Abstract：
Dermatofibrosarcoma protuberans (DFSP) is a rare and marginal cutaneous sarcoma of intermediate-grade malignancy, for which the genomic landscape remains unclear. Understanding the landscape of DFSP will help to further classify the genomic pathway of malignant development in soft tissue.
To identify the comprehensive molecular pathogenesis of DFSP.
In this study, the comprehensive genomic features, with 53 tumour-normal pairs of DFSP, were revealed by whole-genome sequencing.
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 DFSP is correlated with low tumour mutation burden. Novel mutation genes in DFSP were identified, including MUC4/6, KMT2C and BRCA1, and subsequently, three molecular subtypes of DFSP were classified on the basis of MUC4 and MUC6 mutations. Various structural aberrations including genomic rearrangements were identified in DSFPs, particularly in 17q and 22q, which cause oncogene amplification (AKT1, SPHK1, COL1A1, PDGFβ) or tumour suppressor deletion (CDKN2A/B). In addition to gene fusion of COL1A1-PDGFβ [t(17;22)], we identified gene fusion of SLC2A5-BTBD7 [t(1;14)] in DFSP through whole-genome sequencing, and verified it experimentally. Enrichment analysis of altered molecules revealed that DNA repair, cell cycle, phosphoinositide 3-kinase and Janus kinase pathways were primarily involved in DFSP.
This is the first large-scale whole-genome sequencing for DFSP, and our findings describe the comprehensive genomic landscape, highlighting the molecular complexity and genomic aberrations of DFSP. Our findings also provide novel potential diagnostic and therapeutic targets for this disease. What is already known about this topic? Chromosomal translocation between chromosome 17 and chromosome 22 is the main feature in the pathogenesis of dermatofibrosarcoma protuberans (DFSP). What does this study add? We describe the comprehensive genomic landscape of DFSP, highlighting the molecular complexity and genomic aberrations. Our findings provide novel potential diagnostic and therapeutic targets for this disease. What is the translational message? Our study revealed novel molecular subtypes of DFSP based on genetic mutations, which benefits precision diagnosis. We also found oncogene amplification, including AKT1 and SPHK1, which provides novel potential target molecules for further DFSP treatment. In addition to gene fusion of COL1A1-PDGFβ, we identified a novel gene fusion of SLC2A5-BTBD7 in DFSP, which is a novel potential diagnostic and therapeutic target for this disease.
To identify the comprehensive molecular pathogenesis of DFSP.
In this study, the comprehensive genomic features, with 53 tumour-normal pairs of DFSP, were revealed by whole-genome sequencing.
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 DFSP is correlated with low tumour mutation burden. Novel mutation genes in DFSP were identified, including MUC4/6, KMT2C and BRCA1, and subsequently, three molecular subtypes of DFSP were classified on the basis of MUC4 and MUC6 mutations. Various structural aberrations including genomic rearrangements were identified in DSFPs, particularly in 17q and 22q, which cause oncogene amplification (AKT1, SPHK1, COL1A1, PDGFβ) or tumour suppressor deletion (CDKN2A/B). In addition to gene fusion of COL1A1-PDGFβ [t(17;22)], we identified gene fusion of SLC2A5-BTBD7 [t(1;14)] in DFSP through whole-genome sequencing, and verified it experimentally. Enrichment analysis of altered molecules revealed that DNA repair, cell cycle, phosphoinositide 3-kinase and Janus kinase pathways were primarily involved in DFSP.
This is the first large-scale whole-genome sequencing for DFSP, and our findings describe the comprehensive genomic landscape, highlighting the molecular complexity and genomic aberrations of DFSP. Our findings also provide novel potential diagnostic and therapeutic targets for this disease. What is already known about this topic? Chromosomal translocation between chromosome 17 and chromosome 22 is the main feature in the pathogenesis of dermatofibrosarcoma protuberans (DFSP). What does this study add? We describe the comprehensive genomic landscape of DFSP, highlighting the molecular complexity and genomic aberrations. Our findings provide novel potential diagnostic and therapeutic targets for this disease. What is the translational message? Our study revealed novel molecular subtypes of DFSP based on genetic mutations, which benefits precision diagnosis. We also found oncogene amplification, including AKT1 and SPHK1, which provides novel potential target molecules for further DFSP treatment. In addition to gene fusion of COL1A1-PDGFβ, we identified a novel gene fusion of SLC2A5-BTBD7 in DFSP, which is a novel potential diagnostic and therapeutic target for this disease.
摘要：
隆突性皮肤纤维肉瘤（DFSP）是一种罕见的中度恶性边缘皮肤肉瘤，基因组景观尚不清楚。了解DFSP的景观将有助于进一步对软组织恶性发育的基因组途径进行分类。
确定DFSP的综合分子发病机制。
在这项研究中,全面的基因组特征，有53对肿瘤正常的DFSP，通过全基因组测序揭示。
DFSP中具有突变特征1（CpG二核苷酸处的C>T突变），导致DNA复制中更高的突变。有趣的是,DFSP的复发与低肿瘤突变负荷相关。在DFSP中发现了新的突变基因，包括MUC4/6、KMT2C和BRCA1，随后，根据MUC4和MUC6突变对DFSP的三种分子亚型进行分类。在DSFP中鉴定出包括基因组重排在内的各种结构畸变，特别是在17q和22q中，导致癌基因扩增（AKT1，SPHK1，COL1A1，PDGFβ）或肿瘤抑制基因缺失（CDKN2A/B）。除了COL1A1-PDGFβ[t（17;22）]的基因融合外，我们通过全基因组测序鉴定了DFSP中SLC2A5-BTBD7[t（1;14）]的基因融合，并通过实验验证了它。对改变的分子的富集分析显示DNA修复，细胞周期,磷酸肌醇3激酶和Janus激酶途径主要参与DFSP。
这是DFSP的首次大规模全基因组测序，我们的发现描述了全面的基因组景观，突出了DFSP的分子复杂性和基因组畸变。我们的发现也为这种疾病提供了新的潜在诊断和治疗靶点。关于这个主题已经知道什么？染色体17和染色体22之间的染色体易位是隆突性皮肤纤维肉瘤（DFSP）发病机理的主要特征。这项研究增加了什么？我们描述了DFSP的综合基因组景观，突出分子复杂性和基因组畸变。我们的发现为这种疾病提供了新的潜在诊断和治疗靶点。翻译信息是什么？我们的研究揭示了基于基因突变的DFSP的新分子亚型，这有利于精确诊断。我们还发现了癌基因扩增，包括AKT1和SPHK1，这为进一步的DFSP治疗提供了新的潜在靶分子。除了COL1A1-PDGFβ的基因融合外，我们在DFSP中鉴定了SLC2A5-BTBD7的新基因融合体，这是一种新的潜在的诊断和治疗这种疾病的目标。
确定DFSP的综合分子发病机制。
在这项研究中,全面的基因组特征，有53对肿瘤正常的DFSP，通过全基因组测序揭示。
DFSP中具有突变特征1（CpG二核苷酸处的C>T突变），导致DNA复制中更高的突变。有趣的是,DFSP的复发与低肿瘤突变负荷相关。在DFSP中发现了新的突变基因，包括MUC4/6、KMT2C和BRCA1，随后，根据MUC4和MUC6突变对DFSP的三种分子亚型进行分类。在DSFP中鉴定出包括基因组重排在内的各种结构畸变，特别是在17q和22q中，导致癌基因扩增（AKT1，SPHK1，COL1A1，PDGFβ）或肿瘤抑制基因缺失（CDKN2A/B）。除了COL1A1-PDGFβ[t（17;22）]的基因融合外，我们通过全基因组测序鉴定了DFSP中SLC2A5-BTBD7[t（1;14）]的基因融合，并通过实验验证了它。对改变的分子的富集分析显示DNA修复，细胞周期,磷酸肌醇3激酶和Janus激酶途径主要参与DFSP。
这是DFSP的首次大规模全基因组测序，我们的发现描述了全面的基因组景观，突出了DFSP的分子复杂性和基因组畸变。我们的发现也为这种疾病提供了新的潜在诊断和治疗靶点。关于这个主题已经知道什么？染色体17和染色体22之间的染色体易位是隆突性皮肤纤维肉瘤（DFSP）发病机理的主要特征。这项研究增加了什么？我们描述了DFSP的综合基因组景观，突出分子复杂性和基因组畸变。我们的发现为这种疾病提供了新的潜在诊断和治疗靶点。翻译信息是什么？我们的研究揭示了基于基因突变的DFSP的新分子亚型，这有利于精确诊断。我们还发现了癌基因扩增，包括AKT1和SPHK1，这为进一步的DFSP治疗提供了新的潜在靶分子。除了COL1A1-PDGFβ的基因融合外，我们在DFSP中鉴定了SLC2A5-BTBD7的新基因融合体，这是一种新的潜在的诊断和治疗这种疾病的目标。
