Abstract 5002: The prognostic relevance and underlying mechanisms of the novel oxygen sensor ADO in cancers
Authors: Huang Jie , Shen Juan , Qiu Yao , Qian Jiannan , Li Jiawei , Chen Xueqin , Ma Shenglin 
Published: June 2022

Purpose: Hypoxia is widely recognized as a determiner in cancer. Cysteamine dioxygenase (ADO) is demonstrated to be a novel oxygen sensor, globally expressed in animals and plants. However, the functions of ADO in human cancers remain unclear. This study was to identify the survival association of ADO in cancers and to excavate its underlying mechanisms.

Methods: Transcriptional expression profiles, clinical characteristics, single nucleotide variation (SNV) data, and 450K methylation data were downloaded from all cancer types in the cancer genome atlas (TCGA). Two independent liver cancer datasets GSE14520 and GSE36376 were downloaded for further validation.

Results: The expression of ADO gene was differentially expressed in various cancers. High expression of ADO indicated a worse OS and PFS in adrenocortical carcinoma (ACC), acute myeloid leukemia, liver hepatocellular carcinoma (LIHC), while predicted better OS and PFS in brain lower-grade glioma (LGG), and kidney renal clear cell carcinoma (KIRC). Across various cancers, ADO was positively correlated with tumor-associated pathways including G2/M_checkpoint, MYC_targets, and TGFB while negatively correlated with Genes_upregulated_by_reactive_oxygen_species (ROS) through ssGSEA analysis. The expression of ADO gene was highly correlated with hypoxic marker HIF1A, HIF2A, KDM5A, and KDM6A in almost all cancer types while poorly correlated with Hallmark_hypoxia geneset and Regulation_of_cellular response_to_hypoxia geneset, which indicated that ADO might work independently with HIF1A-mediated response. ADO was positively correlated with the methylation of most chromatin regulators in LGG and LIHC. ADO expression positively correlated with most immune checkpoint molecules in most cancers. Notably, a highly positive correlation between ADO and CD276, ENTPD1, or HMGB1 was observed in most cancer types. In liver cancer, ADO was positively correlated with the infiltration of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, myeloid dendritic cells. However, ADO expression was not strongly relevant to TMB in liver cancer. The increased expression, poor survival indication and immune checkpoint correlation of ADO in liver cancer were further validated by GSE14520 and GSE36376 datasets.

Conclusion: ADO was differentially expressed in various cancers and significantly associated with survival in some cancer types including liver cancer. The underlying mechanism might be associated with the G2/M checkpoint, MYC targets and TGFB pathways, and ADO-mediated HIF1A-independent hypoxic response. The immune cell infiltrates and immune checkpoints association hints that ADO might be a biomarker for immunotherapy in liver cancer.

Citation Format: Jie Huang, Juan Shen, Yao Qiu, Jiannan Qian, Jiawei Li, Xueqin Chen, Shenglin Ma. The prognostic relevance and underlying mechanisms of the novel oxygen sensor ADO in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5002.