炎症无疑是癌症进程的标志之一，目前对于它在肿瘤内的维持及对疾病侵袭性的影响仍未完全理解。本研究从TCGA和GEO数据库中下载了27种肿瘤实体（约5000个样本），对于这些及本地数据进行了多组学分析，以探讨肿瘤侵袭性的分子决定因素。采用分子缺失效应数据探究了炎症诱导的肿瘤侵袭性的机制基础。回顾病人标本及体内疾病模型来验证发现结果。染色体体细胞数目改变（sCNAs）和肿瘤侵袭性之间有显著联系。SOX2扩增是其中最重要的特征之一，这一发现为未知和已知的与侵袭性有关的改变提供了新的线索。机制上，SOX2调节了一组基因，特别是AP1转录因子FOSL2，以维持炎性信号通路，如IL6-JAK-STAT3、TNFA和IL17。特别侵袭性癌症的肿瘤部位FOSL2过度表达。因此，长期的炎症会诱导免疫抑制，并激活胞嘧啶脱氧核苷酸酶，从而出现DNA损伤，这在侵袭性肿瘤中表现出一定的突变特征。DNA损伤会影响到肿瘤抑制基因，例如TP53，在侵袭性肿瘤和较不侵袭性的肿瘤中（38％ vs 14％）中最经常突变，从而释放细胞周期控制。通过对各种肿瘤类型的组织和体内研究验证结果。本研究结果说明了SOX2通过FOSL2/IL6促进DNA损伤和基因组不稳定性，从而维持炎症状态，导致肿瘤侵袭性的产生。©2023作者。

Inflammation is undoubtedly a hallmark of cancer development. Its maintenance within tumors and the consequences on disease aggressiveness are insufficiently understood.Data of 27 tumor entities (about 5000 samples) were downloaded from the TCGA and GEO databases. Multi-omic analyses were performed on these and in-house data to investigate molecular determinants of tumor aggressiveness. Using molecular loss-of-function data, the mechanistic underpinnings of inflammation-induced tumor aggressiveness were addressed. Patient specimens and in vivo disease models were subsequently used to validate findings.There was significant association between somatic copy number alterations (sCNAs) and tumor aggressiveness. SOX2 amplification was the most important feature among novel and known aggressiveness-associated alterations. Mechanistically, SOX2 regulates a group of genes, in particular the AP1 transcription factor FOSL2, to sustain pro-inflammatory signaling pathways, such as IL6-JAK-STAT3, TNFA and IL17. FOSL2 was found overexpressed in tumor sections of specifically aggressive cancers. In consequence, prolonged inflammation induces immunosuppression and activates cytidine deamination and thus DNA damage as evidenced by related mutational signatures in aggressive tumors. The DNA damage affects tumor suppressor genes such as TP53, which is the most mutated gene in aggressive tumors compared to less aggressive ones (38% vs 14%), thereby releasing cell cycle control. These results were confirmed by analyzing tissues from various tumor types and in vivo studies.Our data demonstrate the implication of SOX2 in promoting DNA damage and genome instability by sustaining inflammation via FOSL2/IL6, resulting in tumor aggressiveness.© 2023. The Author(s).