SOX2dosage sustains tumor-promoting inflammation to drive disease aggressiveness by modulating theFOSL2/IL6axis

Background Inflammation is undoubtedly a hallmark of cancer development. Its maintenance within tumors and subsequent consequences on disease aggressiveness is less understood. Methods Multi-omic analyses of 27 (~ 5000 samples) entities from the TCGA, GEO and in-house data was performed to investigate the molecular determinant of tumor aggressiveness. Using molecular loss of function data, the mechanistic underpinnings of inflammation-induced tumor aggressiveness was addressed. Results The data revealed a significant association between somatic copy number alterations (sCNA) and tumor aggressiveness, with amplification of the transcription factor SOX2 being the most important feature among novel and known aggressiveness-associated genes such as ZIC5 and MYEOV. Mechanistically, SOX2 regulates a group of aggressiveness-related genes including the AP1 transcription factor FOSL2 to sustain pro-inflammatory pathway such as IL6-JAK-STAT3, TNFA and IL17 signaling pathways. Prolonged inflammation induces immunosuppression and further leads to activation of cytidine deamination and consequential DNA damage evidenced by enrichment in cytidine deamination mutational signatures in aggressive tumors. The resulting DNA damage affects tumor suppressor genes such as TP53, which was the most mutated gene in aggressive tumors compared with less aggressive tumors (38% vs 14%), thereby releasing cell cycle control. This was exemplified in Glioblastoma multiform, where TP53 and IDH1 mutations are predominant. IDH1 mutations were almost only seen in younger patients (>45 years, > 90%) and may explain the previously reported favorable prognosis. Conclusion Taken together, our data demonstrate the implication of SOX2 in promoting DNA damage and genome instability by sustaining inflammation via FOSL2/IL6, resulting in tumor aggressiveness.