Multi-omics profiles refine L-dopa decarboxylase (DDC) as a reliable biomarker for prognosis and immune microenvironment of clear cell renal cell carcinoma

Kun Chang; Jiaqi Su; Chuanyu Li; Aihetaimujiang Anwaier; Wangrui Liu; Wenhao Xu; Yuanyuan Qu; Hailiang Zhang; Dingwei Ye

doi:10.3389/fonc.2022.1079446

Multi-omics profiles refine L-dopa decarboxylase (DDC) as a reliable biomarker for prognosis and immune microenvironment of clear cell renal cell carcinoma

Front Oncol. 2022 Dec 5:12:1079446. doi: 10.3389/fonc.2022.1079446. eCollection 2022.

Authors

Kun Chang^{1

2

3}, Jiaqi Su^{1

2

3}, Chuanyu Li⁴, Aihetaimujiang Anwaier^{1

2

3}, Wangrui Liu⁴, Wenhao Xu^{1

2

3}, Yuanyuan Qu^{1

2

3}, Hailiang Zhang^{1

2

3}, Dingwei Ye^{1

2

3}

Affiliations

¹ Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
³ Shanghai Genitourinary Cancer Institute, Shanghai, China.
⁴ Department of Neurosurgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.

Abstract

Background: Increasing evidence indicates that L-dopa decarboxylase (DDC), which mediates aberrant amino acid metabolism, is significantly associated with tumor progression. However, the impacts of DDC are not elucidated clearly in clear cell renal cell carcinoma (ccRCC). This study aimed to evaluate DDC prognostic value and potential mechanisms for ccRCC patients.

Methods: Transcriptomic and proteomic expressions of and clinical data including 532 patients with ccRCC (The Cancer Genome Atlas RNA-seq data), 226 ccRCC samples (Gene Expression Omnibus), 101 ccRCC patients from the E-MTAB-1980 cohort, and 232 patients with ccRCC with proteogenomic data (Fudan University Shanghai Cancer Center) were downloaded and analyzed to investigate the prognostic implications of DDC expression. Cox regression analyses were implemented to explore the effect of DDC expression on the prognosis of pan-cancer. The "limma" package identified the differentially expressed genes (DEGs) between high DDC subgroups and low DDC groups. Functional enrichments were performed based DEGs between DDC subgroups. The differences of immune cell infiltrations and immune checkpoint genes between DDC subgroups were analyzed to identify potential influence on immune microenvironment.

Results: We found significantly decreased DDC expression in ccRCC tissues compared with normal tissues from multiple independent cohorts based on multi-omics data. We also found that DDC expression was correlated with tumor grades and stages.The following findings revealed that lower DDC expression levels significantly correlated with shorter overall survival (P <0.001) of patients with ccRCC. Moreover, we found that DDC expression significantly correlated with an immunosuppressive tumor microenvironment, higher intra-tumoral heterogeneity, elevated expression of immune checkpoint CD274, and possibly mediated malignant behaviors of ccRCC cells via the PI3k/Akt signaling pathway.

Conclusion: The present study is the first to our knowledge to indicate that decreased DDC expression is significantly associated with poor survival and an immune-suppressive tumor microenvironment in ccRCC. These findings suggest that DDC could serve as a biomarker for guiding molecular diagnosis and facilitating the development of novel individual therapeutic strategies for patients with advanced ccRCC.

Keywords: amino acids metabolism; biomarker; clear cell renal cell carcinoma (ccRCC); l-DOPA decarboxylase; prognosis; tumor microenvironment.