Genomic Alterations of Dermatofibrosarcoma Protuberans Revealed by Whole Genome Sequencing

Background: Dermatofibrosarcoma protuberans (DFSP) is a rare and marginal cutaneous sarcoma between benign and malignant, whose genomic landscape of remains unclear. Methods: In this study, the comprehensive genomic features with 53 tumor-normal pairs of DFSP were revealed by the whole genome sequencing. Real-Time PCR was performed to validate the CNV, immunohistochemistry (IHC) was performed to examine the target protein expression in clinical samples and Sanger sequencing was performed to verify the fusion gene. Findings: The mutational signature 1 (C>T mutation at CpG dinucleotides) is featured in DFSP, resulting in higher mutations in DNA replication. Interestingly, the recurrence of the DFSP is correlated to low TMB. Novel mutation genes in DFSP were identified, including Muc4,6, KMT2C, BRCA1, and subsequently, three molecular sub-types of DFSPs were classified on the basis of Muc4 and Muc6 mutations. Various structural aberrations including genomic rearrangements were identified in DSFPs, particular in 17q and 22q, which cause oncogenes amplification (AKT1, SPHK1, COL1A1, PDGFβ) or tumor suppressors deletion (CDKN2A,B). Importantly, in addition to the reported gene fusion of COL1A1-PDGFβ (t(17;22)) in DFSP, we identified a novel gene fusion SLC2A5-BTBD7(t(1;14)) through our whole-genome sequencing, and verified it experimentally. Enrichment analysis of altered molecules revealed that DNA repair, cell cycle, PI3K and JAK pathways were primarily involved in DFSP. Interpretation: This is the first large-scale whole genome sequencing for DFSP, and our findings demonstrated the comprehensive genomic landscape that highlights the molecular complexity and genomic aberrations of DFSP and provides novel potential diagnostic and therapeutic targets for this disease. Funding Statement: This work was supported by the National Natural Science Foundation of China (81620108024, 82073458, 81974476, 81830096,), Shanghai Municipal Health Commission, and Collaborative Innovation Cluster Project (No. 2019CXJQ02), overseas Expertise Introduction Project for Discipline Innovation (111 Project, No. B20017). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: All the samples were mainly collected from the Department of Dermatology, The Third Affiliated Hospital, Sun Yat-sen University, and the sampling procedure was approved by the Medical Ethics Committee of The Third Affiliated Hospital, Sun Yat-sen University(protocol number: [2018]02-254-01), and written informed consent from each patient was obtained.