Thind Amarinder Singh, Ashford Bruce, Strbenac Dario, Mitchell Jenny, Lee Jenny, Mueller Simon A, Minaei Elahe, Perry Jay R, Ch'ng Sydney, Iyer N Gopalakrishna, Clark Jonathan R, Gupta Ruta, Ranson Marie
School of Medicine, University of Wollongong, Wollongong, NSW, Australia.
Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.
Front Oncol. 2022 Aug 2;12:919118. doi: 10.3389/fonc.2022.919118. eCollection 2022.
Metastatic cutaneous squamous cell carcinoma (CSCC) is a highly morbid disease requiring radical surgery and adjuvant therapy, which is associated with a poor prognosis. Yet, compared to other advanced malignancies, relatively little is known of the genomic landscape of metastatic CSCC. We have previously reported the mutational signatures and mutational patterns of CCCTC-binding factor (CTCF) regions in metastatic CSCC. However, many other genomic components (indel signatures, non-coding drivers, and structural variants) of metastatic CSCC have not been reported. To this end, we performed whole genome sequencing on lymph node metastases and blood DNA from 25 CSCC patients with regional metastases of the head and neck. We designed a multifaceted computational analysis at the whole genome level to provide a more comprehensive perspective of the genomic landscape of metastatic CSCC. In the non-coding genome, 3' untranslated region (3'UTR) regions of (48% of specimens), (48% of specimens), and (20% of specimens) along with the tumor-suppressing long non-coding RNA (lncRNA) LINC01003 (64% of specimens) were significantly functionally altered (Q-value < 0.05) and represent potential non-coding biomarkers of CSCC. Recurrent copy number loss in the tumor suppressor gene was observed. Gene amplification was much less frequent, and few genes were recurrently amplified. Single nucleotide variants driver analyses from three tools confirmed and as recurrently mutated genes but also identified as a potential novel driver in this disease. Furthermore, indel signature analysis highlighted the dominance of ID signature 13 (ID13) followed by ID8 and ID9. ID9 has previously been shown to have no association with skin melanoma, unlike ID13 and ID8, suggesting a novel pattern of indel variation in metastatic CSCC. The enrichment analysis of various genetically altered candidates shows enrichment of "TGF-beta regulation of extracellular matrix" and "cell cycle G1 to S check points." These enriched terms are associated with genetic instability, cell proliferation, and migration as mechanisms of genomic drivers of metastatic CSCC.
转移性皮肤鳞状细胞癌（CSCC）是一种高致死性疾病，需要进行根治性手术和辅助治疗，其预后较差。然而，与其他晚期恶性肿瘤相比，人们对转移性CSCC的基因组格局了解相对较少。我们之前报道过转移性CSCC中CCCTC结合因子（CTCF）区域的突变特征和突变模式。然而，转移性CSCC的许多其他基因组成分（插入缺失特征、非编码驱动因子和结构变异）尚未见报道。为此，我们对25例头颈部区域转移的CSCC患者的淋巴结转移灶和血液DNA进行了全基因组测序。我们在全基因组水平上设计了多方面的计算分析，以更全面地了解转移性CSCC的基因组格局。在非编码基因组中，（48%的标本）、（48%的标本）和（20%的标本）的3'非翻译区（3'UTR）区域以及肿瘤抑制性长链非编码RNA（lncRNA）LINC01003（64%的标本）在功能上有显著改变（Q值<0.05），代表了CSCC潜在的非编码生物标志物。观察到肿瘤抑制基因存在复发性拷贝数缺失。基因扩增频率低得多，很少有基因发生复发性扩增。来自三种工具的单核苷酸变异驱动因子分析证实和是复发性突变基因，但也确定是该疾病潜在的新型驱动因子。此外，插入缺失特征分析突出了ID特征13（ID13）的主导地位，其次是ID8和ID9。与ID13和ID8不同，之前已证明ID9与皮肤黑色素瘤无关，这表明转移性CSCC中存在一种新的插入缺失变异模式。对各种基因改变候选物的富集分析显示“转化生长因子-β对细胞外基质的调节”和“细胞周期G1至S检查点”的富集。这些富集的术语与遗传不稳定性、细胞增殖和迁移相关，是转移性CSCC基因组驱动因子的机制。
