Comprehensive analysis of a homeobox family gene signature in clear cell renal cell carcinoma with regard to prognosis and immune significance

The homeobox (HOX) family genes have been linked to multiple types of tumors, while their effect on malignant behaviors of clear cell renal cell carcinoma (ccRCC) and clinical significance remains largely unknown. Here, we comprehensively analyzed the expression profiles and prognostic value of HOX genes in ccRCC using datasets from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. We developed a prognostic signature comprising eight HOX genes (HOXB1, HOXA7, HOXB5, HOXD8, HOXD9, HOXB9, HOXA9, and HOXA11) for overall survival prediction in ccRCC and it allowed patients to be subdivided into high- and low-risk groups. Kaplan-Meier survival analysis in all the internal and external cohorts revealed significant difference in clinical outcome of patients in different risk groups, indicating the satisfactory predictive power of the signature. Additionally, we constructed a prognostic nomogram by integrating signature-derived risk score and clinical factors such as gender, age, T and M status, which might be helpful for clinical decision-making and designing tailored management schedules. Immunological analysis revealed that the regulatory T cells (Tregs) infiltrated differently between the two subgroups in both TCGA and ICGC cohorts. ssGSEA method showed that the enrichment scores for mast cells were significantly lower in high-risk group compared with the low-risk group, which was consistent in both TCGA and ICGC cohorts. As for the related immune function, the enrichment scores of APC co-inhibition, para-inflammation, and type II IFN response were consistently lower in high-risk group in both cohorts. Of the eight HOX genes, the mRNA and protein levels of HOXD8 were downregulated in ccRCC than that in normal tissues, and decreased expression of HOXD8 was associated with increased tumor grade and stage, and lymph node metastasis. Survival analysis revealed that lower expression of HOXD8 predicted worse overall survival in ccRCC. In conclusion, our HOX gene-based signature was a favorable indicator to predict the prognosis of ccRCC cases and associated with immune cell infiltration. HOXD8 might be a tumor suppressor gene in ccRCC and a potential predictor of tumor progression.