Oncogenomic profiling of cutaneous pericytic tumours reveals distinct drivers and shared biological processes

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Harms , Nicolas de Saint Aubain , Emily L. Clarke , William Merchant , Ahmed K. Alomari , Neil Rajan , Peter Ferguson , Maximillian A. Weigelt , Carlos Monteagudo , Steven D. Billings , Mark J. Arends , Ingrid Ferreira , Thomas Brenn , Louise van der Weyden , David J. Adams doi: https://doi.org/10.1101/2025.07.31.25332530 Martin Del Castillo Velasco-Herrera 1 Wellcome Sanger Institute, Wellcome Genome Campus , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Saamin Cheema 1 Wellcome Sanger Institute, Wellcome Genome Campus , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kim Wong 1 Wellcome Sanger Institute, Wellcome Genome Campus , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jamie Billington 1 Wellcome Sanger Institute, Wellcome Genome Campus , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ian Vermes 1 Wellcome Sanger Institute, Wellcome Genome Campus , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Elizabeth Anderson 1 Wellcome Sanger Institute, Wellcome Genome Campus , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Elizabeth Ferla 1 Wellcome Sanger Institute, Wellcome Genome Campus , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Paul W. Harms 2 Departments of Pathology and Dermatology, University of Michigan , Ann Arbor, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Nicolas de Saint Aubain 3 Department of Pathology, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles , Brussels, Belgium Find this author on Google Scholar Find this author on PubMed Search for this author on this site Emily L. Clarke 4 Department of Histopathology, Leeds Teaching Hospitals NHS Trust , Leeds, UK 5 Division of Pathology and Data Analytics, University of Leeds , UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site William Merchant 4 Department of Histopathology, Leeds Teaching Hospitals NHS Trust , Leeds, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ahmed K. Alomari 6 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine , Indianapolis, Indiana, USA 7 Department of Dermatology, Indiana University School of Medicine , Indianapolis, Indiana, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Neil Rajan 8 Department of Dermatology, Royal Victoria Infirmary , Newcastle upon Tyne, UK 9 Translational and Clinical Research Institute, Newcastle University , Newcastle upon Tyne, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Peter Ferguson 10 Tissue Pathology and Diagnostic Oncology , Royal Prince Alfred Hospital 11 Faculty of Medicine and Health, The University of Sydney , Sydney, NSW, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Maximillian A. Weigelt 12 Department of Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute , Cleveland Clinic, Cleveland, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Carlos Monteagudo 13 Department of Pathology, University Clinic Hospital, Valencia - INCLIVA Biomedical Research Institute and Department of Pathology, University of Valencia , Spain Find this author on Google Scholar Find this author on PubMed Search for this author on this site Steven D. Billings 12 Department of Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute , Cleveland Clinic, Cleveland, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mark J. Arends 14 University of Edinburgh, Division of Pathology, Centre for Comparative Pathology, CRUK Edinburgh Centre, Institute of Genetics and Cancer , Western General Hospital, Crewe Road South, Edinburgh, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ingrid Ferreira 1 Wellcome Sanger Institute, Wellcome Genome Campus , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Thomas Brenn 2 Departments of Pathology and Dermatology, University of Michigan , Ann Arbor, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Louise van der Weyden 1 Wellcome Sanger Institute, Wellcome Genome Campus , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site David J. Adams 1 Wellcome Sanger Institute, Wellcome Genome Campus , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: da1{at}sanger.ac.uk Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract To-date the genomic landscape of cutaneous pericytic tumours (PTs), which represent a morphological continuum, have not been comprehensively explored. In order to identify the driver events of PTs from across their histological spectrum, and potentially aid the current classification system, we sequenced DNA (whole-exome) and RNA (pulldown transcriptome) from tumour-normal pairs classified by two different dermatopathologists of angioleiomyoma (n=37), glomus tumour (n=30) and myopericytoma (n=11); with all sequencing data deposited in the European Genome and Phenome Archive. The tumour mutational burden of all three tumour types was low with the exception of a single glomus tumour (GT; PD56659a), in which COSMIC mutational signatures SBS7a/b were identified, suggesting UV exposure ( Fig. 1a ). Recurrently mutated genes in angioleiomyoma (ALM) included PIK3CA and MAPK1 (2/37 each, with one tumour having three mutations in PIK3CA ; Fig. 1a ). PIK3CA was identified as a significantly mutated gene (using two independent algorithms; q-value<0.1), suggesting it is a driver gene of ALM. In agreement with a previous report, 1 we found an ALM with a PDGFRB mutation. However, we did not observe the previously reported NOTCH3 mutations, 1 although we did observe mutations in other NOTCH family members. Recurrently mutated genes in GT included NF1 and PCLO (3/30 each; PD56659a having two mutations in each gene), and PDGFRB and TEK (2/30 each; Fig. 1a ). NF1 was identified as a significantly mutated gene (using two independent algorithms; q-value<0.1), suggesting it is a driver gene of GT. In agreement with a previous report, 1 we found GTs with mutations in PDGFRB or NOTCH3 . Recurrently mutated genes in myopericytoma (MPC) included LRP1B (2/11, 18%; Fig. 1a ). In agreement with previous reports, 1 , 2 we found MPCs with mutations in PDGFRB or NOTCH3 . One study reported the presence of BRAF V600E in a subset of MPC, however, this has not been replicated in later studies, 2 , 3 consistent with our findings. Download figure Open in new tab Fig. 1. Overall mutational landscape of pericytic tumours. a) For each of the three tumour types, the panels show the tumour mutational burden, recurrently mutated genes (n≥2) or previously reported mutated genes/families, significant focal (<10Mb) copy number alterations (listing any known cancer-associated genes within the amplification or deletion), fusion genes, associated metadata (tumour site and patient sex) and sample ID. b) Protein-Protein interaction network identified using STRING v12.0 amongst all the altered genes in PTs. Each node contains bar plots with the proportion of samples analysed per tumour type that contain alterations, by either mutations, gene fusions or CNAs y-axis 0 to 70%. c) Gene ontology enrichment analysis showing the statistically significant biological processes like, angiogenesis, positive regulation of smooth muscle cells, and blood vessel development are associated to the genes found to be altered in PTs. Considering copy number (CN) alterations as potential driver events of pericytic tumours (PT), we focussed on statistically significantly focal (<10Mb) gains (amplifications) and losses (deletions; Fig. 1 ). ALM showed regions of significant CN gain (n=6) and loss (n=6), some found in up to 25% of tumours, and four regions encompassing known cancer-associated genes; FAT1 in the 4.7 Mb amplification at 4q35.2, MYH11 in the 112 kb amplification at 16p13.11, TNFAIP3 in the 390 kb deletion at 6q23.3, and KEL in the 177 kb deletion at 7q34. GT showed ten regions of significant CN gain, some found in up to 30% of tumours, with the 100 kb amplification at 7q34 encompassing the cancer-associated gene, MGAM ( Fig. 1a ). MPC did not show any significant CN alterations. As fusion genes are driver events in many tumour types, we looked for their presence in PTs, particularly focussing on recurrent fusions. Thirteen fusions were identified in the ALM cohort, including THBS1::IGF1R which was recently identified as a novel fusion gene in a myopericytic tumour, 4 however, none were recurrent ( Fig. 1a ). In contrast, the CARMN::NOTCH2 fusion (previously known as MIR143::NOTCH2 ) was found in 13/18 (72%) of GT cases with RNAseq data (two cases also carrying the reciprocal fusion; Fig. 1a ), consistent with previous reports of this fusion being found in both benign and malignant GT of cutaneous (extremities), visceral and soft tissue origin (36% - 76%; frequencies vary by site). 3 , 5 However, it is important to note that whilst a previous study did not find the CARMN::NOTCH2 fusion in any MPC (0/6) or ALM (0/18) samples, 5 we found CARMN::NOTCH2 (and its reciprocal fusion) in a single MPC sample, suggesting its presence is not exclusive to GT. It is worth noting that this particular case showed histological features of both MPC and GT. In the MPC cohort, the CARMN::TKX fusion was found in 6/7 (86%) cases, with one case showing a CARMN::NOTCH2 fusion instead. However, is important to note that the CARMN::TKX fusion was also present in a single ALM sample (with confirmed histological presence of thick muscular bundles) which is consistent with previous reports, 6 thus its presence is not exclusive to MPC. In summary, our comprehensive characterisation of the genomic landscape of a large cohort of PTs has identified distinct driver events between the different tumour types, despite a morphological spectrum; the CARMN::TXK fusion gene in MPC, the CARMN::NOTCH2 fusion gene, CN gains and NF1 mutations in GT, and CN deletions/gains and PIK3CA mutations in ALM. Importantly, the CARMN::TXK and CARMN::NOTCH2 fusion genes were not exclusive to a particular tumour subtype which is relevant when considering these events as diagnostic markers. However, when considering all the genes altered in the PTs (either by mutation, copy number alteration or fusion partner), there is some commonality in terms of shared protein interactions and biological processes ( Fig. 1b-c ), in agreement with their morphological overlap. Data Availability All sequencing data deposited in the European Genome and Phenome Archive. Funding sources This study was funded by the Medical Research Council (MR/V000292/1) and Wellcome Trust (220540/Z/20/A). NR is supported by the Newcastle NIHR Biomedical Research Centre. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Conflicts of interest The authors have no competing or financial interests to declare. References ↵ Iwamura R , Komatsu K , Kusano M et al. PDGFRB and NOTCH3 Mutations are Detectable in a Wider Range of Pericytic Tumors, Including Myopericytomas, Angioleiomyomas, Glomus Tumors, and Their Combined Tumors . Modern Pathology 2023 ; 36 : 100070 . OpenUrl CrossRef PubMed ↵ Hung YP , Fletcher CDM. Myopericytomatosis: Clinicopathologic Analysis of 11 Cases With Molecular Identification of Recurrent PDGFRB Alterations in Myopericytomatosis and Myopericytoma . Am J Surg Pathol 2017 ; 41 : 1034 – 44 . OpenUrl PubMed ↵ Agaram NP , Zhang L , Jungbluth AA et al. A Molecular Reappraisal of Glomus Tumors and Related Pericytic Neoplasms With Emphasis on NOTCH-gene Fusions . The American Journal of Surgical Pathology 2020 ; 44 : 1556 – 62 OpenUrl PubMed ↵ Kato K , Yamashita K , Dobashi A et al. Novel THBS1::IGF1R fusion in myopericytic tumour . Histopathology 2024 ; 85 : 197 – 201 . OpenUrl PubMed ↵ Mosquera JM , Sboner A , Zhang L et al. Novel MIR143-NOTCH fusions in benign and malignant glomus tumors . Genes Chromosomes Cancer 2013 ; 52 : 1075 – 87 . OpenUrl CrossRef PubMed Web of Science ↵ Panagopoulos I , Andersen K , Brunetti M et al. Pathogenetic Dichotomy in Angioleiomyoma . Cancer Genomics Proteomics 2023 ; 20 : 556 – 66 . OpenUrl Abstract / FREE Full Text View the discussion thread. Back to top Previous Next Posted August 08, 2025. Download PDF Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Oncogenomic profiling of cutaneous pericytic tumours reveals distinct drivers and shared biological processes Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. 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Adams medRxiv 2025.07.31.25332530; doi: https://doi.org/10.1101/2025.07.31.25332530 Share This Article: Copy Citation Tools Oncogenomic profiling of cutaneous pericytic tumours reveals distinct drivers and shared biological processes Martin Del Castillo Velasco-Herrera , Saamin Cheema , Kim Wong , Jamie Billington , Ian Vermes , Elizabeth Anderson , Elizabeth Ferla , Paul W. Harms , Nicolas de Saint Aubain , Emily L. Clarke , William Merchant , Ahmed K. Alomari , Neil Rajan , Peter Ferguson , Maximillian A. Weigelt , Carlos Monteagudo , Steven D. Billings , Mark J. Arends , Ingrid Ferreira , Thomas Brenn , Louise van der Weyden , David J. 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