMS cases (one unclassified, one ERMS) with FGFR1 overexpression but lacking FGFR1 fusions were identified by RNA sequencing. These two cases and the FGFR1::TACC1-positive case clustered together with the ERMS group by RNAseq. This is the first report of RMS harboring recurrent FGFR1 fusions. However, it remains unclear if FGFR1 fusions define a novel subset of RMS or alternatively, whether this alteration can sporadically drive the pathogenesis of known RMS subtypes, such as ERMS. Additional larger series with integrated genomic and epigenetic datasets are needed for better subclassification, as the resulting oncogenic kinase activation underscores the potential for targeted therapy.

Keywords: rhabdomyosarcoma, fusion, FGFR1, ANK1, TACC1

INTRODUCTION

Rhabdomyosarcoma (RMS) is the most frequent pediatric soft tissue sarcoma and encompasses a heterogeneous clinical and molecular spectrum 1. Most prior genomic studies in RMS have focused on identification of molecular biomarkers for risk stratification 2,3 and guiding the development of future targeted therapies 4,5. Consequently, the presence of PAX3/7::FOXO1 fusions in alveolar RMS (ARMS), TP53 alterations in embryonal RMS (ERMS), or the MYOD1 mutations in a specific subtype of spindle cell RMS (SRMS) result in risk and treatment escalation 6. Besides FOXO1-related rearrangements in ARMS, two additional RMS subtypes have emerged as being characterized by recurrent gene fusions, including infantile SRMS, often involving VGLL or NCOA2 genes and showing favorable outcome, and intra-osseous spindle and epithelioid RMS with EWSR1/FUS::TFCP2 fusions and a highly aggressive clinical course 7–13. Despite recent large genomic studies, recurrent fusions resulting in kinase oncogenic activation have not been reported to date in RMS. In this study we report FGFR1 driver fusions in two cases of RMS, with distinct histology, and compare the clinicopathologic and molecular findings to a group of ERMS showing FGFR1 activation through other mechanisms. This report is highly relevant, as clinical responses to FGFR-targeted therapies have been documented in both adult and pediatric sarcomas 14,15, underscoring the significance of screening for FGFR1 alterations.

MATERIAL AND METHODS

Study Cohort

The study was approved by the MSKCC IRB committee (02–060). All study subjects provided written informed consent to the use of their genomic data for research. This study has been conducted in accordance with the International Ethical Guidelines for Biomedical Research Involving Human Subjects (CIOMS). Patient demographics, clinical findings, treatment modalities, and follow-up information were collected from the patients’ charts. Histologic slides from the two study cases as well as the control group of RMS with alternative FGFR1 activation were available for review by two expert sarcoma pathologists (CRA, JC), by incorporating morphology, immunohistochemistry and molecular findings.

Immunohistochemistry

Immunohistochemistry (IHC) was performed against desmin, myogenin, MyoD1 and P53. The relevant antibodies and the dilutions used in this study are referenced in Supplementary Table 1.

RNA-Sequencing

The index case (case #1) was tested by MSK-Fusion, an amplicon-based targeted RNA NGS assay using the Archer™ FusionPlex™ standard protocol, as described previously16. Briefly, RNA was extracted from tumor formalin-fixed paraffin-embedded material followed by cDNA synthesis. Fusion unidirectional GSPs have been designed to target specific exons in 123 genes known to be involved in chromosomal rearrangements based on current literature. FASTQ files, generated by the MiSeq reporter software (Version 2.6.2.3), were analyzed with the Archer™ analysis software (Version 5.0.4).

The second case (case #2), as well as the control cohort (cases #3, 4) were subjected to whole transcriptome bulk RNA-sequencing at Institut Curie, as previously described17. Briefly, total RNA was extracted from fresh-frozen tumor tissue. Library construction was prepared using the TruSeq Stranded mRNA Library Prep (Illumina Inc., San Diego, CA). mRNAs were captured using poly-A beads, fragmented, and reverse transcribed into DNA. Amplified libraires were then sequenced on NextSeq500 paired end 2×150bp (Illumina Inc., San Diego, CA). This assay was used for fusion detection, variant calling, and RNA expression data for subsequent unsupervised clustering. Fusion detection was done from FASTQ files aligned on hg19 normal genome using two approaches: (A) targeted analysis, using an in-house tool designed to search for well-characterized fusion sequences; and (B) exploratory analysis attempting to capture fusion transcripts, using 5 fusion different detection tools: Defuse V0.6.2, StarFusion v1.2.0 (STAR v 2.5.4a), Fusion Catcher v1.00, FusionMap (Oshell toolkit v10.0.1.50) and ARRIBA v1.2.0. Fusion confirmation was achieved when read by two separate tools.

Variant calling was performed by read alignment with STAR (v2.5.3a, on hg19 reference genome). Read cleaning was done as described by GATK good practices (v3.5) for marking duplicates, base recalibrations and indel realignments. Variant calling was performed on a list of 499 genes (Cancer Gene Census, COSMIC 24.05.2016) using Haplotype Caller (GATK v.3.5) and Mutect2 (GATK v.4). Reads with mapping quality lower than 6 and sequenced bases quality lower than 20 were not considered for the variant calling. Variants were annotated with ANNOVAR (v2018Apr16) and formatted with the Python package hgvs (v1.2.5). Intra- and inter-analysis occurrence of variants were used to eliminate noise from the sequencing technology.

In parallel, the classification of samples to cancer subtypes was inferred using a variational autoencoder (VAE) model. This model includes expression data (generated with STAR v2.7.0e) of 21,916 well-annotated cases (normal and cancer tissues) serving as control groups18.

Targeted panel-based DNA sequencing

For case #2, DNA sequencing was done in addition to RNA-Seq to further explore variant calling and obtain a copy number profile. The DNA sequencing “DRAGON” panel is a custom 571-cancer gene panel (Illumina TruSeq Custom Amplicon). The method has been previously described4,17.

Nanopore Sequencing

Nanopore sequencing, as previously detailed19, was employed when the quality of reads from RNA-sequencing failed to adequately confirm the presence of translocations, ensuring a reliable distinction from potential artifacts arising due to multiple rearrangements. Briefly, library preparation was performed using Oxford Nanopore Technologies Ligation Sequencing Kit SQK-LSK110 on 2 μg of genomic DNA. We targeted regions encompassing the entire loci (including 5’-UTR, 3’-UTR and intronic regions) and 5 kb flanking regions upstream and downstream of 120 genes, including FGFR1. Downstream bioinformatic analysis was performed using NanoCliD, a custom bioinformatic pipeline (https://github.com/InstituteCurieClinicalBioinformatics/NanoCliD). The data processing toolkit called ‘guppy’ allowed to convert FAST5 files to FASTQ files. Alignments were manually reviewed on Integrative Genomic Viewer.

RESULTS

Clinical Summary

The two male patients whose tumors harbored FGFR1 fusions (cases #1, and #2, Table 1) presented with pelvic masses. The index case (case #1) was a 24-year-old male presenting with a 3.5 cm localized paratesticular mass, which was resected with negative margins without any additional neo- or adjuvant therapy. Case #2 was a 7-year-old male with a 10.5 cm localized perineal mass, located between the rectum and the bladder, of uncertain anatomic origin (prostatic or soft tissue tumor) (Table 1). The patient was treated with 3 cycles of neoadjuvant vincristine, D-actinomycin, cyclophosphamide and after incomplete response, 3 cycles of ifosfamide, epirubicin, etoposide (VAC/IVE) chemotherapy followed by an incomplete tumor excision (R1), one cycle of adjuvant VAC/IVE and local radiotherapy (total dose 54 Gray). Local relapse was detected during maintenance therapy with vinorelbine and cyclophosphamide. The patient was then switched to vincristine, irinotecan, temozolomide (VIT) chemotherapy regimen with partial response followed by another incomplete resection (R1), and subsequent 5 cycles of adjuvant VIT and 32Gy re-irradiation. The patient is currently disease-free with post-treatment follow-up time of 17 months and 3.10 years after initial diagnosis.

Table 1:

Clinical findings for the study and control group of RMS with FGFR1 upregulation

Case# Sex Age at diagnosis Tumor Type Location IRS Group Tumor Size (cm) N Status M Status Vital Status Disease Relapse Follow-up time since last treatment (years)
1 M 24 years RMS (NOS) paratesticular I 3.5 0 0 NED No 0.5
2 M 7 years ERMS Pelvis III 10.5 0 0 NED Yes, Local 1.6
3 F 11 months ERMS Trunk I 6 0 0 NED No 1.4
4 F 5 months RMS (NOS) Skull Base I 4.5 0 0 DOD Yes, Local 4.1
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NOS, not otherwise specified; NED, no evidence of disease; DOD, Died of disease.

In order to identify other cases of RMS with FGFR1 gene alterations, we searched our molecular database, and identified two additional cases harboring multiple chr8p11 rearrangements and associated with FGFR1 mRNA overexpression, albeit without detectable FGFR1 fusions, possible due to the suboptimal quality standard as described above (cases #3, 4, Table 1). These cases were used as a comparison to the two cases with FGFR1 fusions. One of the tumors, which occurred in a 11-month-old female, was a 6 cm para-scapular soft tissue mass, in the setting of Li-Fraumeni disease (case#3). The other one occurred in a 5-month-old female with Turner syndrome, presenting with a 4.5 cm pterygomaxillary fissure lesion (case #4). Case#3 was treated as per RMS-2005 group D with 9 courses of IVA (ifosfamide, vincristine, D-actinomycin) (NCT00339118) and delayed complete tumor excision without adjuvant radiotherapy. The patient is currently disease-free with post-treatment follow-up time of 21 months and 2.0 years after initial diagnosis. Case #4 received 4 cycles of neoadjuvant IVA showing partial response (60% volume decrease), followed by complete surgical resection (R0) and 5 cycles of adjuvant IVA. The disease locally relapsed 5 months later and was treated with carboplatin and doxorubicin with good partial response. However, the patient ultimately experienced diffuse meningeal disease progression while on second line chemotherapy and died from disease 10 months after diagnosis of relapse.

Histopathologic and Immunohistochemical Features

The index case harboring an FGFR1::ANK1 fusion (case #1) showed a distinctive morphology composed of relatively monomorphic round cells arranged in solid sheets (Figure 1.a.) and pseudoalveolar spaces, separated by a densely collagenized stroma (Figure 1.b. c.). The tumor cells showed scant eosinophilic cytoplasm and round nuclei with variably irregular nuclear contours and hyperchromasia. The tumor was associated with a high mitotic activity (>10 MF/10 HPFs) and patchy areas of necrosis. In addition, some areas had a ‘starry sky’ appearance due to a conspicuous histiocytic infiltrate (Figure 1.d.). There were no areas of spindling, strap cells or anaplasia noted, nor myxoid stromal changes. The main considerations based on morphologic appearance was an alveolar RMS (ARMS) versus a sclerosing-variant of spindle cell RMS with a predominant dense pattern. By immunohistochemistry, the tumor showed diffuse positivity for desmin and MyoD1 (Figure 1.e.) and multifocal expression for myogenin (Figure 1.f.) (Table 2).

Figure 1: Morphologic and immunohistochemical findings for case #1.

Figure 1:

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a. Low power view showing nested growth pattern separated by fibrous septa; b. intermediate power showing both solid nests and alveolar growth; c. higher magnification of the alveolar pattern showing picket-fence arrangement at the periphery and centrally discohesive cells; d. solid growth with high mitotic activity, ‘starry sky’ appearance, apoptotic bodies and karyorrhexis. IHC showing in e. diffuse staining for MyoD1 and multifocal staining for myogenin in f.

Table 2 :

Histopathologic and molecular findings of the study and control group of RMS patients with FGFR1 upregulation

Case# Syndromic context Fusion Detection Tool Fusion FGFR1 mRNA Expression RMS histotype RNAseq Clustering Desmin Myogenin MyoD1 Genomic alterations (somatic)
1 No Archer™ FusionPlex™ FGFR1::ANK1 High ARMS vs sclerosing NA + + + FGFR1 Amplification
2 No RNA-Seq FGFR1::TACC1 High ERMS ERMS + + + TP53 hotspot SNV
Likely pathogenic variants in TET2, PRF1
3 Li-Fraumeni RNA-Seq No High ERMS with anaplasia ERMS + + + Somatic TP53 c.559+1G>A
FGFR1 amplification
4 Turner RNA-Seq No High RMS, unclassified, with anaplasia ERMS NA + NA FGFR1 Amplification
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NA, not available; RNAseq, RNA sequencing

Case #2 harboring an FGFR1::TACC1 fusion was composed of a spindle cell proliferation arranged in loose short fascicles, separated by abundant myxoid stroma (Figure 2.a.). The tumor cells showed mostly scant eosinophilic cytoplasm, but some strap cells and occasional striations were also seen. In areas, the tumor was associated with significant degree of pleomorphism in keeping with anaplasia (Figure 2.b.). The tumor showed 8 mitoses per 10 HPF, patchy necrosis (5% estimate), numerous apoptotic figures and karyorrhexis. Overall features were reminiscent of ERMS with anaplasia. By immunohistochemistry, the tumor showed diffuse staining for desmin (Figure 2.c.) and heterogenous expression of myogenin (Figure 2.d.) and of MyoD1 (Figure 2.e.). IHC for P53 showed somewhat heterogeneous, albeit strong nuclear staining (Figure 2.f., Table 2).

Figure 2: Morphologic and immunohistochemical findings for case #2.

Figure 2:

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a. Morphologic appearance with short spindle cells in a background of myxoid stroma; b. evidence of nuclear pleomorphism, in keeping with anaplasia. Immunohistochemistry (IHC) for: c. desmin, showing diffuse expression; d. myogenin, heterogeneous expression and highlighting some pleomorphic nuclei; and e. MyoD1, heterogeneous expression; and f. P53, showing heterogeneous, strong nuclear staining. Scale bars: 50 um.

Among the control group, case #3 had a typical ERMS morphology with anaplasia (Supplementary Figure 1, Table 2). The immunohistochemical results showed diffuse desmin and heterogenous myogenin positivity. The mitotic count was very high (33 mitoses per 10 HPF), but no tumor necrosis was seen. Case #4 was diagnosed as an unclassified RMS, composed of middle-sized round to ovoid cells with hyperchromatic nuclei, increased mitotic activity and areas of tumor necrosis. Immunohistochemically, the tumor cells showed diffuse expression of desmin and quite diffuse expression of myogenin (Table 2).

FGFR1 gene alterations and additional secondary genetic alterations

The targeted Archer™ FusionPlex™ assay performed on the index case (case #1) detected an in-frame fusion between exons 1–18 of FGFR1 (3’ – 5’) and exons 18–43 of ANK1 gene (3’ – 5’). The predicted chimeric protein retained the extracellular immunoglobulin (Ig)-like C2 and protein tyrosine kinase domains of FGFR1, as well as the ankyrin repeat, ZU5, and death domains of ANK1 (Figure 3.a., upper panel).

Figure 3: Fusion transcripts and molecular expression data.

Figure 3:

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a. upper panel. Schematic representation of the t(8;8)(p11.21;p11.23) translocation between the FGFR1 (ENST00000425967) (red) and ANK1 (ENST00000265709) (blue) genes resulting in an in-frame fusion transcript between exon 18 of FGFR1 with exon 18 of ANK1. a. lower panel. Schematic representation of the t(8;8) (p11.22;p11.23) translocation between the FGFR1 (ENST00000447712) (red) and TACC1 (ENST00000317827) (blue) genes resulting in an in-frame fusion transcript between exon 17 of FGFR1 with exon 7 of TACC1. The predicted individual chimeric proteins are also depicted demonstrating the conserved protein domains within the fusion. b. By unsupervised UMAP clustering plots of RNA expression data, cases #2, 3, 4 grouped together in a tight cluster with the ERMS control group, separate from the ARMS group.

The RNA-sequencing (RNA-Seq) in case # 2 detected an in-frame gene fusion between exons 1–17 of FGFR1 (3’ – 5’) and exons 7–13 of TACC1 (5’ – 3’), resulting from an inversion on chr8p11.23 (Figure 3.a., lower panel). Similar to the index case, the predicted chimeric protein retained the extracellular immunoglobulin (Ig)-like C2 and protein tyrosine kinase domains (TKD) of FGFR1, while TACC1 retained the transforming acidic coiled-coil-containing (TACC) and adhesion protein domains (Figure 3.a., lower panel.). High levels of mRNA expression detected in the index case 1 by Archer FusionPlex (Supplementary Figure 2). The FGFR1 mRNA expression of case 2, RMS with FGFR1 activation and control ARMS and ERMS are illustrated in Supplementary Figure 3.

Additionally, RNA-Seq variant calling in case #2 detected a TP53 p.(Arg273Cys) point mutation coupled to loss of heterozygosity and additional likely pathogenic variants in TET2 and PRF1 (Table 2). Panel-based DNA sequencing identified an FGFR1 amplification, confirmed the pathogenic variants found by RNA-seq, and did not find evidence for DICER1 pathogenic variants. The TP53 pathogenic variant observed in the tumor was not detected on subsequent germline testing.

The two additional RMS cases with particularly high levels of FGFR1 mRNA expression (cases #3, 4) were identified by screening of a large collection of RMS types tested by whole transcriptome RNA-seq (Supplementary Figure 3). In both cases the presence of FGFR1 fusions could not be confirmed, however, the RNA-Seq data revealed instead multiple chr8p11 rearrangements in both cases. Additionally, variant calling and DNA sequencing in case#3 detected a homozygous TP53 c.559+1G>A splicing SNV, which was subsequently also found on germline testing, thus confirming the diagnosis of Li-Fraumeni syndrome. No additional somatic alterations were found in case #4. Nanopore sequencing was done in case#3 to better characterize the chr8 rearrangement events, showing an FGFR1 amplification coupled with multiple rearrangements involving FGFR1, TACC1, and ANK1.

By unsupervised clustering of RNA expression data, cases #2, 3, 4 grouped together in a tight cluster with the ERMS control group available on the same platform (Figure 3.b.).

DISCUSSION

Rhabdomyosarcoma (RMS) is the most frequent pediatric soft tissue sarcoma with a median age at diagnosis of 5 years. In the past decade, the fine-tuning of multimodal chemotherapy regimens has greatly improved the survival for patients with localized diseases, reaching relapse-free rates of 70%20–22. In spite of this success, no breakthroughs in targeted therapies options have emerged in patients with RMS, despite an increase in genomic testing in the clinical practice. This relates in part to the pathogenesis of most RMS histotypes being driven either by aberrant transcription factors secondary to gene fusions, activating mutations in the RAS pathway or by loss of function alterations in tumor suppressor genes which are difficult to target. Although occasional cases of RMS have been reported with amplification of genes encoding certain protein kinases, i.e. FGFR4 in ARMS4, these are thought to represent secondary rather than driver events. In this study, we describe two RMS cases driven by FGFR1 fusion events, FGFR1::ANK1 and FGFR1::TACC1. Both fusions retained the kinase domain in the fusion oncoprotein and in the index case also resulted in FGFR1 overexpression. Although the morphologic features were rather distinct, one showing hybrid features of ARMS and sclerosing RMS, while the other resembling ERMS with anaplasia, both occurred in male patients with either paratesticular or pelvic primary site.

Fibroblast growth factor receptors (FGFRs), similar to other receptor tyrosine kinases, consist of an extracellular ligand binding domain, which binds to fibroblast growth factor (FGF) ligands, a transmembrane domain, and an intracellular kinase domain23. In physiologic states, binding of FGF triggers FGFR dimerization and kinase domain autophosphorylation, leading to downstream signaling, including RAS/MAPK and PI3K/AKT24. In cancer, FGFR alterations promote stemness, proliferation, angiogenesis, epithelial-mesenchymal transition, invasion and drug resistance25–27.

Most FGFR alterations in sarcomas represent gene amplifications28,29, which have been reported with variable incidences in dedifferentiated liposarcoma, leiomyosarcoma and malignant peripheral nerve sheath tumors30–32. The FGFR alterations found in these tumor types are exclusively copy number amplifications or activating single nucleotide variations28. In contrast, FGFR1-related fusions are rare in sarcomas and have mostly been described in central nervous system malignancies33–35. Thus, FGFR1::TACC1 fusion identified in case #2 has been a recurrent event in pediatric low-grade gliomas (pLGG), occurring in 2–3% of cases36, further supporting its oncogenic nature. Moreover, clinical activity of an FGFR inhibitor has been reported in a pLGG patient with this fusion37. FGFR1::TACC1 fusions were also described in other sarcoma types as isolated case reports, such as a pediatric uterine leiomyosarcoma38, uterine sarcoma39, and undifferentiated sarcoma40. Other variant FGFR1 fusions with alternative gene partners have been described in as well as benign lesions, such as a calcified chondroid mesenchymal neoplasm with FGFR1::PLAG141, pediatrc mesenchymal tumors42 and aneurysmal bone cyst43. In contrast, a handful of FGFR fusions have been described in gastrointestinal stromal tumors (GIST) lacking activating KIT/PDGFRA mutations44–46 and in one KIT exon 11 mutant GIST which acquired an FGFR2::TACC2 fusion in the setting of multi-drug resistance27. In addition, an FGFR1::EBF2 fusion was reported in an CD34-positive infantile spindle cell sarcoma, NOS, which responded to erdafitinib (a pan-FGFR inhibitor)35.

In RMS, FGFR alterations have been reported in 7–13% of cases3,4,47,48, mostly activating point mutations or/and amplifications and involving FGFR43. FGFR1 overexpression in RMS was also described possibly related to hypomethylation of a CpG island upstream to FGFR1 exon 149 or to increased copy number50. An isolated case of an FGFR-related gene fusion has been reported in an RMS to date, raising the possibility of an FOXO1::FGFR1 fusion, which was detected by FISH in a suspected case of ARMS with focal desmin and myogenin expression51. However, no confirmatory RNA analysis was provided to validate the fusion. In the current study, both predicted fusion oncoproteins retained most FGFR1 functional domains including the ligand binding, transmembrane domain and TKD. Functionally, these fusions are membrane bound and constitutively activated by the addition of C-terminal dimerization domains.

Recent phase II clinical trials for patients with urothelial carcinoma and cholangiocarcinoma harboring FGFR1/2 amplification have shown a clinical benefit using FGFR inhibitors, in particular, with erdafitinib15,52. In the sarcoma field, a single case of a FGFR1 fusion-positive unclassified infantile spindle cell tumor also showed an objective response to erdafitinib35.

In RMS, the most common FGFR alteration occurs in FGFR4 gene, which is altered in 10% of cases, either by amplifications or mutations, and was used as a potential therapeutic target in a few in vitro studies using FGFR4-CAR-T cells53,54. In one preclinical study, futibatinib, a pan-FGFR inhibitor, showed growth inhibition in RMS cell lines while inhibiting phosphorylation of FGFR4 and its downstream targets55. However, an FGFR4 V550L-mutant cell line developed from a patient with ERMS responded to FGFR4-specific inhibitors, but not to a pan-FGFR inhibitor56.

Of interest, the two additional RMS cases with FGFR1 activation included in the control group had distinct clinical presentations, both occurring in two syndromic female patients, including an 11 month-old infant with Li-Fraumeni and a 5 month-old with Turner’s syndrome. The first case harbored typical morphologic features of ERMS, while the second was deemed unclassified with atypical histologic features. However, both cases clustered together with the conventional group of ERMS by RNA sequencing. Despite the identification of chr8 rearrangements, the precise mechanism of the FGFR1 mRNA overexpression could not be elucidated. However, by Nanopore sequencing assay and DNA sequencing, one of the cases showed the presence of FGFR1 amplification, which may explain the genomic instability at this locus. Among the genetic cancer predisposition conditions associated with a high risk of childhood RMS, the most common include Li-Fraumeni syndrome, DICER1 syndrome, Beckwith-Wiedemann syndrome, and some RASopathies, such as neurofibromatosis type 1, Costello syndrome, and Noonan syndrome57–60.

Turner syndrome is associated with a complex cancer phenotype (i.e. breast, colon, renal cancers, etc)61, but sarcomas are not prevalent, and this is the first reported case of RMS occurring in this syndromic setting and associated with a highly aggressive behavior.

Although limited, the follow-up information available suggests an aggressive outcome, possibly related to the coexisting TP53 mutation in one case (case 2). Thus, one of the study patients (case 2) developed a local recurrence during maintenance therapy, while the patient with Turner syndrome followed a fulminant course of meningeal spread and died of disease. In the setting of syndromic patients, the long-term prognosis of RMS associated with TP53 pathogenic germline variants is strongly influenced by the high incidence of multiple primary tumors60.

In summary, we report for the first time driver FGFR fusions in RMS, with two FGFR1::TACC1 and FGFR1::ANK1 fusion events resulting in FGFR1 oncogenic activation. Although the two cases were not associated with a consistent phenotype, which included different RMS histotypes, they occurred in patients with similar clinical presentations. Thus, further studies are needed to establish if the rare occurrence of FGFR fusions showcase a novel RMS subtype or alternatively FGFR1 fusions may represent rare drivers in different RMS types. As one of the study group cases and one of the control cases remained unclassified, further genomic testing is recommended in challenging RMS cases for further subclassification, in an attempt to uncover potential targets and to select patients for tailored strategies with FGFR inhibitors when appropriate.

Supplementary Material

Fig S3

Supplementary Figure 3. Relative expression of FGFR1 (ENSG00000077782) in log2(TPM+1), for control groups of ERMS (light red), ARMS (purple) and normal skeletal muscle tissue samples (GTEX public database) (green) in comparison to RMS with FGFR1 activation (yellow) and the FGFR1::TACC1 fusion positive case (dark red).

Fig S2

Supplementary Figure 2. FGFR1 marked overexpression of index case 1 on Archer Fusion Plex platform.

Fig Table S1
Fig Table S2
Fig Table S3
Supinfo

Supplementary Figure 1. Pathologic features of case 3 with FGFR1 activation. Morphologic appearance showed an ERMS morphology with strap cells (A), focal anaplasia (B). By IHC the tumor showed positivity for desmin (C) and myogenin (D).

Fig Table S4

Acknowledgments

Supported in part by: P50 CA217694 (CRA), P30 CA008748 (CRA), Kristin Ann Carr Foundation (CRA), Cycle for survival (CRA), The Belgian Kids’ Fund for Pediatric Research (HTW), S. Wisinia (DO, HTW)

Footnotes

CONFLICT OF INTEREST STATEMENT. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

DATA AVAILABILITY STATEMENT.

Data sharing will be provided on a reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Fig S3

Supplementary Figure 3. Relative expression of FGFR1 (ENSG00000077782) in log2(TPM+1), for control groups of ERMS (light red), ARMS (purple) and normal skeletal muscle tissue samples (GTEX public database) (green) in comparison to RMS with FGFR1 activation (yellow) and the FGFR1::TACC1 fusion positive case (dark red).

NIHMS2013096-supplement-Fig_S3.pdf (44.7KB, pdf)
Fig S2

Supplementary Figure 2. FGFR1 marked overexpression of index case 1 on Archer Fusion Plex platform.

NIHMS2013096-supplement-Fig_S2.pdf (279.8KB, pdf)
Fig Table S1
NIHMS2013096-supplement-Fig_Table_S1.docx (14.5KB, docx)
Fig Table S2
NIHMS2013096-supplement-Fig_Table_S2.docx (16.4KB, docx)
Fig Table S3
NIHMS2013096-supplement-Fig_Table_S3.docx (17.3KB, docx)
Supinfo

Supplementary Figure 1. Pathologic features of case 3 with FGFR1 activation. Morphologic appearance showed an ERMS morphology with strap cells (A), focal anaplasia (B). By IHC the tumor showed positivity for desmin (C) and myogenin (D).

NIHMS2013096-supplement-Supinfo.jpg (2.7MB, jpg)
Fig Table S4
NIHMS2013096-supplement-Fig_Table_S4.docx (17.1KB, docx)

Data Availability Statement

Data sharing will be provided on a reasonable request.

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