Elimination of BRAF p.V600E under selective pressure of BRAF-targeted therapy and expansion of a PIK3CA p.E542K clone in a patient with recurrent malignant glomus tumor

Elimination of BRAF p.V600E under selective pressure of BRAF-targeted therapy and expansion of a PIK3CA p.E542K clone in a patient with recurrent malignant glomus tumor | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Elimination of BRAF p.V600E under selective pressure of BRAF-targeted therapy and expansion of a PIK3CA p.E542K clone in a patient with recurrent malignant glomus tumor Ilias Ziakas, Stavriani C. Makri, John M. Gross, Suping Chen, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7041059/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 13 You are reading this latest preprint version Abstract Glomus tumors are rare mesenchymal tumors that resemble modified smooth muscle cells of the normal glomus body. BRAF p.V600E has previously been detected in glomus tumors and is associated with more aggressive clinical behavior. Here, we report a case of a patient with a malignant BRAF -mutant glomus tumor that initially responded to BRAF targeted therapy, likely leading to the elimination of the clone harboring the BRAF p.V600E. Notably, upon disease progression, BRAF p.V600E was not detected in multiple regions of the recurrent tumor, whereas another clone harboring PIK3CA p.E542K expanded, highlighting the complex genomic landscape of malignant glomus tumors under the selective pressure of targeted therapy. Biological sciences/Cancer Health sciences/Oncology Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Glomus tumors (GT) are rare mesenchymal neoplasms that resemble the Sucquet-Hoyer canal of the normal glomus body, which controls blood pressure and thermal regulation. They account for 1.6% of all soft tissue tumors 1 . While GTs commonly occur in the subungual region of the fingers, which has a high concentration of glomus bodies, they can arise from virtually anywhere in the body 1 . GTs are classified based on WHO criteria as benign, glomus tumor of uncertain malignant potential (GT-UMP), or malignant 2 – 4 . Malignant glomus tumors, also called glomangiosarcomas, tend to recur locally though rarely can metastasize. Here, we present the case of young adult female with malignant glomus tumor of the brachial plexus harboring a BRAF p.V600E mutation. She initially attained prolonged clinical benefit following treatment with a selective BRAF inhibitor. However, upon disease progression, multi-region next generation sequencing revealed loss of the BRAF p.V600E mutation and the emergence of an oncogenic PIK3CA p.E542K mutation. This case, previously reported as the first instance of BRAF-targeted therapeutic intervention in malignant glomus tumor, provides insights into tumor evolution under therapeutic pressure, illustrating clonal selection and expansion in response to targeted therapy 5 . Results Clinical course An 18-year-old female with no significant past medical history was referred to our institution from abroad for evaluation and management of severe right shoulder pain. The pain had started one year prior and was insidious in onset, with no inciting event or trauma (Fig. 1 ). MRI of the right upper extremity revealed two brachial plexus masses suggestive of tumors of neurogenic origin, along with C5-C6 nerve root thickening. The patient underwent open surgical exploration of the right infraclavicular brachial plexus, which revealed that both tumors were intimately involved with nerve elements. Given the axillary nerve involvement, further aggressive dissection of the remaining tumor was deferred to minimize the risk of significant neurologic deficits. Histopathologic analysis led to the diagnosis of malignant glomus tumor 3 . Molecular genetic analysis with polymerase chain-reaction (PCR) revealed the presence of a BRAF p.V600E mutation at a variant allele frequency (VAF) of 40%. This was further confirmed by next-generation sequencing (NGS), which detected a heterozygous BRAF p.V600E mutation with a VAF of 37.76% ( Table 1 ) . Given the inability to achieve complete surgical resection of the tumor, we opted to monitor closely with serial imaging. Both the proximal and the distal lesions remained stable in size for two years before the distal mass began to enlarge on follow-up imaging. Table 1 Next generation sequencing comparing sequence alterations at the time of diagnosis (sample 1) and at second relapse (samples 2, 3A, 3B and 3C). Gene Chromosomal position Base Change AA change VAF (%): (sample 1) (Tumor purity > 90%) VAF (%): (sample 2) (Tumor purity 80%) VAF (%): (sample 3A) (Tumor purity 90%) VAF (%): (sample 3B) (Tumor purity 90%) VAF (%): (sample 3C) (Tumor purity 90%) Origin ADGRA2 chr8:37689051 C > T p.T348I 50.05 48.1 45.48 48.2 32.99 Possibly germline ARHGAP26 chr5:142526934 G > A p.R659Q 36.42 Not detected Not detected Not detected Not detected Somatic ATRX chrX:76939445 T > C p.I435V 49.92 56.83 57.4 49.17 53.76 Possibly germline BRAF chr7:140453136 A > T p.V600E 37.76 Not detected Not detected Not detected Not detected Somatic FANCL chr2:58386928 G > GTAAT p.T367fs 33.8 25.42 29.27 31.24 31.25 Possibly germline KDM6A chrX:44935983 T > C p.L915S 46.78 45.45 47.49 48.42 49.75 Possibly germline MCL1 chr1:150550965 T > G p.M231L 48.54 47.23 46.06 44.5 45.65 Possibly germline MED12 chrX:70339711 C > T p.T127M Not detected Not detected Not detected Not detected 32.62 Somatic PIK3CA chr3:178936082 G > A p.E542K Not detected Not detected 47.58 46.44 15.56 Somatic PRKDC chr8:48805837 C > T p.A1237T 48.74 46.58 48.17 49.27 54.04 Possibly germline RNF43 chr17:56440643 G > A p.P192L 47.14 45.99 47.04 50.5 41.75 Possibly germline SYNE1 chr6:152527409 C > T p.G7638D 49 43.42 45.11 46.42 48.51 Possibly germline WDR90 chr16:716543 G > A p.R1610Q 52.56 46.46 50 52.36 48.85 Possibly germline XPO1 chr2:61719196 T > C p.I621V 50.17 42.89 46.13 47.87 49.55 Possibly germline Management of the patient’s first radiologic progression was discussed at the Johns Hopkins multidisciplinary sarcoma tumor board. Surgical resection was again deemed high-risk due to the potential for loss of neurologic function in the right arm. After careful consideration and in the context of the BRAF p.V600E mutation, we initiated systemic therapy with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, based on their demonstrated activity across multiple cancer types 6 – 8 . Notably, this recommendation was made off-label and nearly five years prior to the FDA approval of the dabrafenib/trametinib combination as a tissue-agnostic therapy for BRAF p.V600E-mutant solid tumors. Dabrafenib was started at 150 mg twice daily and trametinib was added three weeks later at 2 mg daily. MRI imaging and PET-CT performed two weeks after starting trametinib showed a reduction in tumor size 5 . After approximately one year, trametinib was discontinued due to liver toxicity, but the patient remained on dabrafenib. Over the next three years, serial imaging demonstrated continued reduction in the size of the distal mass, with stable thickening of the right C5-C6 nerve roots, consistent with a partial response (Fig. 2 a, 2 b) 5 . The patient elected to stop dabrafenib after approximately three years. Over the following four years, she underwent serial imaging every three months, which showed stable disease. After a nearly 57-month treatment-free interval, MRI revealed disease progression, with a recurrent soft tissue neck mass along the right C5-C6 nerve roots with possible right supraclavicular involvement ( Fig. 2 c). Core needle biopsy of the right C5-C6 nerve mass confirmed a malignant glomus tumor (Fig. 3 d). Notably, neither immunohistochemistry nor next-generation sequencing of the progressing tumor detected the BRAF p.V600E mutation. The BRAF locus had a normal copy number, indicating that the BRAF mutation was not lost through chromosomal deletion. Additional genomic alterations identified at recurrence included a chromosome 11q amplification (chr11q amp) involving the YAP1 , BIRC2 and BIRC3 genes, along with loss of chromosome 9q and gain of chromosome 19q (Table 2 ), alterations not present at initial diagnosis. Given the rapidly progressing tumor, the patient underwent surgical resection one month after the core needle biopsy ( Fig. 2 d ) . Table 2 Next generation sequencing comparing structural alterations at the time of diagnosis (sample 1), and at second relapse (sample 2, 3A, 3B and 3C). Log2R represents the logarithmic ratio of the observed read depth (or coverage) of a specific genomic region in the sample compared to the expected read depth, derived from a normal control sample set. Sample 1: Sample 2: Sample 3A: Sample 3B: Sample 3C: Chromosome Arm/band Driver genes in the altered locus CNV/Average Log2R CNV/Average Log2R CNV/Average Log2R CNV/Average Log2R CNV/Average Log2R 8 whole chromosome many Copy Neutral Copy Neutral Copy Neutral Copy Neutral Copy Gain, + 0.5 9 q many Copy Neutral Copy Loss, -1 Copy Loss, -1 Copy Loss, -1 Copy Loss, -1 9 q NOTCH1 Copy Neutral Copy Neutral Copy Neutral Copy Gain, + 1.16 Copy Neutral 11 q YAP1, BIRC3, BIRC2 Copy Neutral Amplification, + 3.86 Amplification, + 3.51 Amplification, + 3.41 Amplification, + 3.41 19 q many Copy Neutral Copy Gain, + 0.5 Copy Gain, + 0.5 Copy Gain, + 0.5 Copy Gain, + 0.5 Molecular Tumor Board review This case was subsequently presented at the Johns Hopkins Molecular Tumor Board for further discussion. In the biopsy specimen of the recurrent C5-C6 nerve root tumor in the neck, the BRAF p.V600E alteration was detected in only 1 out of 573 reads (0.17%) (Supp. Figure 1 ) , falling below the assay’s reportable range and at a level consistent with background sequencing error 9 . The absence of BRAF p.V600E was both surprising and unusual, as typically the BRAF p.V600E mutation is clonal and retained in the majority of BRAF-mutant cancers that recur following BRAF-targeted therapy. In such cases, resistance is often driven by additional genomic alterations in the MAPK pathway or secondary BRAF mutations that drive acquired resistance 10 – 13 . In evaluating the BRAF locus, there was no indication of locus deletion, suggesting that the BRAF p.V600E cancer cell population represented a fraction of the parental clone and may have been eliminated due to BRAF-targeted therapy. To further substantiate these findings, the Molecular Tumor Board recommended performing next-generation sequencing (NGS) of multiple regions of the recurrent tumor to assess whether the apparent absence of BRAF p.V600E was a consequence of intratumoral heterogeneity or representative of the entire tumor. Macroscopically, all regions of the resection tumor appeared similar (Fig. 3 e). Additionally, histopathological evaluation with hematoxylin and eosin staining confirmed the tumor’s homogeneity at a microscopic level, with pathology consistent with a malignant glomus tumor ( Fig. 3 f, g, h ) . Notably, the specimens from the second relapse demonstrated a more aggressive phenotype compared to the sample from the initial diagnosis ( Fig. 3 a, 3 c ). NGS was performed on three spatially distinct regions from the surgical specimen (designated Parts 3A, 3B, 3C) using the same NGS panel ( Table 1 ). The BRAF p.V600E mutation was again not detected in any of the three samples, with zero mutant reads on visual inspection (Supp. Figure 1 ) , supporting a true absence of the mutation rather than intra-tumoral heterogeneity 9 . Importantly, there was no evidence of deletion at the BRAF locus that might drive BRAF V600E loss, and all three samples had high tumor purity (~ 90%), ruling out false-negative results due to insufficient tumor content. (Supp. Figure 2 ) . Taken together, these findings suggest that the BRAF- mutant clone regressed in response to BRAF-targeted therapy. The copy number alterations detected in the biopsy of the recurrent neck tumor, including the chr11q amp, 9q loss, and 19q gain, were identified in all three samples from the surgical resection (Supp. Figure 2 ) . Additionally, a hotspot PIK3CA p.E542K was detected in all three regions of the resected recurrent tumor with VAFs of 15%, 46%, and 47% ( Table 1 ) . The lower VAF in one sample suggests that the PIK3CA- mutant clone represents a minor clone in that region of the tumor. To further investigate the emergence of the PI3KCA mutation, we re-examined both the sample from initial diagnosis and the most recent core needle biopsy of the recurrent tumor for any mutant reads of PIK3CA p.E542K below the reportable threshold. No mutant reads were detected at the PIK3CA locus, and the tumor purity of all samples was > 80%, supporting true acquisition of the PIK3CA mutation later in tumor evolution. Adding to the complexity of the tumor’s evolutionary trajectory, chromosome 11q amplification, 9q deletion, and 19q gain were detected in the recurrent tumor biopsy and all three surgical samples but were absent from the tumor at initial diagnosis. Moreover, the PIK3CA p.E542K was found in all three samples from the surgical resection but absent in the earlier biopsy of the recurrent mass and in the initial mass ( Table 1 ) . These findings suggest the presence of two distinct tumor clones at diagnosis: one harboring the BRAF p.V600E detected in the initial tumor and an aneuploid clone harboring the structural alterations detected in the recurrent tumor, which later expanded after the regression of the BRAF- mutant clone and may be responsible for to the current relapse. Regarding the discrepancy between the PIK3CA p.E542K that was not detected in the core biopsy of the recurrent tumor but was detected in all three regions of the surgically resected mass, one possible explanation is that the PIK3CA mutation was acquired in the one-month interval between the core needle biopsy and the surgical resection of the neck mass in the context of rapid disease progression ( Fig. 4 ) . Alternatively, spatial heterogeneity may account for this difference, with the mutation present in unsampled regions of the tumor at the time of biopsy. Discussion Genomic landscape of glomus tumors Molecular genetic studies in glomus tumors remain limited, especially in the context of tumor evolution. GTs have been associated with the neurocutaneous tumor predisposition syndrome neurofibromatosis type 1 (NF1), in which germline loss of NF1 , a RAS GTPase activating protein, leads to activation of the RAS-ERK signaling pathway 14 . However, most glomus tumors are sporadic. One study identified NOTCH rearrangements in 16 out of 17 malignant GTs and associated pericytic neoplasms, with 88% of these being NOTCH2 rearrangements 15 . NOTCH2 and NOTCH3 regulate vascular smooth muscle development 16 . This, combined with the high frequency of NOTCH fusions in glomus tumors, suggests that they are early events in the pathogenesis of GT 17 . Other reported alterations in malignant GTs include KRAS p.G12A mutations, ATG:RAF1 fusions, SMARCB1 truncating mutations, and CCND3 point mutations 18 – 21 . BRAF mutations, particularly BRAF p.V600E, have emerged as potential oncogenic drivers in malignant glomus tumors. In one targeted sequencing study, three of 28 glomus tumors were found to harbor the BRAF p.V600E mutation 21 . Another study of 102 glomus tumors identified BRAF p.V600E in six cases, all of which were classified as malignant glomus tumor or GT-UMP, suggesting that BRAF mutations are associated with more aggressive tumor biology 4 , 17 . While most reported BRAF p.V600E-mutant GTs have occurred in the extremities, cases have also been described in other anatomic sites, including the orbit 17 , 22 , 23 . Although data remain limited, the profound response to BRAF and MEK inhibition observed in our patient, as well as in a recently published case of metastatic BRAF p.V600E-mutant malignant GT, underscores the therapeutic potential of combined BRAF and MEK inhibition in treating malignant GTs harboring BRAF p.V600E mutations 5 , 24 . To our knowledge, these are the only two reported cases of genome-driven targeted therapy against oncogenic BRAF mutations in malignant glomus tumor. Elimination of BRAF p.V600E mutant clones during tumor evolution To explore the frequency of BRAF p.V600E loss during tumor evolution, we analyzed next generation sequencing data from the publicly available MSK-IMPACT cohort through CBioPortal 25 – 28 . Among 10,336 patients, 562 had sequencing performed on more than one tumor sample. Within this subset, BRAF p.V600E was detected in 20 patients. After excluding six patients whose samples came from unrelated primary tumors and two without clear longitudinal samples, 12 patients remained with serially sequenced BRAF -mutant tumors. In this cohort, BRAF p.V600E was retained in all but one case: a patient with a primary rectal tumor harboring BRAF p.V600E, which was absent in a liver metastasis. Similar to our case, the BRAF mutant cancer cell population likely was eliminated, and the BRAF wild type population grew out. However, this finding should be interpreted with caution. The variant allele frequency of BRAF p.V600E in the rectal tumor was 5% with 70% tumor purity, suggesting that the mutation was subclonal. No shared genomic alterations were found between the rectal and liver specimens, suggesting the possibility of significant tumor heterogeneity or separate tumor lineages. Additionally, the liver metastasis had only 20% tumor purity, reducing the sensitivity for detecting low-frequency mutations. Thus, while this case raises the possibility of elimination of a BRAF p.V600E clone during tumor progression, technical and biological factors such as tumor heterogeneity, subclonality, tissue sampling bias, and low tumor purity may also explain the absence of detectable mutation in the liver metastasis. Clear examples of elimination of a BRAF p.V600E clone following targeted therapy remain rare and difficult to verify in large retrospective datasets. Further supporting the rarity of BRAF p.V600E loss, a study of pediatric low-grade gliomas found that the mutation status was conserved in 98% of patients 29 . Loss was observed in only one patient by immunohistochemistry testing in a subsequent surgery performed 35 months after the initial diagnosis, although confirmatory sequencing was not available. This patient had not received systemic therapy or radiation, and there was no clear radiographic evidence of progression at the time of second surgery, raising the possibility of sampling bias rather than BRAF mutant allele loss 29 . Another report described a recurrent glioblastoma in which BRAF p.V600E loss was proposed as a resistance mechanism to BRAF-targeted therapy 30 . Overall, these findings indicate that BRAF p.V600E loss during tumor evolution under the selective pressure of targeted therapy is a very rare event across cancer types, highlighting the uniqueness of our case. Acquisition of PIK3CA mutations under selective pressure of BRAF targeted therapy A notable aspect of this case is the emergence of a clone harboring a PIK3CA p.E542K in tandem with the loss of the BRAF p.V600E mutant clone. PIK3CA alterations are exceedingly rare in glomus tumors; to date, only one gastric glomus tumor harboring a PIK3CA p.E545K mutation has been reported 31 . The emergence of PIK3CA alterations has been reported as a resistance mechanism to BRAF- targeted therapy in other cancers, including thyroid, melanoma and colorectal cancer 32 – 35 . In one case, a patient with BRAF p.V600E-mutant classic papillary thyroid cancer (PTC) treated with vemurafenib for five months developed anaplastic transformation. Whole exome sequencing and next-generation sequencing of the pretreatment PTC nodal metastases and post-transformation anaplastic thyroid cancer (ATC) metastases showed emergence of PIK3CA p.H1047R in the post-transformation tumor. However, unlike in our case, BRAF p.V600E remained detectable in all ATC samples 36 . To our knowledge, this is the first reported case in which a PIK3CA p.E542K subclone emerged after the regression of a BRAF p.V600E population in response to BRAF-targeted therapy. Conclusion To our knowledge, this is the first reported case of the loss of a BRA F-mutant clone following BRAF- targeted therapy, alongside the emergence of a different clone harboring a PIK3CA p.E542K mutation, an alteration that has never been reported in patients with malignant glomus tumors. This is also the first report to characterize the evolutionary trajectory of malignant glomus tumors through serial NGS. Our findings highlight the complex genomic evolutionary landscape of malignant glomus tumors, delineating the impact of selective pressure applied by targeted therapy in conjunction with tumor heterogeneity. This case highlights the value of serial molecular profiling to guide therapeutic decisions, especially in patients with rare tumors. Methods Case Report A single patient treated at Johns Hopkins Hospital (JHH) was identified for this case report. A retrospective chart review was conducted to collect relevant clinical data. The patient provided written informed consent for the publication of this anonymized data. Next generation sequencing Molecular testing was performed in the Clinical Laboratory Improvement Amendments (CLIA)-certified Johns Hopkins Medical Laboratory at the Johns Hopkins Hospital (Baltimore, MD). Targeted NGS was performed on formalin-fixed, paraffin-embedded tumor tissue using the Johns Hopkins Solid Tumor panel, version 9 ( https://pathology.jhu.edu/test-directory/ngs-solid-tumor-panel ). For the BRAF p.V600E PCR Assay, DNA was extracted from the tissue and amplified by PCR targeting exon 15 of the BRAF gene. The amplification products were sequenced using pyrosequencing technology. CNVkit software (version 0.9.6, https://cnvkit.readthedocs.io/en/stable/ , accessed May 30, 2025) was used to infer genome-wide copy number variations (CNVs) from targeted next-generation sequencing (NGS) data. A genome-wide scatter plot was generated, integrating bin-level Log2R coverages and segmentation calls to visualize copy number alterations across the genome. Declarations Competing Interests S.A. has received research support from Neurofibromatosis Therapeutic Acceleration Program (unrelated), Amgen Therapeutics (unrelated) and Honoraria from Alexion (unrelated). A.J.B. has received consulting fees from AstraZeneca (unrelated). V.A. has received funding from AstraZeneca (Inst) (unrelated); Bristol-Myers Squibb (Inst) (unrelated); Delfi Diagnostics (Inst) (unrelated); Personal Genome Diagnostics (Inst) (unrelated); Honoraria from Foundation Medicine (unrelated); Personal Genome Diagnostics (unrelated) and has Consulting or Advisory Role in AstraZeneca (unrelated) and NeoGenomics Laboratories Research (unrelated). C.A.P. has received research grants from Kura Oncology and Novartis Institutes for Biomedical Research (unrelated to this manuscript); and consulting fees from Day One Therapeutics (unrelated). J.J.T. has received research support from Pfizer (Inst) (unrelated). The other co-authors declare that they have no competing interests. Author Contribution Idea conception: J.J.T., C.A.P., and I.Z. Manuscript writing, data collection, and figure creation: I.Z., S.C.M, N.N, R.X, Y.Z., J.M.G, S.A., V.A., C.A.P, J.J.T. Significant contributions to clinical patient care: C.A.P, A.J.B, S.A., S.C., Y.Z., R.X., C.G, J.G, V.A., J.J.T. All authors reviewed the manuscript. Acknowledgement We thank the patient and her family for allowing us to participate in her care, providing patient-reported outcomes, and giving us permission to report on her case. We thank the Johns Hopkins Molecular Tumor Board for their support of this work and their thoughtful discussion guiding the care of this patient. We thank the Johns Hopkins Molecular Diagnostics Laboratory for their support of this report and molecular studies of this patient’s tumor. The Johns Hopkins Molecular Tumor Board Investigators include Deborah Armstrong, Marina Baretti, Taxiarchis Botsis, Jenna V. Canzoniero, Maria Durham, Amna Jamali, David O. Kamson, Katerina Karaindrou, Rachel Karchin, Kory Kreimeyer, John Laterra, Jennifer Lehman, Christian Meyer, Mimi Najjar, Cesar A. 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Characterizing temporal genomic heterogeneity in pediatric low-grade gliomas. Acta Neuropathol Commun 8, 182 (2020). https://doi.org/10.1186/s40478-020-01054-w Haile, H. et al. Management of asynchronous multifocal adult glioblastoma with loss of BRAF(V600E) -mutant clonality: a case report. Acta Neuropathol Commun 13, 18 (2025). https://doi.org/10.1186/s40478-024-01894-w Deng, M. et al. Clinicopathologic features of gastric glomus tumor: A report of 15 cases and literature review. Pathol Oncol Res 28, 1610824 (2022). https://doi.org/10.3389/pore.2022.1610824 Roelli, M. A. et al. PIK3CA(H1047R)-induced paradoxical ERK activation results in resistance to BRAF(V600E) specific inhibitors in BRAF(V600E) PIK3CA(H1047R) double mutant thyroid tumors. Oncotarget 8, 103207–103222 (2017). https://doi.org/10.18632/oncotarget.21732 Irvine, M. et al. Oncogenic PI3K/AKT promotes the step-wise evolution of combination BRAF/MEK inhibitor resistance in melanoma. Oncogenesis 7, 72 (2018). https://doi.org/10.1038/s41389-018-0081-3 Shi, H. et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov 4, 80–93 (2014). https://doi.org/10.1158/2159-8290.CD-13-0642 Huijberts, S., Boelens, M. C., Bernards, R. & Opdam, F. L. Mutational profiles associated with resistance in patients with BRAFV600E mutant colorectal cancer treated with cetuximab and encorafenib +/- binimetinib or alpelisib. Br J Cancer 124, 176–182 (2021). https://doi.org/10.1038/s41416-020-01147-2 Lee, M. et al. Genomic and Transcriptomic Correlates of Thyroid Carcinoma Evolution after BRAF Inhibitor Therapy. Mol Cancer Res 20, 45–55 (2022). https://doi.org/10.1158/1541-7786.MCR-21-0442 Additional Declarations Competing interest reported. S.A. has received research support from Neurofibromatosis Therapeutic Acceleration Program (unrelated), Amgen Therapeutics (unrelated) and Honoraria from Alexion (unrelated). A.J.B. has received consulting fees from AstraZeneca (unrelated). V.A. has received funding from AstraZeneca (Inst) (unrelated); Bristol-Myers Squibb (Inst) (unrelated); Delfi Diagnostics (Inst) (unrelated); Personal Genome Diagnostics (Inst) (unrelated); Honoraria from Foundation Medicine (unrelated); Personal Genome Diagnostics (unrelated) and has Consulting or Advisory Role in AstraZeneca (unrelated) and NeoGenomics Laboratories Research (unrelated). C.A.P. has received research grants from Kura Oncology and Novartis Institutes for Biomedical Research (unrelated to this manuscript); and consulting fees from Day One Therapeutics (unrelated). J.J.T. has received research support from Pfizer (Inst) (unrelated). The other co-authors declare that they have no competing interests. Supplementary Files SupplementaryfiguresNPJfinal.pdf Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 24 Aug, 2025 Reviews received at journal 23 Aug, 2025 Reviews received at journal 22 Aug, 2025 Reviews received at journal 21 Aug, 2025 Reviewers agreed at journal 14 Aug, 2025 Reviews received at journal 13 Aug, 2025 Reviewers agreed at journal 13 Aug, 2025 Reviewers agreed at journal 12 Aug, 2025 Reviewers agreed at journal 31 Jul, 2025 Reviewers invited by journal 30 Jul, 2025 Editor assigned by journal 29 Jul, 2025 Submission checks completed at journal 08 Jul, 2025 First submitted to journal 03 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7041059","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":494420896,"identity":"89b3987f-405c-4151-bc4d-8dd2795c9563","order_by":0,"name":"Ilias Ziakas","email":"","orcid":"","institution":"The Johns Hopkins Molecular Tumor Board, Johns Hopkins University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ilias","middleName":"","lastName":"Ziakas","suffix":""},{"id":494420897,"identity":"24536d21-7398-451a-a694-9b7cceb7eb95","order_by":1,"name":"Stavriani C. Makri","email":"","orcid":"","institution":"Johns Hopkins School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Stavriani","middleName":"C.","lastName":"Makri","suffix":""},{"id":494420898,"identity":"4e998f59-f642-4d5e-a33d-1f439d43e6c0","order_by":2,"name":"John M. Gross","email":"","orcid":"","institution":"Johns Hopkins School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"John","middleName":"M.","lastName":"Gross","suffix":""},{"id":494420899,"identity":"8ead867c-7f26-45ac-acec-c5b0f120a274","order_by":3,"name":"Suping Chen","email":"","orcid":"","institution":"Johns Hopkins School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Suping","middleName":"","lastName":"Chen","suffix":""},{"id":494420900,"identity":"22ea26e6-14f3-42e0-9945-d9a3b720afba","order_by":4,"name":"Ying Zou","email":"","orcid":"","institution":"Johns Hopkins School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Zou","suffix":""},{"id":494420901,"identity":"78730434-9100-446d-9c41-476cc0658f8e","order_by":5,"name":"Rena Xian","email":"","orcid":"","institution":"Johns Hopkins School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Rena","middleName":"","lastName":"Xian","suffix":""},{"id":494420902,"identity":"9888145f-669e-4856-8d25-3f4376111ab6","order_by":6,"name":"Christopher Gocke","email":"","orcid":"","institution":"Johns Hopkins School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Christopher","middleName":"","lastName":"Gocke","suffix":""},{"id":494420903,"identity":"2cfe06bc-24a9-46aa-bfcb-1905458dafd9","order_by":7,"name":"Noushin Niknafs","email":"","orcid":"","institution":"Johns Hopkins School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Noushin","middleName":"","lastName":"Niknafs","suffix":""},{"id":494420905,"identity":"d5711a15-18c3-4cba-8d7c-c07142d5d131","order_by":8,"name":"Shivani Ahlawat","email":"","orcid":"","institution":"Johns Hopkins School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Shivani","middleName":"","lastName":"Ahlawat","suffix":""},{"id":494420906,"identity":"0df10157-c0f9-4d26-b89c-7b95b8c11283","order_by":9,"name":"Allan J. 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Pratilas","email":"","orcid":"","institution":"Johns Hopkins School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Christine","middleName":"A.","lastName":"Pratilas","suffix":""},{"id":494420911,"identity":"e66d913e-0c1d-44b7-8007-7d8fd81027f2","order_by":13,"name":"Jessica J. Tao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAt0lEQVRIiWNgGAWjYBACxgYgkWBgw2wAZrIRo6UNSDyoSCNBC0gR44MzhxkMYDyCgHl+88MHiW3n2c3FDjcwfCg7TIzD2IwNEttuM1vOTmxgnHGOKC0MZhIgLQa3ExuYeduI0sL+DajlHETLX+K08JhJJJw5ANHCSJyWnGKDhIpksJaDPefSCWsxbD6+8eEPA7tkg9vpDx/8KLMmQksDhE4GEQcIqwcCeShtR5TqUTAKRsEoGJkAAE7PPTnNuUviAAAAAElFTkSuQmCC","orcid":"","institution":"The Johns Hopkins Molecular Tumor Board, Johns Hopkins University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Jessica","middleName":"J.","lastName":"Tao","suffix":""}],"badges":[],"createdAt":"2025-07-03 19:38:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7041059/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7041059/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88309827,"identity":"6bda230a-9a03-4598-9385-2a2c730d269a","added_by":"auto","created_at":"2025-08-05 06:43:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":127580,"visible":true,"origin":"","legend":"\u003cp\u003eTimeline summarizing the patient’s clinical history, genomic findings and treatment interventions.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-7041059/v1/461ccc613334f1122296254c.png"},{"id":88309829,"identity":"ab4b6b18-1504-4a60-8fcf-d8038ed102f5","added_by":"auto","created_at":"2025-08-05 06:43:45","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":412494,"visible":true,"origin":"","legend":"\u003cp\u003eMRI images of the tumor throughout the patient's clinical course. a) Initial diagnosis: Coronal short tau inversion recovery (STIR) maximum intensity projection (MIP) of the brachial plexus depicts two right axillary masses (white arrows) and right C5 and C6 nerve roots thickening (yellow arrow) in the interscalene triangle at presentation. b) Residual and treated disease (after surgery and BRAF therapy) (white arrow) with residual thickening of right C5 and C6 nerve roots (yellow arrow) in the interscalene triangle three years after initiation of BRAF targeted therapy. c) Disease progression in the interscalene triangle in the upper trunk (yellow arrow) (2nd recurrence). d) Rapid progression, with increasing size of mass (yellow arrow) two months after image shown in c.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-7041059/v1/d447834888c7cc9688d93d9b.png"},{"id":88311884,"identity":"0f364b6f-dd26-4eb7-9940-4a5680f5ef16","added_by":"auto","created_at":"2025-08-05 07:07:45","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":935095,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative pictures of the pathological specimens are as follows: (a, b, c) show the resection specimen from initial diagnosis which features characteristic glomus tumor cells with abundant eosinophilic cytoplasm. (d) is a sample from the most recent core needle biopsy performed after the tumor began to grow following 57 months of BRAF-targeted therapy. (e) provides a gross image of the tumor specimen from the most recent surgery, showing a homogenous fresh cut appearance. (f, g, h) depict samples 3A, 3B and 3C from the most recent surgery. All samples exhibit a homogenous appearance microscopically. Notably, when compared to the specimen from initial diagnosis, these specimens are more cellular with the tumor cells demonstrating higher grade, consistent with a more aggressive malignant glomus tumor.\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-7041059/v1/e7073c946fcd491bfc85a263.png"},{"id":88310352,"identity":"6e42de9e-9d98-4d2a-b227-40622d4e8939","added_by":"auto","created_at":"2025-08-05 06:51:45","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":59648,"visible":true,"origin":"","legend":"\u003cp\u003ePhylogenetic tree representing the suggested evolutionary trajectory of the tumor: starting from germline (G), an initiating event led to the emergence of two different clones, one harboring BRAF p.V600E and an aneuploid clone harboring chr9q loss alongside chr11q and chr19q gains. At the time of the second relapse, the aneuploid tumor led to the formation of multiple subclones, including a clone harboring the PIK3CA p. E542K​.\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-7041059/v1/457f9cceaa90f4c6c3967439.png"},{"id":88312946,"identity":"3d151d5e-e89c-44a9-a092-750eb42d7f69","added_by":"auto","created_at":"2025-08-05 07:15:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2367370,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7041059/v1/55b0b925-7542-4d41-97f2-a836f7589617.pdf"},{"id":88309828,"identity":"5a0dfe22-0d34-4806-a2e0-2dfb45d71be7","added_by":"auto","created_at":"2025-08-05 06:43:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":219673,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryfiguresNPJfinal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7041059/v1/bd6fbb9dc1f8e59c549c9dfe.pdf"}],"financialInterests":"Competing interest reported. S.A. has received research support from Neurofibromatosis Therapeutic Acceleration Program (unrelated), Amgen Therapeutics (unrelated) and Honoraria from Alexion (unrelated). A.J.B. has received consulting fees from AstraZeneca (unrelated). V.A. has received funding from AstraZeneca (Inst) (unrelated); Bristol-Myers Squibb (Inst) (unrelated); Delfi Diagnostics (Inst) (unrelated); Personal Genome Diagnostics (Inst) (unrelated); Honoraria from Foundation Medicine (unrelated); Personal Genome Diagnostics (unrelated) and has Consulting or Advisory Role in AstraZeneca (unrelated) and NeoGenomics Laboratories Research (unrelated). C.A.P. has received research grants from Kura Oncology and Novartis Institutes for Biomedical Research (unrelated to this manuscript); and consulting fees from Day One Therapeutics (unrelated). J.J.T. has received research support from Pfizer (Inst) (unrelated). The other co-authors declare that they have no competing interests.","formattedTitle":"Elimination of BRAF p.V600E under selective pressure of BRAF-targeted therapy and expansion of a PIK3CA p.E542K clone in a patient with recurrent malignant glomus tumor","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGlomus tumors (GT) are rare mesenchymal neoplasms that resemble the Sucquet-Hoyer canal of the normal glomus body, which controls blood pressure and thermal regulation. They account for 1.6% of all soft tissue tumors\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. While GTs commonly occur in the subungual region of the fingers, which has a high concentration of glomus bodies, they can arise from virtually anywhere in the body\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. GTs are classified based on WHO criteria as benign, glomus tumor of uncertain malignant potential (GT-UMP), or malignant\u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Malignant glomus tumors, also called glomangiosarcomas, tend to recur locally though rarely can metastasize.\u003c/p\u003e\u003cp\u003eHere, we present the case of young adult female with malignant glomus tumor of the brachial plexus harboring a \u003cem\u003eBRAF\u003c/em\u003e p.V600E mutation. She initially attained prolonged clinical benefit following treatment with a selective BRAF inhibitor. However, upon disease progression, multi-region next generation sequencing revealed loss of the \u003cem\u003eBRAF\u003c/em\u003e p.V600E mutation and the emergence of an oncogenic \u003cem\u003ePIK3CA\u003c/em\u003e p.E542K mutation. This case, previously reported as the first instance of BRAF-targeted therapeutic intervention in malignant glomus tumor, provides insights into tumor evolution under therapeutic pressure, illustrating clonal selection and expansion in response to targeted therapy\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eClinical course\u003c/span\u003e\u003c/p\u003e\u003cp\u003eAn 18-year-old female with no significant past medical history was referred to our institution from abroad for evaluation and management of severe right shoulder pain. The pain had started one year prior and was insidious in onset, with no inciting event or trauma (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). MRI of the right upper extremity revealed two brachial plexus masses suggestive of tumors of neurogenic origin, along with C5-C6 nerve root thickening. The patient underwent open surgical exploration of the right infraclavicular brachial plexus, which revealed that both tumors were intimately involved with nerve elements. Given the axillary nerve involvement, further aggressive dissection of the remaining tumor was deferred to minimize the risk of significant neurologic deficits. Histopathologic analysis led to the diagnosis of malignant glomus tumor\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Molecular genetic analysis with polymerase chain-reaction (PCR) revealed the presence of a \u003cem\u003eBRAF\u003c/em\u003e p.V600E mutation at a variant allele frequency (VAF) of 40%. This was further confirmed by next-generation sequencing (NGS), which detected a heterozygous \u003cem\u003eBRAF\u003c/em\u003e p.V600E mutation with a VAF of 37.76% \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. Given the inability to achieve complete surgical resection of the tumor, we opted to monitor closely with serial imaging. Both the proximal and the distal lesions remained stable in size for two years before the distal mass began to enlarge on follow-up imaging.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eNext generation sequencing comparing sequence alterations at the time of diagnosis (sample 1) and at second relapse (samples 2, 3A, 3B and 3C).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGene\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChromosomal position\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBase Change\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAA change\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eVAF (%):\u003c/p\u003e\u003cp\u003e(sample 1) (Tumor\u003c/p\u003e\u003cp\u003epurity\u0026thinsp;\u0026gt;\u0026thinsp;90%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVAF (%): (sample 2) (Tumor purity 80%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eVAF (%): (sample 3A) (Tumor purity 90%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVAF (%): (sample 3B)\u003c/p\u003e\u003cp\u003e(Tumor purity 90%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eVAF (%): (sample 3C)\u003c/p\u003e\u003cp\u003e(Tumor purity 90%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eOrigin\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eADGRA2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003echr8:37689051\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eC\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep.T348I\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e50.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e48.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e45.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e48.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e32.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePossibly germline\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eARHGAP26\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003echr5:142526934\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep.R659Q\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNot detected\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNot detected\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNot detected\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNot detected\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSomatic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eATRX\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003echrX:76939445\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eT\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep.I435V\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e49.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e56.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e57.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e49.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e53.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePossibly germline\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eBRAF\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003echr7:140453136\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eA\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep.V600E\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e37.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNot detected\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNot detected\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNot detected\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNot detected\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSomatic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eFANCL\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003echr2:58386928\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG\u0026thinsp;\u0026gt;\u0026thinsp;GTAAT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep.T367fs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e33.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e25.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e29.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e31.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e31.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePossibly germline\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eKDM6A\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003echrX:44935983\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eT\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep.L915S\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e46.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e45.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e47.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e48.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e49.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePossibly germline\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eMCL1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003echr1:150550965\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eT\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep.M231L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e48.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e47.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e46.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e44.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e45.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePossibly germline\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eMED12\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003echrX:70339711\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eC\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep.T127M\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNot detected\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNot detected\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNot detected\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNot detected\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e32.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSomatic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ePIK3CA\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003echr3:178936082\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep.E542K\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNot detected\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNot detected\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e47.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e46.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e15.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSomatic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ePRKDC\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003echr8:48805837\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eC\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep.A1237T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e48.74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e46.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e48.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e49.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e54.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePossibly germline\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eRNF43\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003echr17:56440643\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep.P192L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e47.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e45.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e47.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e50.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e41.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePossibly germline\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eSYNE1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003echr6:152527409\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eC\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep.G7638D\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e43.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e45.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e46.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e48.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePossibly germline\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eWDR90\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003echr16:716543\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep.R1610Q\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e52.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e46.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e52.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e48.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePossibly germline\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eXPO1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003echr2:61719196\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eT\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep.I621V\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e50.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e42.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e46.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e47.87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e49.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePossibly germline\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eManagement of the patient\u0026rsquo;s first radiologic progression was discussed at the Johns Hopkins multidisciplinary sarcoma tumor board. Surgical resection was again deemed high-risk due to the potential for loss of neurologic function in the right arm. After careful consideration and in the context of the \u003cem\u003eBRAF\u003c/em\u003e p.V600E mutation, we initiated systemic therapy with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, based on their demonstrated activity across multiple cancer types\u003csup\u003e\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Notably, this recommendation was made off-label and nearly five years prior to the FDA approval of the dabrafenib/trametinib combination as a tissue-agnostic therapy for \u003cem\u003eBRAF\u003c/em\u003e p.V600E-mutant solid tumors. Dabrafenib was started at 150 mg twice daily and trametinib was added three weeks later at 2 mg daily. MRI imaging and PET-CT performed two weeks after starting trametinib showed a reduction in tumor size\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAfter approximately one year, trametinib was discontinued due to liver toxicity, but the patient remained on dabrafenib. Over the next three years, serial imaging demonstrated continued reduction in the size of the distal mass, with stable thickening of the right C5-C6 nerve roots, consistent with a partial response (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb)\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. The patient elected to stop dabrafenib after approximately three years. Over the following four years, she underwent serial imaging every three months, which showed stable disease.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAfter a nearly 57-month treatment-free interval, MRI revealed disease progression, with a recurrent soft tissue neck mass along the right C5-C6 nerve roots with possible right supraclavicular involvement \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). Core needle biopsy of the right C5-C6 nerve mass confirmed a malignant glomus tumor (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed). Notably, neither immunohistochemistry nor next-generation sequencing of the progressing tumor detected the \u003cem\u003eBRAF\u003c/em\u003e p.V600E mutation. The \u003cem\u003eBRAF\u003c/em\u003e locus had a normal copy number, indicating that the \u003cem\u003eBRAF\u003c/em\u003e mutation was not lost through chromosomal deletion. Additional genomic alterations identified at recurrence included a chromosome 11q amplification (chr11q amp) involving the \u003cem\u003eYAP1\u003c/em\u003e, \u003cem\u003eBIRC2\u003c/em\u003e and \u003cem\u003eBIRC3\u003c/em\u003e genes, along with loss of chromosome 9q and gain of chromosome 19q (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), alterations not present at initial diagnosis. Given the rapidly progressing tumor, the patient underwent surgical resection one month after the core needle biopsy \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eNext generation sequencing comparing structural alterations at the time of diagnosis (sample 1), and at second relapse (sample 2, 3A, 3B and 3C). Log2R represents the logarithmic ratio of the observed read depth (or coverage) of a specific genomic region in the sample compared to the expected read depth, derived from a normal control sample set.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSample 1:\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSample 2:\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSample 3A:\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSample 3B:\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSample 3C:\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChromosome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eArm/band\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDriver genes in the altered locus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCNV/Average Log2R\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCNV/Average Log2R\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCNV/Average Log2R\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCNV/Average Log2R\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCNV/Average Log2R\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ewhole chromosome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emany\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCopy Neutral\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCopy Neutral\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCopy Neutral\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCopy Neutral\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCopy Gain, +\u0026thinsp;0.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eq\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emany\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCopy Neutral\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCopy Loss,\u003c/p\u003e\u003cp\u003e-1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCopy Loss,\u003c/p\u003e\u003cp\u003e-1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCopy Loss,\u003c/p\u003e\u003cp\u003e-1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCopy Loss,\u003c/p\u003e\u003cp\u003e-1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eq\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNOTCH1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCopy Neutral\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCopy Neutral\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCopy Neutral\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCopy Gain, +\u0026thinsp;1.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCopy Neutral\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eq\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eYAP1, BIRC3, BIRC2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCopy Neutral\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAmplification, +\u0026thinsp;3.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAmplification, +\u0026thinsp;3.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eAmplification, +\u0026thinsp;3.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAmplification, +\u0026thinsp;3.41\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eq\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003emany\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCopy Neutral\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCopy Gain, +\u0026thinsp;0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCopy Gain, +\u0026thinsp;0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCopy Gain, +\u0026thinsp;0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCopy Gain, +\u0026thinsp;0.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eMolecular Tumor Board review\u003c/span\u003e\u003c/p\u003e\u003cp\u003eThis case was subsequently presented at the Johns Hopkins Molecular Tumor Board for further discussion. In the biopsy specimen of the recurrent C5-C6 nerve root tumor in the neck, the \u003cem\u003eBRAF\u003c/em\u003e p.V600E alteration was detected in only 1 out of 573 reads (0.17%) \u003cb\u003e(Supp.\u003c/b\u003e Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e, falling below the assay\u0026rsquo;s reportable range and at a level consistent with background sequencing error\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. The absence of \u003cem\u003eBRAF\u003c/em\u003e p.V600E was both surprising and unusual, as typically the \u003cem\u003eBRAF\u003c/em\u003e p.V600E mutation is clonal and retained in the majority of BRAF-mutant cancers that recur following BRAF-targeted therapy. In such cases, resistance is often driven by additional genomic alterations in the MAPK pathway or secondary BRAF mutations that drive acquired resistance\u003csup\u003e\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. In evaluating the \u003cem\u003eBRAF\u003c/em\u003e locus, there was no indication of locus deletion, suggesting that the \u003cem\u003eBRAF\u003c/em\u003e p.V600E cancer cell population represented a fraction of the parental clone and may have been eliminated due to BRAF-targeted therapy. To further substantiate these findings, the Molecular Tumor Board recommended performing next-generation sequencing (NGS) of multiple regions of the recurrent tumor to assess whether the apparent absence of \u003cem\u003eBRAF\u003c/em\u003e p.V600E was a consequence of intratumoral heterogeneity or representative of the entire tumor.\u003c/p\u003e\u003cp\u003eMacroscopically, all regions of the resection tumor appeared similar (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ee). Additionally, histopathological evaluation with hematoxylin and eosin staining confirmed the tumor\u0026rsquo;s homogeneity at a microscopic level, with pathology consistent with a malignant glomus tumor \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ef, g, h\u003cb\u003e)\u003c/b\u003e. Notably, the specimens from the second relapse demonstrated a more aggressive phenotype compared to the sample from the initial diagnosis \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea, \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec\u003cb\u003e).\u003c/b\u003e NGS was performed on three spatially distinct regions from the surgical specimen (designated Parts 3A, 3B, 3C) using the same NGS panel \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e The \u003cem\u003eBRAF\u003c/em\u003e p.V600E mutation was again not detected in any of the three samples, with zero mutant reads on visual inspection \u003cb\u003e(Supp.\u003c/b\u003e Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e, supporting a true absence of the mutation rather than intra-tumoral heterogeneity\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Importantly, there was no evidence of deletion at the \u003cem\u003eBRAF\u003c/em\u003e locus that might drive \u003cem\u003eBRAF\u003c/em\u003e V600E loss, and all three samples had high tumor purity (~\u0026thinsp;90%), ruling out false-negative results due to insufficient tumor content. \u003cb\u003e(Supp.\u003c/b\u003e Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. Taken together, these findings suggest that the \u003cem\u003eBRAF-\u003c/em\u003emutant clone regressed in response to BRAF-targeted therapy.\u003c/p\u003e\u003cp\u003eThe copy number alterations detected in the biopsy of the recurrent neck tumor, including the chr11q amp, 9q loss, and 19q gain, were identified in all three samples from the surgical resection \u003cb\u003e(Supp.\u003c/b\u003e Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. Additionally, a hotspot \u003cem\u003ePIK3CA\u003c/em\u003e p.E542K was detected in all three regions of the resected recurrent tumor with VAFs of 15%, 46%, and 47% \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. The lower VAF in one sample suggests that the \u003cem\u003ePIK3CA-\u003c/em\u003emutant clone represents a minor clone in that region of the tumor.\u003c/p\u003e\u003cp\u003eTo further investigate the emergence of the \u003cem\u003ePI3KCA\u003c/em\u003e mutation, we re-examined both the sample from initial diagnosis and the most recent core needle biopsy of the recurrent tumor for any mutant reads of \u003cem\u003ePIK3CA\u003c/em\u003e p.E542K below the reportable threshold. No mutant reads were detected at the \u003cem\u003ePIK3CA\u003c/em\u003e locus, and the tumor purity of all samples was \u0026gt;\u0026thinsp;80%, supporting true acquisition of the \u003cem\u003ePIK3CA\u003c/em\u003e mutation later in tumor evolution.\u003c/p\u003e\u003cp\u003eAdding to the complexity of the tumor\u0026rsquo;s evolutionary trajectory, chromosome 11q amplification, 9q deletion, and 19q gain were detected in the recurrent tumor biopsy and all three surgical samples but were absent from the tumor at initial diagnosis. Moreover, the \u003cem\u003ePIK3CA\u003c/em\u003e p.E542K was found in all three samples from the surgical resection but absent in the earlier biopsy of the recurrent mass and in the initial mass \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. These findings suggest the presence of two distinct tumor clones at diagnosis: one harboring the \u003cem\u003eBRAF\u003c/em\u003e p.V600E detected in the initial tumor and an aneuploid clone harboring the structural alterations detected in the recurrent tumor, which later expanded after the regression of the \u003cem\u003eBRAF-\u003c/em\u003emutant clone and may be responsible for to the current relapse.\u003c/p\u003e\u003cp\u003eRegarding the discrepancy between the \u003cem\u003ePIK3CA\u003c/em\u003e p.E542K that was not detected in the core biopsy of the recurrent tumor but was detected in all three regions of the surgically resected mass, one possible explanation is that the \u003cem\u003ePIK3CA\u003c/em\u003e mutation was acquired in the one-month interval between the core needle biopsy and the surgical resection of the neck mass in the context of rapid disease progression \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. Alternatively, spatial heterogeneity may account for this difference, with the mutation present in unsampled regions of the tumor at the time of biopsy.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eGenomic landscape of glomus tumors\u003c/span\u003e\u003c/p\u003e\u003cp\u003eMolecular genetic studies in glomus tumors remain limited, especially in the context of tumor evolution. GTs have been associated with the neurocutaneous tumor predisposition syndrome neurofibromatosis type 1 (NF1), in which germline loss of \u003cem\u003eNF1\u003c/em\u003e, a RAS GTPase activating protein, leads to activation of the RAS-ERK signaling pathway\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. However, most glomus tumors are sporadic. One study identified \u003cem\u003eNOTCH\u003c/em\u003e rearrangements in 16 out of 17 malignant GTs and associated pericytic neoplasms, with 88% of these being \u003cem\u003eNOTCH2\u003c/em\u003e rearrangements\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. \u003cem\u003eNOTCH2\u003c/em\u003e and \u003cem\u003eNOTCH3\u003c/em\u003e regulate vascular smooth muscle development\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. This, combined with the high frequency of \u003cem\u003eNOTCH\u003c/em\u003e fusions in glomus tumors, suggests that they are early events in the pathogenesis of GT\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Other reported alterations in malignant GTs include \u003cem\u003eKRAS\u003c/em\u003e p.G12A mutations, \u003cem\u003eATG:RAF1\u003c/em\u003e fusions, \u003cem\u003eSMARCB1\u003c/em\u003e truncating mutations, and \u003cem\u003eCCND3\u003c/em\u003e point mutations\u003csup\u003e\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003eBRAF\u003c/em\u003e mutations, particularly \u003cem\u003eBRAF\u003c/em\u003e p.V600E, have emerged as potential oncogenic drivers in malignant glomus tumors. In one targeted sequencing study, three of 28 glomus tumors were found to harbor the \u003cem\u003eBRAF\u003c/em\u003e p.V600E mutation\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Another study of 102 glomus tumors identified \u003cem\u003eBRAF\u003c/em\u003e p.V600E in six cases, all of which were classified as malignant glomus tumor or GT-UMP, suggesting that \u003cem\u003eBRAF\u003c/em\u003e mutations are associated with more aggressive tumor biology\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. While most reported \u003cem\u003eBRAF\u003c/em\u003e p.V600E-mutant GTs have occurred in the extremities, cases have also been described in other anatomic sites, including the orbit\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAlthough data remain limited, the profound response to BRAF and MEK inhibition observed in our patient, as well as in a recently published case of metastatic \u003cem\u003eBRAF\u003c/em\u003e p.V600E-mutant malignant GT, underscores the therapeutic potential of combined BRAF and MEK inhibition in treating malignant GTs harboring \u003cem\u003eBRAF\u003c/em\u003e p.V600E mutations\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. To our knowledge, these are the only two reported cases of genome-driven targeted therapy against oncogenic \u003cem\u003eBRAF\u003c/em\u003e mutations in malignant glomus tumor.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eElimination of\u003c/span\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eBRAF\u003c/span\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003ep.V600E mutant clones during tumor evolution\u003c/span\u003e\u003c/p\u003e\u003cp\u003eTo explore the frequency of \u003cem\u003eBRAF\u003c/em\u003e p.V600E loss during tumor evolution, we analyzed next generation sequencing data from the publicly available MSK-IMPACT cohort through CBioPortal\u003csup\u003e\u003cspan additionalcitationids=\"CR26 CR27\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Among 10,336 patients, 562 had sequencing performed on more than one tumor sample. Within this subset, \u003cem\u003eBRAF\u003c/em\u003e p.V600E was detected in 20 patients.\u003c/p\u003e\u003cp\u003eAfter excluding six patients whose samples came from unrelated primary tumors and two without clear longitudinal samples, 12 patients remained with serially sequenced \u003cem\u003eBRAF\u003c/em\u003e-mutant tumors. In this cohort, \u003cem\u003eBRAF\u003c/em\u003e p.V600E was retained in all but one case: a patient with a primary rectal tumor harboring \u003cem\u003eBRAF\u003c/em\u003e p.V600E, which was absent in a liver metastasis. Similar to our case, the BRAF mutant cancer cell population likely was eliminated, and the BRAF wild type population grew out. However, this finding should be interpreted with caution. The variant allele frequency of \u003cem\u003eBRAF\u003c/em\u003e p.V600E in the rectal tumor was 5% with 70% tumor purity, suggesting that the mutation was subclonal. No shared genomic alterations were found between the rectal and liver specimens, suggesting the possibility of significant tumor heterogeneity or separate tumor lineages. Additionally, the liver metastasis had only 20% tumor purity, reducing the sensitivity for detecting low-frequency mutations. Thus, while this case raises the possibility of elimination of a \u003cem\u003eBRAF\u003c/em\u003e p.V600E clone during tumor progression, technical and biological factors such as tumor heterogeneity, subclonality, tissue sampling bias, and low tumor purity may also explain the absence of detectable mutation in the liver metastasis. Clear examples of elimination of a \u003cem\u003eBRAF\u003c/em\u003e p.V600E clone following targeted therapy remain rare and difficult to verify in large retrospective datasets.\u003c/p\u003e\u003cp\u003eFurther supporting the rarity of \u003cem\u003eBRAF\u003c/em\u003e p.V600E loss, a study of pediatric low-grade gliomas found that the mutation status was conserved in 98% of patients\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Loss was observed in only one patient by immunohistochemistry testing in a subsequent surgery performed 35 months after the initial diagnosis, although confirmatory sequencing was not available. This patient had not received systemic therapy or radiation, and there was no clear radiographic evidence of progression at the time of second surgery, raising the possibility of sampling bias rather than \u003cem\u003eBRAF\u003c/em\u003e mutant allele loss\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Another report described a recurrent glioblastoma in which BRAF p.V600E loss was proposed as a resistance mechanism to BRAF-targeted therapy\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Overall, these findings indicate that \u003cem\u003eBRAF\u003c/em\u003e p.V600E loss during tumor evolution under the selective pressure of targeted therapy is a very rare event across cancer types, highlighting the uniqueness of our case.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eAcquisition of\u003c/span\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003ePIK3CA\u003c/span\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003emutations under selective pressure of BRAF targeted therapy\u003c/span\u003e\u003c/p\u003e\u003cp\u003eA notable aspect of this case is the emergence of a clone harboring a \u003cem\u003ePIK3CA\u003c/em\u003e p.E542K in tandem with the loss of the \u003cem\u003eBRAF\u003c/em\u003e p.V600E mutant clone. \u003cem\u003ePIK3CA\u003c/em\u003e alterations are exceedingly rare in glomus tumors; to date, only one gastric glomus tumor harboring a \u003cem\u003ePIK3CA\u003c/em\u003e p.E545K mutation has been reported\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe emergence of \u003cem\u003ePIK3CA\u003c/em\u003e alterations has been reported as a resistance mechanism to \u003cem\u003eBRAF-\u003c/em\u003etargeted therapy in other cancers, including thyroid, melanoma and colorectal cancer\u003csup\u003e\u003cspan additionalcitationids=\"CR33 CR34\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. In one case, a patient with \u003cem\u003eBRAF\u003c/em\u003e p.V600E-mutant classic papillary thyroid cancer (PTC) treated with vemurafenib for five months developed anaplastic transformation. Whole exome sequencing and next-generation sequencing of the pretreatment PTC nodal metastases and post-transformation anaplastic thyroid cancer (ATC) metastases showed emergence of \u003cem\u003ePIK3CA\u003c/em\u003e p.H1047R in the post-transformation tumor. However, unlike in our case, \u003cem\u003eBRAF\u003c/em\u003e p.V600E remained detectable in all ATC samples\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. To our knowledge, this is the first reported case in which a \u003cem\u003ePIK3CA\u003c/em\u003e p.E542K subclone emerged after the regression of a \u003cem\u003eBRAF\u003c/em\u003e p.V600E population in response to BRAF-targeted therapy.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTo our knowledge, this is the first reported case of the loss of a \u003cem\u003eBRA\u003c/em\u003eF-mutant clone following \u003cem\u003eBRAF-\u003c/em\u003etargeted therapy, alongside the emergence of a different clone harboring a \u003cem\u003ePIK3CA\u003c/em\u003e p.E542K mutation, an alteration that has never been reported in patients with malignant glomus tumors. This is also the first report to characterize the evolutionary trajectory of malignant glomus tumors through serial NGS. Our findings highlight the complex genomic evolutionary landscape of malignant glomus tumors, delineating the impact of selective pressure applied by targeted therapy in conjunction with tumor heterogeneity. This case highlights the value of serial molecular profiling to guide therapeutic decisions, especially in patients with rare tumors.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eCase Report\u003c/span\u003e\u003c/p\u003e\u003cp\u003eA single patient treated at Johns Hopkins Hospital (JHH) was identified for this case report. A retrospective chart review was conducted to collect relevant clinical data. The patient provided written informed consent for the publication of this anonymized data.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eNext generation sequencing\u003c/span\u003e\u003c/p\u003e\u003cp\u003eMolecular testing was performed in the Clinical Laboratory Improvement Amendments (CLIA)-certified Johns Hopkins Medical Laboratory at the Johns Hopkins Hospital (Baltimore, MD). Targeted NGS was performed on formalin-fixed, paraffin-embedded tumor tissue using the Johns Hopkins Solid Tumor panel, version 9 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pathology.jhu.edu/test-directory/ngs-solid-tumor-panel\u003c/span\u003e\u003cspan address=\"https://pathology.jhu.edu/test-directory/ngs-solid-tumor-panel\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). For the BRAF p.V600E PCR Assay, DNA was extracted from the tissue and amplified by PCR targeting exon 15 of the BRAF gene. The amplification products were sequenced using pyrosequencing technology.\u003c/p\u003e\u003cp\u003eCNVkit software (version 0.9.6, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://cnvkit.readthedocs.io/en/stable/\u003c/span\u003e\u003cspan address=\"https://cnvkit.readthedocs.io/en/stable/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, accessed May 30, 2025) was used to infer genome-wide copy number variations (CNVs) from targeted next-generation sequencing (NGS) data. A genome-wide scatter plot was generated, integrating bin-level Log2R coverages and segmentation calls to visualize copy number alterations across the genome.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eCompeting Interests\u003c/h2\u003e\n\u003cp\u003eS.A. has received research support from Neurofibromatosis Therapeutic Acceleration Program (unrelated), Amgen Therapeutics (unrelated) and Honoraria from Alexion (unrelated). A.J.B. has received consulting fees from AstraZeneca (unrelated). V.A. has received funding from AstraZeneca (Inst) (unrelated); Bristol-Myers Squibb (Inst) (unrelated); Delfi Diagnostics (Inst) (unrelated); Personal Genome Diagnostics (Inst) (unrelated); Honoraria from Foundation Medicine (unrelated); Personal Genome Diagnostics (unrelated) and has Consulting or Advisory Role in AstraZeneca (unrelated) and NeoGenomics Laboratories Research (unrelated). C.A.P. has received research grants from Kura Oncology and Novartis Institutes for Biomedical Research (unrelated to this manuscript); and consulting fees from Day One Therapeutics (unrelated). J.J.T. has received research support from Pfizer (Inst) (unrelated). The other co-authors declare that they have no competing interests.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eIdea conception: J.J.T., C.A.P., and I.Z. Manuscript writing, data collection, and figure creation: I.Z., S.C.M, N.N, R.X, Y.Z., J.M.G, S.A., V.A., C.A.P, J.J.T. Significant contributions to clinical patient care: C.A.P, A.J.B, S.A., S.C., Y.Z., R.X., C.G, J.G, V.A., J.J.T. All authors reviewed the manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgement\u003c/h2\u003e\n\u003cp\u003eWe thank the patient and her family for allowing us to participate in her care, providing patient-reported outcomes, and giving us permission to report on her case. We thank the Johns Hopkins Molecular Tumor Board for their support of this work and their thoughtful discussion guiding the care of this patient. We thank the Johns Hopkins Molecular Diagnostics Laboratory for their support of this report and molecular studies of this patient\u0026rsquo;s tumor. The Johns Hopkins Molecular Tumor Board Investigators include Deborah Armstrong, Marina Baretti, Taxiarchis Botsis, Jenna V. Canzoniero, Maria Durham, Amna Jamali, David O. Kamson, Katerina Karaindrou, Rachel Karchin, Kory Kreimeyer, John Laterra, Jennifer Lehman, Christian Meyer, Mimi Najjar, Cesar A. Santa-Maria, Karisa Schreck, Mohamed Sherief, Jonathan Spiker, Faith Too, Timsy Wanchoo, Jaime Wehr, Antonio C. Wolff.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe datasets analyzed in the current study are available in the cBioPortal repository for Cancer Genomics (https://www.cbioportal.org/).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAltarifi, M. E., Kalas, A., Alnajjar, A., Yasin Dali, M. \u0026amp; Alkhowailed, M. S. Glomus tumor: A rare differential diagnosis for subungual lesions. \u003cem\u003eRadiol Case Rep\u003c/em\u003e 19, 6034\u0026ndash;6038 (2024). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.radcr.2024.08.116\u003c/span\u003e\u003cspan address=\"10.1016/j.radcr.2024.08.116\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJo, V. Y. \u0026amp; Fletcher, C. D. 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Mutational profiles associated with resistance in patients with BRAFV600E mutant colorectal cancer treated with cetuximab and encorafenib +/- binimetinib or alpelisib. \u003cem\u003eBr J Cancer\u003c/em\u003e 124, 176\u0026ndash;182 (2021). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41416-020-01147-2\u003c/span\u003e\u003cspan address=\"10.1038/s41416-020-01147-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLee, M. \u003cem\u003eet al.\u003c/em\u003e Genomic and Transcriptomic Correlates of Thyroid Carcinoma Evolution after BRAF Inhibitor Therapy. \u003cem\u003eMol Cancer Res\u003c/em\u003e 20, 45\u0026ndash;55 (2022). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1158/1541-7786.MCR-21-0442\u003c/span\u003e\u003cspan address=\"10.1158/1541-7786.MCR-21-0442\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-precision-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjprecisiononcology","sideBox":"Learn more about [npj Precision Oncology](http://www.nature.com/npjprecisiononcology/)","snPcode":"41698","submissionUrl":"https://submission.springernature.com/new-submission/41698/3","title":"npj Precision Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7041059/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7041059/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eGlomus tumors are rare mesenchymal tumors that resemble modified smooth muscle cells of the normal glomus body. \u003cem\u003eBRAF\u003c/em\u003e p.V600E has previously been detected in glomus tumors and is associated with more aggressive clinical behavior. Here, we report a case of a patient with a malignant \u003cem\u003eBRAF\u003c/em\u003e-mutant glomus tumor that initially responded to BRAF targeted therapy, likely leading to the elimination of the clone harboring the \u003cem\u003eBRAF\u003c/em\u003e p.V600E. Notably, upon disease progression, \u003cem\u003eBRAF\u003c/em\u003e p.V600E was not detected in multiple regions of the recurrent tumor, whereas another clone harboring \u003cem\u003ePIK3CA\u003c/em\u003e p.E542K expanded, highlighting the complex genomic landscape of malignant glomus tumors under the selective pressure of targeted therapy.\u003c/p\u003e","manuscriptTitle":"Elimination of BRAF p.V600E under selective pressure of BRAF-targeted therapy and expansion of a PIK3CA p.E542K clone in a patient with recurrent malignant glomus tumor","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-05 06:43:40","doi":"10.21203/rs.3.rs-7041059/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-24T20:54:38+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-23T20:44:59+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-22T22:42:21+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-22T01:26:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"173715696358356477344518400652520824913","date":"2025-08-14T04:22:58+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-13T10:14:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"65034760907713301010862398718517620970","date":"2025-08-13T07:06:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"158304581833546665975485888080320394191","date":"2025-08-12T22:29:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"140826826031424828771362738005304325249","date":"2025-07-31T11:29:50+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-30T15:53:06+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-29T18:42:14+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-08T06:28:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Precision Oncology","date":"2025-07-03T19:26:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-precision-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjprecisiononcology","sideBox":"Learn more about [npj Precision Oncology](http://www.nature.com/npjprecisiononcology/)","snPcode":"41698","submissionUrl":"https://submission.springernature.com/new-submission/41698/3","title":"npj Precision Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"df296f36-3c5b-4e03-8fa4-5e1e84cf6b63","owner":[],"postedDate":"August 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[{"id":52514642,"name":"Biological sciences/Cancer"},{"id":52514643,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2025-08-24T21:08:09+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-05 06:43:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7041059","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7041059","identity":"rs-7041059","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}