Integrated genomic analysis of proteasome alterations across 11,057 patients with 33 cancer types: clinically relevant outcomes in framework of 3P medicine

Na Li; Xianquan Zhan

doi:10.1007/s13167-021-00256-z

Integrated genomic analysis of proteasome alterations across 11,057 patients with 33 cancer types: clinically relevant outcomes in framework of 3P medicine

EPMA J. 2021 Sep 30;12(4):605-627. doi: 10.1007/s13167-021-00256-z. eCollection 2021 Dec.

Authors

Na Li^{1

2}, Xianquan Zhan^{1

2

3}

Affiliations

¹ Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, 440 Jiyan Road, Jinan, Shandong 250117 People's Republic of China.
² Medical Science and Technology Innovation Center, Shandong First Medical University, 6699 Qingdao Road, Jinan, Shandong 250117 People's Republic of China.
³ Gastroenterology Research Institute and Clinical Center, Shandong First Medical University, 38 Wuying Shan Road, Jinan, Shandong 250031 People's Republic of China.

Abstract

Relevance: Proteasome, a cylindrical complex containing 19S regulatory particle lid, 19S regulatory particle base, and 20S core particle, acted as a major mechanism to regulate the levels of intracellular proteins and degrade misfolded proteins, which involved in many cellular processes, and played important roles in cancer biological processes. Elucidation of proteasome alterations across multiple cancer types will directly contribute to cancer medical services in the context of predictive, preventive, and personalized medicine (PPPM / 3P medicine).

Purpose: This study aimed to investigate proteasome gene alterations across 33 cancer types for discovery of effective biomarkers and therapeutic targets in the framework of PPPM practice in cancers.

Methods: Proteasome gene data, including gene expression RNAseq, somatic mutation, tumor mutation burden (TMB), copy number variant (CNV), microsatellite instability (MSI) score, clinical characteristics, immune phenotype, 22 immune cells, cancer stemness index, drug sensitivity, and related pathways, were systematically analyzed with publically available database and bioinformatics across 11,057 patients with 33 cancer types.

Results: Differentially expressed proteasome genes were extensively found between tumor and control tissues. PSMB4 occurred the top mutation event among proteasome genes, and those proteasome genes were significantly associated with TMB and MSI score. Most of proteasome genes were positively related to CNV among single deletion, control copy number, and single gain. Kaplan-Meier curves and COX regression survival analysis showed proteasome genes were significantly associated with patient survival rate across 33 cancer types. Furthermore, the expressions of proteasome genes were significantly different among different clinical stages and immune subtypes. The expressions of proteasome genes were correlated with immune-related scores (ImmuneScore, StromalScore, and ESTIMATEScore), 22 immune cells, and cancer stemness. The sensitivities of multiple drugs were closely related to proteasome gene expressions. The identified proteasome and proteasome-interacted proteins were significantly enriched in various cancer-related pathways.

Conclusions: This study provided the first landscape of proteasome alterations across 11,057 patients with 33 cancer types and revealed that proteasome played a significant and wide functional role in cancer biological processes. These findings are the precious scientific data to reveal the common and specific alterations of proteasome genes among 33 cancer types, which benefits the research and practice of PPPM in cancers.

Supplementary information: The online version contains supplementary material available at 10.1007/s13167-021-00256-z.

Keywords: Biomarker; Drug sensitivity; Immune; Mutation; Pan-cancer; Predictive preventive personalized medicine (PPPM / 3P medicine); Proteasome; Related pathways; Stemness; Therapeutic targets.